From bb8ba650142f321985fc2f2b14e341e86a7408c4 Mon Sep 17 00:00:00 2001 From: Bozhao Nan <57164369+bznan@users.noreply.github.com> Date: Fri, 22 Oct 2021 18:18:11 -0400 Subject: [PATCH 1/3] update the 750 AstraZeneca ELN pbtxt file (#122) * uploading Dataset pbtxt for AstraZeneca dataset * Delete AZ_dataset.pbtxt one ligand smiles missing * AZ dataset The .pbtxt file generated from 750 reactions from AstraZeneca ELN. * Delete AZ_dataset.pbtxt One Smiles missing * updated AZ dataset pbtxt file Solving one missing catalyst smiles string. * Delete AZ_dataset.pbtxt * upload AstraZeneca dataset pbtxt file A pbtxt file includes 750 reactions generated from AstraZeneca ELN * Delete AZ_dataset.pbtxt * uploading AZ dataset pbtxt file A pbtxt file includes 750 reactions generated from AZ ELN * upload data spreadsheet for AZ ELN The spreadsheet for 750 reactions generated from AZ ELN * Reaction Template using web submission * reaction index modified * updated AZ_ELN pbtxt file This pbtxtx file includes 750 Buchwald_Hartwig reactions generated from AstraZeneca ELN. New features have been updated including reaction type, index, created date, dataset description, experimental Note. * Delete AZ_ELN.pbtxt * Delete AZ_dataset.xlsx * Change the time stamp errors * Delete AZ_dataset.pbtxt * update AZ_dataset.pbtxt correct ligand amount information of the original AZ_dataset.pbtxt file. --- AZ_dataset.pbtxt | 125803 ++++++++++++++++++++++++++++++++++++++++++++ 1 file changed, 125803 insertions(+) create mode 100644 AZ_dataset.pbtxt diff --git a/AZ_dataset.pbtxt b/AZ_dataset.pbtxt new file mode 100644 index 00000000..a50bc0a1 --- /dev/null +++ b/AZ_dataset.pbtxt @@ -0,0 +1,125803 @@ +name: "750 AstraZeneca ELN dataset" +description: "This dataset includes 750 Buchwald-Hartwig reactions generated from AstraZeneca ELN which is used in yield prediction work:\302\24010.26434/chemrxiv.14589498.v2" +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "0" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00222 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)N1CCNCC1" + } + amount { + moles { + value: 0.00177 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC1=C(C=C2C(=C1)N=CC(=C2NC3=C(C=C(C=C3)F)F)C(=O)OCC)Br" + } + amount { + moles { + value: 0.000886 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 8.86e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 4.43e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a solution of ethyl 6-bromo-4-(2,4-difluorophenylamino)-7-ethoxyquinoline-3-carboxylate (400 mg, 0.89 mmol) and 1-(Isopropyl)piperazine (254 l, 1.77 mmol) in dioxane was added cesium carbonate (722 mg, 2.22 mmol), tris(dibenzylideneacetone)dipalladium(0) (40.6 mg, 0.04 mmol) and rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (55.2 mg, 0.09 mmol). Reaction vessel in oil bath set to 110 C. 11amAfter 5 hours, MS shows product (major peak 499), and SM (minor peak 453).on, MS shows product peak. Reaction cooled, concentrated onto silica, and purified on ISCO. 40g column, 1:1 EA:Hex, then 100% EA.289mg yellow solid. NMR (EN00180-62-1) supports product, but some oxidised BINAP impurity (LCMS 6" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC1=C(C=C2C(=C1)N=CC(=C2NC3=C(C=C(C=C3)F)F)C(=O)OCC)N4CCN(CC4)C(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 65.39 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/01/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "1" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.019 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC=CC=C1" + } + amount { + volume { + value: 0.0332 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=NC2=C1C=C(C(=C2F)N)C(=O)OC" + } + amount { + moles { + value: 0.00762 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)I" + } + amount { + moles { + value: 0.00914 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000762 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000305 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (441 mg, 0.76 mmol) andnbsp;Tris(dibenzylideneacetone)dipalladium(0) (279 mg, 0.30 mmol) were added to a round bottom flask which was evacuated and flushed with nitrogen 3 times, anisole (16.600 ml) was added and the mixture evacuated and flushed with nitrogen 3 times and then heated to 50C for 10 minutes. Cesium carbonate (6204 mg, 19.04 mmol), methyl 5-amino-4-fluoro-1-methyl-1H-benzo[d]imidazole-6-carboxylate (1700 mg, 7.62 mmol) and Iodobenzene (1.023 ml, 9.14 mmol) were stirred in anisole (33.2 ml), the flask was evacuated and flushed with nitrogen three times and then heated to 50C. The catalyst mixture was transferred into the flask with the reactants (by syringe) and the mixture heated to 100 C for 18 hours. The reaction mixture was diluted with isohexane (60 ml) and the solid collected by filtration and washed with more isohexane (30 ml). The solid was slurried in DCM MeOH and adsorbed onto silica then purified by flash silica ch eluting with 2% 3.7N NH3 MeOH in DCM to give methyl 4-fluoro-1-methyl-5-(phenylamino)-1H-benzo[d]imidazole-6-carboxylate (1310 mg, 57.5 %) as anbsp;yellow solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1C=NC2=C1C=C(C(=C2F)NC3=CC=CC=C3)C(=O)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 57.47 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/16/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "3" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0168 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC=CC=C1" + } + amount { + volume { + value: 0.0149 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=NC2=C1C=C(C(=C2F)N)C(=O)OC" + } + amount { + moles { + value: 0.00672 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)I" + } + amount { + moles { + value: 0.00806 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000672 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000269 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (389 mg, 0.67 mmol) andnbsp;Tris(dibenzylideneacetone)dipalladium(0) (246 mg, 0.27 mmol) were added to a round bottom flask which was evacuated and flushed with nitrogen 3 times, anisole (14.900 ml) was added and the mixture evacuated and flushed with nitrogen 3 times and then heated to 50C for 10 minutes. Cesium carbonate (5474 mg, 16.80 mmol), methyl 5-amino-4-fluoro-1-methyl-1H-benzo[d]imidazole-6-carboxylate (1500 mg, 6.72 mmol) and Iodobenzene (0.902 ml, 8.06 mmol) were stirred in anisole (29.8 ml), the flask was evacuated and flushed with nitrogen three times and then heated to 50C. The catalyst mixture was transferred into the flask with the reactants (by syringe) and the mixture heated to 100 C for 18 hours. The reaction mixture was diluted with isohexane (50 ml) the solid collected by filtration and washed with more isohexane (25 ml). The solid was slurried in dichloromethane (40 ml) and methanol (10 ml) and filtered, washing the rid with more dichloromethane methanol. The filtratre (containing product) was evaporated onto silica and purified by flash silica chromatography, eluting with 2% 3.7N NH3 MeOH in DCM. Pure fractions were evaporated to dryness to afford methyl 4-fluoro-1-methyl-5-(phenylamino)-1H-benzo[d]imidazole-6-carboxylate (1316 mg, 65.4 %) as a light yellow solid. nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1C=NC2=C1C=C(C(=C2F)NC3=CC=CC=C3)C(=O)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 65.43 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/06/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "4" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0168 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC=CC=C1" + } + amount { + volume { + value: 0.0298 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=NC2=C1C=C(C(=C2F)N)C(=O)OC" + } + amount { + moles { + value: 0.00672 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)I" + } + amount { + moles { + value: 0.00806 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000672 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000269 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (389 mg, 0.67 mmol) andnbsp;Tris(dibenzylideneacetone)dipalladium(0) (246 mg, 0.27 mmol) were added to a round bottom flask which was evacuated and flushed with nitrogen 3 times, anisole (14.900 ml) was added and the mixture evacuated and flushed with nitrogen 3 times and then heated to 50C for 10 minutes. Cesium carbonate (5474 mg, 16.80 mmol), methyl 5-amino-4-fluoro-1-methyl-1H-benzo[d]imidazole-6-carboxylate (1500 mg, 6.72 mmol) and Iodobenzene (0.902 ml, 8.06 mmol) were stirred in anisole (29.800 ml), the flask was evacuated and flushed with nitrogen three times and then heated to 50C. The catalyst mixture was transferred into the flask with the reactants (by syringe) and the mixture heated to 100 C for 18 hours. The reaction mixture was diluted with isohexane (50 m) and the solid collected by filtration and washed with more isohexane (25 ml). The solid was slurried in DCM MeOH and adsorbed onto silica then purified by flash silica cy eluting with 2% 3.7N NH3 MeOH in DCM to give methyl 4-fluoro-1-methyl-5-(phenylamino)-1H-benzo[d]imidazole-6-carboxylate (1510 mg, 75 %) as a light yellow solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1C=NC2=C1C=C(C(=C2F)NC3=CC=CC=C3)C(=O)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 75.07 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/08/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "7" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00276 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.13 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1N)S(=O)(=O)N" + } + amount { + moles { + value: 0.0358 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)Cl)C" + } + amount { + moles { + value: 0.0276 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00276 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00193 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;3-(2-chloropyridin-4-yloxy)-2,6-dimethylpyridine (6.47 g, 27.57 mmol), Sulfanilamide (6.17 g, 35.84 mmol), CESIUM CARBONATE (13.47 g, 41.35 mmol) and XANTPHOS (1.595 g, 2.76 mmol) were stirred in DMA (130 ml). Purged this stirred mixture by bubbling nitrogen through for an hour, then added the Palladium acetate. Heated to 130C in a metal block (block at 150C) and held at this temperature for 3 hours. LCMS (monitorbase) then showed DP as MH+ = 370.99 and MH- = 369.03 at 1.82 minutes, 84%. Allowed to cool to room temperature. The reaction mixture was evaporated to dryness at 50C givingi ia dirty-yellow solid residue. Treated with 150 ml water and the resulting yellow solid filtered off and washed with water. Dried by desiccation under high vacuum over phosphorous pentoxide at room temperature to constant weight. This afforded 11.98 g pale-yellow solid [A].LCMS(monitorbase) showed it to be DP as MH+ = 370.99 and MH- = 36 minutes, 90%.inbsp;iThis material was crystallised from acetonitrile; dissolved up in ~1 litre boiling acetonitrile and the cloudy solution filtered hot through a fluted paper. Crystallisation of product from the filtrate was eventually achieved, with difficulty, by rapid cooling in drikoldacetone and seedingscratching as it warmed up.nbsp;Cooled in icewater then the solid was collected by filtration and washed with chilled acetonitrile. Dried by desiccation under high vacuum at room temperature to constant weight. This afforded 6.03 g creamy-whitenbsp;solid [B].LCMS (monitorbase) then showed DP as MH+ = 370.99 and MH- = 369.03 at 1.49 minutes, 96%.Material B was combined with the same product from P14-A and this total of 7.32 g recrystallised from the minimum of acetonitrile (~550 ml) with hot filtration again to remove trace insoluble matter. Cooled in icewater and seededscratched to induce crystallisation then stood in the fridge overnight. The solid was collected by filtration and washed with chilled acetonitrile. Dried by desiccation under high vacuum initially at room temperature, then at 60C, to constant weight. This afforded 5.04 g creamy-whitenbsp;solid [C].LCMS (monitorbase) then showed DP as MH+ = 371.06 and MH- = 369.08 at 1.85 minutes, 99%.Unfortunately nmr showed entrapped acetonitrile at an unacceptable level (~0.5 equiv.). To remove this material C was stirred in ~100 ml ether for an hour, recollected and washed with ether. Dried at 60C as before to constant weight. This afforded 4.73 g creamy-white solid " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)NC3=CC=C(C=C3)S(=O)(=O)N)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 46.32 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/15/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "8" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00426 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.2 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1N)S(=O)(=O)N" + } + amount { + moles { + value: 0.0554 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)Cl)C" + } + amount { + moles { + value: 0.0426 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00426 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00298 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 130.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "XANTPHOS (2.466 g, 4.26 mmol) was added to 3-(2-chloropyridin-4-yloxy)-2,6-dimethylpyridine (10g, 42.61 mmol), Sulfanilamide (9.54 g, 55.39 mmol) and CESIUM CARBONATE (20.83 g, 63.92 mmol) in DMA (200 ml) at 20C. Nitrogen was bubbled through the reaction mixture for 1 hour then PALLADIUM(II) ACETATE (0.670 g, 2.98 mmol) added. The suspension was stirred at 130 C for 3 hours. The reaction mixture was filtered then evaporated to dryness. The residue was triturated with water (150 mL) and filtered to give crude product as a cream solid - 90% pure. The crude solid was triturated with hot acetonitrile (300 mL) and filtered to afford crude product as a cream solid - 98% by LCMS. This was combined with the product from EN02084-31 and dissolved in boiling acetonitrile (approx 1 L). The solution was concentrated to 500 mL and cooled to ice bath temperature with stirring. A precipitate formed which and the suspension was stirred at room temperature overnight. The solid was filtered to afford 4-(4-(2,6-diridin-3-yloxy)pyridin-2-ylamino)benzenesulfonamide (12.00 g, 76 %) as a cream solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)NC3=CC=C(C=C3)S(=O)(=O)N)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 76.03 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/11/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "9" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000847 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.04 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1N)S(=O)(=O)N" + } + amount { + moles { + value: 0.0111 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)Cl)C" + } + amount { + moles { + value: 0.00852 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000847 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000579 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 130.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;3-(2-chloropyridin-4-yloxy)-2,6-dimethylpyridine (2 g, 8.52 mmol), Sulfanilamide (1.91 g, 11.09 mmol), CESIUM CARBONATE (4.17 g, 12.80 mmol) and XANTPHOS (490 mg, 0.85 mmol) were stirred in DMA (40 ml). Purged this stirred mixture by bubbling nitrogen through for an hour, then added the Palladium acetate. Heated to 130C in a metal block (block at 150C) and held at this temperature for 3 hours. LCMS (monitorbase) then showed DP as MH+ = 370.99 and MH- = 369.03 at 1.83 minutes, 83%. Allowed to cool to room temperature. The reaction mixture was evaporated to dryness at 50C giving a light-green solid residue. Attempted to partition this residue between DCM (~50 ml) and saturated aqueous sodium hydrogen carbonate (~50 ml). The insoluble matter was filtered off and washed through with water, then DCM. This dirty-yellow solid was dried by desiccation overnight. Wt = 2.04 g. LCMS showed it to be DP, 94%. This material was crystallised from acetonitrile;p in ~150 ml boiling acetonitrile and the cloudy solution treated with a little Norit SX4 decolourising carbon. Filtered hot through a fluted paper. Slow crystallisation of a creamy-white solid occurred on cooling to room temperature. Cooled in icewater then the bulky solid was collected by filtration and washed with chilled acetonitrile. Dried by desiccation under high vacuum at room temperature overnight. This afforded 1.29 g creamy-white bulky solid [A].LCMS (monitorbase) then showed DP as MH+ = 370.99 and MH- = 369.03 at 1.83 minutes, 99%." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)NC3=CC=C(C=C3)S(=O)(=O)N)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 40.86 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/01/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "10" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00277 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.13 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1N)S(=O)(=O)N" + } + amount { + moles { + value: 0.036 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)Cl)C" + } + amount { + moles { + value: 0.0277 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00277 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00194 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 130.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "XANTPHOS (1.603 g, 2.77 mmol) was added to 3-(2-chloropyridin-4-yloxy)-2,6-dimethylpyridine (6.5 g, 27.70 mmol), Sulfanilamide (6.20 g, 36.01 mmol) and CESIUM CARBONATE (13.54 g, 41.55 mmol) in DMA (130 ml) at 20C. Nitrogen was bubbled through the reaction mixture for 1 hour then PALLADIUM(II) ACETATE (0.435 g, 1.94 mmol) added. The suspension was stirred at 130 C for 3 hours. The reaction mixture was cooled to ambient temperature and filtered then evaporated to dryness. The residue was triturated with water (150 mL) and filtered to give crude product as a cream solid which was 90% pure by LCMS. The crude solid was triturated with hot MeCN (300 mL) to give a solid which was collected by filtration and dried under vacuum to give a cream solid (7.86g) which was 95% pure by LCMS. The solid was dissolved in the minimum amount of boiling MeCN (650 mL) and filtered to remove remaining trace solids. The filtrate was concentrated to approximately 400 mL and stirred at ice bath temperature until a preciormed. The suspension was stirred at room temperature overnight then filtered to afford a cream solid (6.4g) which was 100% pure by LCMS. Combined with EN02084-42 to get a single larger batch." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)NC3=CC=C(C=C3)S(=O)(=O)N)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 62.38 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/05/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "11" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0156 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00573 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=NC=C1Br)Br" + } + amount { + moles { + value: 0.0052 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000625 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00052 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 140.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "3,5-dibromopyridine (1.233 g, 5.20 mmol), 1-(piperazin-1-yl)ethanone (0.734 g, 5.73 mmol), PdOAc2 (0.117 g, 0.52 mmol), XANTPHOS (0.361 g, 0.62 mmol), Cs2CO3 (5.09 g, 15.61 mmol), 1,4-dioxane as added to a 10 mL microwave vial. This was degassed and refilled with N2 and then heated at 140 C in microwave for 1h.LCMS showed reaction done with the peak at Rf1.24 showed a fragment mass of 284.Evaporated solvent. Residue purified by ISCO (0-20% MeOH in EtOAc )to get the desired product 1-(4-(5-bromopyridin-3-yl)piperazin-1-yl)ethanone (0.470 g, 31.8 %).Trial # 1:3,5-dibromopyridine (407 mg, 1.72 mmol), 1-(piperazin-1-yl)ethanone (231 mg, 1.81 mmol), PdOAc2 (38.6 mg, 0.17 mmol), XANTPHOS (119 mg, 0.21 mmol), Cs2CO3 (1681 mg, 5.16 mmol), 1,4-dioxane as added to a 10 mL microwave vial. This was degassed and refilled with N2 and then heated at 140 C in microwave for 1h.LCMS showed reaction done with the peak at Rf1.22 showed a fragment mass of 284.Evaporatnt. Residue purified by ISCO (0-20% MeOH in EtOAc )to get the desired product 1-(4-(5-bromopyridin-3-yl)piperazin-1-yl)ethanone (118mg, 24%)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)N1CCN(CC1)C2=CC(=CN=C2)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 31.78 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/15/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "12" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00131 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.0025 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1N)N2C=CN=C2" + } + amount { + moles { + value: 0.000437 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CC(OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.000437 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 4.37e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.37e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "[Reactants], 8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.120 g, 0.44 mmol), Palladium(II) acetate (9.81 mg, 0.04 mmol), 2-(Dicyclohexylphosphino)biphenyl (0.015 g, 0.04 mmol) and Cesium carbonate (0.427 g, 1.31 mmol) in DME (2.5 mL) were placed in a microwave vial and flushed with argon. The reaction mixture was then run in the microwave at 100C for 1 hr. Reaction not complete. Run for another 30 minutes in the microwave. Still not complete. Added 0.1 eq of Palladium(II)acetate and 0.1 eq of 2-(Dicyclohexylphosphino)biphenyl and let the reaction mixture run in the microwave for additional 45 minutes. Reaction complete. The reaction mixture was filtrated through celite and the filtrate was concentrated. The crude product was purified by preparative chromatography giving 0.072 g (41%) of the product. N-(4-(1H-imidazol-1-yl)phenyl)-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CC(OC2=C(C1)C=CC(=N2)NC3=CC=C(C=C3)N4C=CN=C4)C5=CC=CC=C5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 41.47 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/18/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "13" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000425 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" + } + amount { + moles { + value: 0.00017 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N1CC(OC2=C(C1)C=CC(=N2)Cl)C3=CN=CC=C3" + } + amount { + moles { + value: 0.000142 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 1.42e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.42e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "1-(8-chloro-2-(pyridin-3-yl)-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)ethanone (0.043 g, 0.14 mmol), Palladium(II) acetate (3.18 mg, 0.01 mmol), 2-(Dicyclohexylphosphino)biphenyl (4.96 mg, 0.01 mmol) and Cesium carbonate (0.138 g, 0.42 mmol) were placed in a microwave vial and flushed with argon. DME (2 mL) was added and the reaction mixture was run in the microwave at 100C for 60 minutes. No product according to LCMS. Added 0.1 eq of Palladium(II) acetate (3.18 mg, 0.01 mmol) and 0.1 eq of 2-(Dicyclohexylphosphino)biphenyl (4.96 mg, 0.01 mmol) and flushed with argon. Run in the microwave at 100C for 30 minutes and the reaction was complete. The reaction mixture was filtrated through celite and concentrated. The crude product was purified by prep-HPLC. The solvent was evaporated and partitioned between sat. NaHCO3 and dichloromethane. The organic layer was separated, dried (MgSO4) and concentrated giving 0.0234 g (35%) of the prod" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(CN(CC(O4)C5=CN=CC=C5)C(=O)C)C=C3)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 35.13 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/09/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "14" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000707 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000259 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CC(OC2=C(C1)C=CC(=N2)Cl)C3=CN=CC=C3" + } + amount { + moles { + value: 0.000236 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 2.36e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.36e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "[Reactants], Palladium(II) acetate (5.29 mg, 0.02 mmol), 2-(Dicyclohexylphosphino)biphenyl (8.26 mg, 0.02 mmol) and Cesium carbonate (0.230 g, 0.71 mmol) were placed in a microwave vial and flushed with argon. DME (2 mL) was added and the reaction mixture was run in the microwave at 100C for 60 minutes. Reaction not complete. Added 0.1 eq of Palladium(II) acetate (5.29 mg, 0.02 mmol) and 0.1 eq of 2-(Dicyclohexylphosphino)biphenyl (8.26 mg, 0.02 mmol) and flushed with argon. Run in the microwave at 100C for 60 minutes and the reaction was complete. The reaction mixture was filtrated through celite and concentrated. The crude product was purified by prep-HPLC. The solvent was evaporated and partitioned between sat. NaHCO3 and dichloromethane. The organic layer was separated, dried (MgSO4) and concentrated giving 0.029 g (28%) of the prod" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(CN(CC(O4)C5=CN=CC=C5)C)C=C3)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 27.8 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/09/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "17" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 8e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0025 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N" + } + amount { + moles { + value: 0.00105 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1F)Cl" + } + amount { + moles { + value: 0.001 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 8e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 4e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-chloro-4-fluoropyridine (132 mg, 1 mmol), tert-butyl carbamate (123 mg, 1.05 mmol), CESIUM CARBONATE (652 mg, 2.00 mmol) ,TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (36.6 mg, 0.04 mmol) and 9,9-DIMETHYL-4,5-BIS(DIPHENYLPHOSPHINO)XANTHENE (46.3 mg, 0.08 mmol) were suspended in 1,4-dioxane (2.5 ml) ,degased with argon andnbsp;heated to 90 C for 4 hours.After cooling the reaction wasnbsp;quenched with waternbsp;and extracted with ethyl acetate ( x 2 ). The combined organic phasesnbsp;were washed with waternbsp;, a saturated aqueous solution of brine , dried over magnesium sulfate , concentrated thennbsp;purified bynbsp;preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to affordnbsp;tert-butyl 4-fluoropyridin-2-ybamate (41.3 mg, 19.46 %)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC1=NC=CC(=C1)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 19.46 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/10/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "18" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C1CCC2=NCCCN2CC1" + } + amount { + moles { + value: 0.00151 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.12 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=CC(=C1)C=O)N" + } + amount { + moles { + value: 0.0377 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC2=NC=C(N2C=C1)C3=NC(=NC=C3Cl)Cl" + } + amount { + moles { + value: 0.0151 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00151 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000377 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "3-(2,5-dichloropyrimidin-4-yl)imidazo[1,2-a]pyridine (4 g, 15.09 mmol), 4-amino-3-methoxybenzaldehyde (2.281 g, 15.09 mmol), 9,9-DIMETHYL-4,5-BIS(DIPHENYLPHOSPHINO)XANTHENE (0.873 g, 1.51 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (0.345 g, 0.38 mmol) andnbsp;1,8-DIAZABICYCLO [5.4.0] UNDEC-7-ENE (5.64 ml, 37.72 mmol) were dissolved in Dioxane (120 ml) then degazed and purged with argon. The reaction was heated to reflux (bath 120C) for 2H30. Reaction mixture was filtered through a filter cup and concentrated. FR01132-77-01 w=14.65 gThe crude product was purified by flash chromatography (NOVASEP) on silica gel ( 15-40m ) eluting with 0 to 5% methanol in dichloromethane. The solvent was evaporated to dryness to afford 4-(5-chloro-4-(imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-ylamino)-3-methoxybenzaldehyde (34.9 %)nbsp;as a clear yellow solid.PBO-01132-77-02 w=" + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=C(C=CC(=C1)C=O)NC2=NC=C(C(=N2)C3=CN=C4N3C=CC=C4)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 34.9 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/02/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "19" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CCC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000721 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" + } + amount { + moles { + value: 0.000361 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1CC2=CC(=C(C=C2)Br)F" + } + amount { + moles { + value: 0.000397 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000162 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "[Pd]" + } + amount { + moles { + value: 0.000108 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "The aim of the reaction is testoptimization:5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (100 mg, 0.36 mmol), 4-(4-bromo-3-fluorobenzyl)morpholine (109 mg, 0.40 mmol), Palladium, 10% On Charcoal (115 mg, 0.11 mmol), racemic-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (101 mg, 0.16 mmol) and Sodium tert-pentoxide (79 mg, 0.72 mmol) were dissolved in toluene (1.5 mL) and heated to 110 C under argon.The reaction was monitorred by HPLC. After 16 h 81 % conversion was achieved. The reaction was stopped and the mixture was discarded." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=C(C=C(C=C4)CN5CCOCC5)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/28/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "20" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CCC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000721 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" + } + amount { + moles { + value: 0.000361 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1CC2=CC(=C(C=C2)Br)F" + } + amount { + moles { + value: 0.000397 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1P(C2=CC=CC=C2C)C3=CC=CC=C3C" + } + amount { + moles { + value: 0.000162 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "[Pd]" + } + amount { + moles { + value: 0.000108 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "The aim of the reaction is testoptimization:5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (100 mg, 0.36 mmol), 4-(4-bromo-3-fluorobenzyl)morpholine (109 mg, 0.40 mmol), Palladium, 10% On Charcoal (115 mg, 0.11 mmol), Tri-o-tolylphosphine (49.4 mg, 0.16 mmol) and Sodium tert-pentoxide (79 mg, 0.72 mmol) were dissolved in toluene (1.5 mL) and heated to 110 C under argon.The reaction was monitorred by HPLC. After 16 h 88 % conversion was achieved. The reaction was stopped and the mixture was discarded." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=C(C=C(C=C4)CN5CCOCC5)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/28/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "21" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CCC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000721 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" + } + amount { + moles { + value: 0.000361 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1CC2=CC(=C(C=C2)Br)F" + } + amount { + moles { + value: 0.000397 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3" + } + amount { + moles { + value: 0.000162 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "[Pd]" + } + amount { + moles { + value: 0.000108 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "The aim of the reaction is testoptimization:5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (100 mg, 0.36 mmol), 4-(4-bromo-3-fluorobenzyl)morpholine (109 mg, 0.40 mmol), Palladium, 10% On Charcoal (115 mg, 0.11 mmol), Triphenylphosphine (0.038 mL, 0.16 mmol) and Sodium tert-pentoxide (79 mg, 0.72 mmol) were dissolved in toluene (1.5 mL) and heated to 110 C under argon.The reaction was monitorred by HPLC. After 16 h 73 % conversion was achieved. The reaction was stopped and the mixture was discarded." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=C(C=C(C=C4)CN5CCOCC5)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/28/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "22" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CCC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000721 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" + } + amount { + moles { + value: 0.000361 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1CC2=CC(=C(C=C2)Br)F" + } + amount { + moles { + value: 0.000397 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 0.000162 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "[Pd]" + } + amount { + moles { + value: 0.000162 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "The aim of the reaction is testoptimization:5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (100 mg, 0.36 mmol), 4-(4-bromo-3-fluorobenzyl)morpholine (109 mg, 0.40 mmol), Palladium, 10% On Charcoal (115 mg, 0.11 mmol), (R)-(-)-1-[(S)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (91 mg, 0.16 mmol) and Sodium tert-pentoxide (79 mg, 0.72 mmol) were dissolved in toluene (1.5 mL) and heated to 110 C under argon.The reaction was monitorred by HPLC. After 16 h 79 % conversion was achieved. The reaction was stopped and the mixture was discarded." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=C(C=C(C=C4)CN5CCOCC5)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/28/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "23" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CCC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000721 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" + } + amount { + moles { + value: 0.000361 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1CC2=CC(=C(C=C2)Br)F" + } + amount { + moles { + value: 0.000397 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000162 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "[Pd]" + } + amount { + moles { + value: 0.000108 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "The aim of the reaction is testoptimization:5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (100 mg, 0.36 mmol), 4-(4-bromo-3-fluorobenzyl)morpholine (109 mg, 0.40 mmol), Palladium, 10% On Charcoal (115 mg, 0.11 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (94 mg, 0.16 mmol) and Sodium tert-pentoxide (79 mg, 0.72 mmol) were dissolved in toluene (1.5 mL) and heated to 110 C under argon.The reaction was monitorred by HPLC. After 16 h 85 % conversion was achieved. The reaction was stopped and the mixture was discarded." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=C(C=C(C=C4)CN5CCOCC5)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/28/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "24" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CCC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000721 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" + } + amount { + moles { + value: 0.000361 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1CC2=CC(=C(C=C2)Br)F" + } + amount { + moles { + value: 0.000397 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C(=CC=C1)OC)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 0.000162 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "[Pd]" + } + amount { + moles { + value: 0.000108 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "The aim of the reaction is testoptimization:5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (100 mg, 0.36 mmol), 4-(4-bromo-3-fluorobenzyl)morpholine (109 mg, 0.40 mmol), Palladium, 10% On Charcoal (115 mg, 0.11 mmol), 2-Dicyclohexylphosphino-2\',6\'-dimethoxy-1,1\'-biphenyl (66.6 mg, 0.16 mmol) and Sodium tert-pentoxide (79 mg, 0.72 mmol) were dissolved in toluene (1.5 mL) and heated to 110 C under argon.The reaction was monitorred by HPLC. After 16 h 85 % conversion was achieved. The reaction was stopped and the mixture was discarded." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=C(C=C(C=C4)CN5CCOCC5)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/28/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "25" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0117 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.024 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1OC2=C(O1)C(=C(C=C2)Cl)N" + } + amount { + moles { + value: 0.00583 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)NC1=NC=CC(=C1)Cl" + } + amount { + moles { + value: 0.00583 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000699 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000291 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Reaction carried out in two batches in 20 ml microwave tubes. 5-chlorobenzo[d][1,3]dioxol-4-amine (1 g, 5.83 mmol), N-(4-chloropyridin-2-yl)acetamide (0.994 g, 5.83 mmol), XANTPHOS (0.405 g, 0.70 mmol), PALLADIUM(II) ACETATE (0.065 g, 0.29 mmol) and CESIUM CARBONATE (3.80 g, 11.66 mmol) were suspended in 2x DMA (12mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT.nbsp;LCMS showed completion.The reaction mixture was concentrated and diluted with EtOAc , and washed sequentially with water and saturated brine. The organic layer was dried over MgSO4, filtered and evaporated. The crude oil was triturated with EtOAc, Et2O and hexane to give a solid which was collected by filtration and dried under vacuum to give P1 N-(4-(5-chlorobenzo[d][1,3]dioxol-4-ylamino)pyridin-2-yl)acetamide (680mg, 38%)as a tan solid. NMR of this product showed product plus some DMA and aromatic impurities.The filtrate from the above was concentrated and triturated again to give P2 N-(4-(5-chlorobenzo[d][1,3]dioxol-4-ylamino)pyridin-2-yl)acetamide (800mg, 45%) as a pale orange solid. NMR of this product showed it to be much cleaner than P1.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)NC1=NC=CC(=C1)NC2=C(C=CC3=C2OCO3)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 83.06 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/06/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "26" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0274 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.1 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCC2=C(C1=O)C(=CC=C2)N" + } + amount { + moles { + value: 0.0183 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C(=CN=C1Cl)Cl)I" + } + amount { + moles { + value: 0.0183 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00183 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000913 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (0.205 g, 0.91 mmol) was added to a stirred suspension of 2,5-dichloro-4-iodopyridine (5 g, 18.26 mmol), 8-amino-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (3.22 g, 18.26 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.056 g, 1.83 mmol) and cesium carbonate (8.92 g, 27.38 mmol) dissolved in 1,4-dioxane (100 mL). The resulting suspension was degassed (3 times) with nitrogen and was stirred at 100C for 16 hours. The reaction mixture was allowed to cool to room temperature, diluted with DCM (100 mL) and filtered. The residue was washed with DCM. The filtrates was combined evaporated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 0 to 10% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford 8-(2,5-dichloropyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (2.500 g, 42.5 %) as a pale yellow solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 42.5 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/09/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "27" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00329 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCC2=C(C1=O)C(=CC=C2)N" + } + amount { + moles { + value: 0.00219 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C(=CN=C1Cl)Cl)I" + } + amount { + moles { + value: 0.00219 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000219 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00011 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (24.59 mg, 0.11 mmol) was added to a stirred suspension of 2,5-dichloro-4-iodopyridine (600 mg, 2.19 mmol), 8-amino-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (386 mg, 2.19 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (127 mg, 0.22 mmol) and cesium carbonate (1071 mg, 3.29 mmol) in 1,4-dioxane (10 mL). The resulting suspension was degassed with nitrogen and was stirred at 100 C for 18 hours. Reaction was allowed to cool to room temperature, quenched with water and extracted with EtOAc. Combined organic phases were washed with water, brine, dried over MgSO4 and concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 0 to 10% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford 8-(2,5-dichloropyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (447 mg, 63.3 %) as a pale yellow crystalline solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 63.33 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/10/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "28" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0203 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.07 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCC2=C(C1=O)C(=CC=C2)N" + } + amount { + moles { + value: 0.0136 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C(=CN=C1Cl)Cl)I" + } + amount { + moles { + value: 0.0136 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00136 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000678 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (0.152 g, 0.68 mmol) was added to a stirred suspension of 2,5-dichloro-4-iodopyridine (3.71 g, 13.56 mmol), 8-amino-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (2.39 g, 13.56 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.785 g, 1.36 mmol) and cesium carbonate (6.63 g, 20.34 mmol) in 1,4-dioxane (70 mL). The resulting suspension was degassed with nitrogen and was stirred at 100 C for 18 hours. Reaction was allowed to cool to room temperature, quenched with water (100 mL) and extracted with EtOAc*. Combined organic phases were washed with water, brine, dried over MgSO4 and concentrated to dryness. The crude product was purified by flash chromatography* on silica gel eluting with 0 to 10% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford 8-(2,5-dichloropyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (2.160 g, 49.4 %) as a yellow crystalline solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 49.43 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/30/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "29" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0766 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.3 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCC2=C(C1=O)C(=CC=C2)N" + } + amount { + moles { + value: 0.0511 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C(=CN=C1Cl)Cl)I" + } + amount { + moles { + value: 0.0511 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00511 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00255 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (0.573 g, 2.55 mmol) was added to a stirred suspension of 2,5-dichloro-4-iodopyridine (13.99 g, 51.07 mmol), 8-amino-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (9 g, 51.07 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.96 g, 5.11 mmol) and cesium carbonate (24.96 g, 76.61 mmol) dissolved in 1,4-dioxane (300 mL). The resulting suspension was degassed (3 times) with nitrogen and was stirred at 100C for 16 hours. The reaction mixture was allowed to cool to room temperature, diluted with DCM (100 mL) and filtered. The residue was washed with DCM. The filtrates was combined and evaporated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 0 to 10% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford 8-(2,5-dichloropyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (9.80 g, 59.6 %) as a clear white solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 59.55 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/16/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "30" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.329 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.913 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CONC(=O)C1=CC=CC=C1N" + } + amount { + moles { + value: 0.288 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C(=CN=C1Cl)Cl)I" + } + amount { + moles { + value: 0.274 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.0205 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.0137 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2,5-dichloro-4-iodopyridine (75 g, 273.84 mmol), 2-amino-N-methoxybenzamide (47.8 g, 287.53 mmol), cesium carbonate (107 g, 328.60 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (11.88 g, 20.54 mmol) were suspended in 1,4-dioxane (913 ml). Nitrogen was bubbled through the mixture for 20 minutes then diacetoxypalladium (3.07 g, 13.69 mmol) was added. Reaction was heated to reflux overnight under nitrogen. Reaction was allowed to cool to ~50C and filtered. Filtered cake was washed with hot EtOH (2x300 mL)i. iFiltrate was concentrated to dryness to afford crude as a black solid (57 g). Filtered cake was re-washed with CH2Cl2MeOH 91 (3x300 mL). Filtrate was combined with previous crude and concentrated to dryness to afford crude as a black solid (93 g).Crude was stirred in boiling EtOH (380 mL). Insoluble was filtered =gt; iseemed to contain expected product instantaneous cristallisation occured in the filtratei. Flask was left standing overnight. Resug crystals were filtered, washed with Et2O (x2) and dried to afford 2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (33.4 g, 39.1%, EN03787-93-02) as a dark grey crystalline solid =gt; iproduct crystallised with 1eq of EtOH.iInsoluble material was washed with EtOH, CH2Cl2 and dried overnight to afford 2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (26.6 g, EN03787-93-01) =gt; inot fully soluble in DMSO, seemed contaminated by minerals. iIt was suspended in H2O (200 mL) and stirred at room temperature for 20 minutes. It was filtered, washed with EtOH (x2) and dried to afford an orange solid (3.8 g !!) =gt; inot soluble in DMSO, probably only a few expected product in it !!i" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 39.07 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/01/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "31" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0456 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.13 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CONC(=O)C1=CC=CC=C1N" + } + amount { + moles { + value: 0.0399 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C(=CN=C1Cl)Cl)I" + } + amount { + moles { + value: 0.038 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00285 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.0019 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2,5-dichloro-4-iodopyridine (10.4 g, 37.97 mmol), 2-amino-N-methoxybenzamide (6.63 g, 39.87 mmol), cesium carbonate (14.85 g, 45.57 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.648 g, 2.85 mmol) were suspended in 1,4-dioxane (130 mL). Nitrogen was bubbled through the mixture for 10 minutes then diacetoxypalladium (0.426 g, 1.90 mmol) was added. Flask was purged with nitrogen 3 times and heated to reflux for 16 hours. Reaction was allowed to cool to room temperature and diluted with CH2Cl2 (100 mL) (=gt; itroublei) + MeOH (10 mL). Mixture was filtered i(filtrate is clear)i and washed with CH2Cl2MeOH 91 (2x100 mL) =gt; ifiltrate became troubled. iFiltrate was concentrated to dryness to afford crude as a dark brown solid (17.5 g).Filtered cake seemed to contain some product. It was suspended in H2O (200 mL) and stirred for 20 minutes. It was then filtered (ilong and tricky filtration !!i). Solid was dissolved in CH2Cl2MeOH (ibig volume compare to the amount of solid !! it\'s quite insolublei), dried over MgSO4 and concentrated to dryness to afford crude product (0.5 g...) as a dark green solid.Solids were combined (18 g) and recristallised from EtOH (85 mL). Flask was left standing over the weekend. Resulting crystals were filtered, washed with Et2O and dried to afford 2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (8.20 g, 69.2 %) as a dark yellow crystalline solid =gt; iproduct crystallised with 1eq of EtOH.iFiltrate was concentrated. Residue (7.7 g) was recristallised from EtOH (30 mL). Hot solution was seeded with crystals, from 1st batch, and flask was left standing overnight. Resulting crystals were filtered, washed with Et2O and dried to afford a dark yellow crystalline solid (1.68 g, EN03787-82-02) =gt; iimpure material (see UPLCMS amp; 1H NMR 03787-82-02)i" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 69.18 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/18/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "32" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0011 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC=CC=C1N" + } + amount { + moles { + value: 0.00073 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C(=CN=C1Cl)Cl)I" + } + amount { + moles { + value: 0.00073 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.3e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.65e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-amino-N-methylbenzamide (110 mg, 0.73 mmol), 2,5-dichloro-4-iodopyridine (200 mg, 0.73 mmol), diacetoxypalladium (8.20 mg, 0.04 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (42.3 mg, 0.07 mmol) and cesium carbonate (357 mg, 1.10 mmol) suspended in 1,4-dioxane (4 mL) was weighed out in a microwave vial and sealed. argon was let to bubble into the mixture for 5 minutes at rt then the resulting mixture was stirred at 100 C for 1 hour. The reaction mixture was allowed to cool to room temperature under stirring and diluted with dichloromethane. Insolubles were removed by filtration and the filtrate was concentrated. The residue was triturated in DCM, collected by filtration and dried to afford 2-(2,5-dichloropyridin-4-ylamino)-N-methylbenzamide (150 mg, 69.4 %) as anbsp;off-white solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 69.36 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/23/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "33" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0219 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.15 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC=CC=C1N" + } + amount { + moles { + value: 0.011 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C(=CN=C1Cl)Cl)I" + } + amount { + moles { + value: 0.011 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000657 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000438 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;Palladium(II) acetate (0.098 g, 0.44 mmol) was added to 2,5-dichloro-4-iodopyridine (3 g, 10.95 mmol), 2-amino-N-methylbenzamide (1.645 g, 10.95 mmol), Cesium carbonate (7.14 g, 21.91 mmol) and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (0.380 g, 0.66 mmol) in dioxane (150 mL) under nitrogen. The resulting suspension was stirred at 80 C for 18 hours. The reaction mixture was filtered and the filtrate was evaporated to dryness. The crude residue was triturated with DCM to give a solid which was collected by filtration and dried under vacuum to give 2-(2,5-dichloropyridin-4-ylamino)-N-methylbenzamide (1.58 g, 49 %)nbsp;as a tan solid, LCMS indicated 87% pure.nbsp;This was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 2-(2,5-dichloropyridin-4-ylamino)-N-methylbenzamide (1.040 g, 32.1 %) as a yellow solid. nbsp;nbsp;nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 32.06 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/01/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "34" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[K+]" + } + amount { + moles { + value: 0.00181 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0139 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" + } + amount { + moles { + value: 0.00139 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1CC2=CC(=C(C=C2)Cl)F" + } + amount { + moles { + value: 0.00139 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.00042 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000139 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 102.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To degassed 1,4-dioxane (13.900 ml) in a flame-dried and argonflushed 50 mL roundbottomed flask were added 5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (386 mg, 1.39 mmol) and 4-(4-chloro-3-fluorobenzyl)morpholine (320 mg, 1.39 mmol) followed by POTASSIUM TERT-BUTOXIDE (203 mg, 1.81 mmol) whilst stirring. The resulting slurry was flushed with argon followed by addition of TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (128 mg, 0.14 mmol) and 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (200 mg, 0.42 mmol), whereafter the dark violet reaction mixture was again flushed with argon and heated to 102 C and stirred under argon for 15 h. The completion of the reaction was controlled by HPLC and the crude mixture was cooled to ambient temperatuer and then filtrated through Celite and washed through with dichloromethane. The solution was concentrated in vacuo and dissolved in a minimum amount of DMSO and purified via Preparative HPLC. The pooled fract were concentrated in vacuo and added HCl. 5-fluoro-N-(2-fluoro-4-(morpholinomethyl)phenyl)-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (60.0 mg, 9.15 %)nbsp;nbsp;nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=C(C=C(C=C4)CN5CCOCC5)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 9.15 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/27/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "35" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[K+]" + } + amount { + moles { + value: 0.00509 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0392 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" + } + amount { + moles { + value: 0.00388 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1CC2=CC(=C(C=C2)Cl)F" + } + amount { + moles { + value: 0.00392 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.000784 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000392 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 102.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To degassed 1,4-dioxane (39.2 ml) in a flame-dried and argonflushed 250 mL roundbottomed flask were added 5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (1.076 g, 3.88 mmol) and 4-(4-chloro-3-fluorobenzyl)morpholine (0.9 g, 3.92 mmol) followed by POTASSIUM TERT-BUTOXIDE (0.572 g, 5.09 mmol) whilst stirring. The resulting slurry was flushed with argon and stirred for 5-10 minutes followed by addition of TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.359 g, 0.39 mmol) and 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (0.374 g, 0.78 mmol), whereafter the reaction mixture was flushed with argon again and heated to 102 C and stirred under argon for 3 h. No further conversion occurred after 2 hours.The completion of the reaction was controlled by HPLC and the crude mixture was cooled to ambient temperatuer and then filtrated through Celite and washed through with dichloromethane. The solution was concentrated in vacuo and dissolved in 14 ml dichlorhane and purified by ISCO and then by prep-HPLC. The pooled fractions were concentrated in vacuo and added HCl to give 5-fluoro-N-(2-fluoro-4-(morpholinomethyl)phenyl)-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (0.227 g, 11.43 %)nbsp;nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=C(C=C(C=C4)CN5CCOCC5)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 11.43 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/03/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "36" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000736 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.000589 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN=C(S1)N" + } + amount { + moles { + value: 0.000441 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C[C@@H](C1=NC=C(C=N1)F)NC2=NC(=NC(=N2)Cl)N3CCOCC3" + } + amount { + moles { + value: 0.000294 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 2.94e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.47e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 95.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(S)-4-chloro-N-(1-(5-fluoropyrimidin-2-yl)ethyl)-6-morpholino-1,3,5-triazin-2-amine (100 mg, 0.29 mmol), 5-methylthiazol-2-amine (50.4 mg, 0.44 mmol), BINAP (18.33 mg, 0.03 mmol), Pd2(dba)3 (13.48 mg, 0.01 mmol) and Cs2CO3 (240 mg, 0.74 mmol) were combined in a microwave reaction tube and vacuum purged.nbsp;The tube was then charged with nitrogen and dioxane (0.589 mL) was added.nbsp;The tube was then evacuated again and placed under a nitrogen balloon for 8 hours.nbsp;LCMS confirmed formation of the product (m+1 = 418) at t= 2.07 min.nbsp;The reaction mixture was concentrated in vacuo leaing a brown solid (472 mg).nbsp;This material was the redissolved in EtOAc, filtered through Celite, washed with water and dried with Na2SO4.nbsp;Concentration in vacuo gave a rust solid (272 mg).nbsp;This material was purified by ISCO (0-10% MeOHDCM).nbsp;Concentration of the fractions in vacuo gave an orange oil.nbsp;This material was then repurifed by ISCO (4-8% MeOHDCM) and (0-4% MeOHDCM).nbsp;Both gradients resulted in impure material, so the recovered orange oil was purified again by ISCO (60-100% EtOAcHex).nbsp;Concentration in vacuo gave a yellow solid (34.8 mg).nbsp;LCMS showed this material to still be only 80% pure, so it was purified again by ISCO (55-95% EtOAcHex).nbsp;A yellow solid (25.4 mg) was again collected.nbsp;Although LCMS and HPLC showed this material to be only ~80% pure, the NMR confirmed this material to be the desired product, (S)-N2-(1-(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methylthiazol-2-yl)-6-morpholino-1,3,5-triazine-2,4-diamine, with 95% purity.nbsp;1H NMR (300 MHz, CHLOROFORM-idi) d ppm 11.87 (br. s., 1 H) 9.48 (br. s., 1 H) 8.58 (s, 2 H) 7.01 (s, 1 H) 5.35 (t, 1 H) 3.28 - 4.23 (m, 8 H) 2.38 (s, 3 H) 1.59 (d, 4 H)nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN=C(S1)NC2=NC(=NC(=N2)N3CCOCC3)N[C@@H](C)C4=NC=C(C=N4)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 20.67 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/28/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "37" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 8.37e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1N)C" + } + amount { + moles { + value: 0.0014 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C#N)Cl" + } + amount { + moles { + value: 0.000698 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 8.37e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 5.58e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-(2-chloro-5-cyanopyridin-4-ylamino)-N-methylbenzamide (200 mg, 0.70 mmol), Palladium(II) acetate (12.53 mg, 0.06 mmol), 1,3-dimethyl-1H-pyrazol-4-amine (155 mg, 1.40 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (48.4 mg, 0.08 mmol) and Cesium carbonate (273 mg, 0.84 mmol) were suspended in dioxane (5 mL)nbsp;into a test tube.nbsp;The reaction was purged for 5 mins with nitrogen and then heated to 90 C for 24 hours with stirring.nbsp;The reaction was cooled to cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desirednbsp;crude product was eluted from the column using 7M NH3MeOH andnbsp;fractions were evaporated to dryness to afford crude product .The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dr afford 2-(5-cyano-2-(1,3-dimethyl-1H-pyrazol-4-ylamino)pyridin-4-ylamino)-N-methylbenzamide (126 mg, 50.0 %) as a beige solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NC)C#N)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 49.98 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/07/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "39" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 4.19e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C(=CC(=N1)OC)N" + } + amount { + moles { + value: 0.000698 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C#N)Cl" + } + amount { + moles { + value: 0.000349 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 4.19e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.79e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-(2-chloro-5-cyanopyridin-4-ylamino)-N-methylbenzamide (100 mg, 0.35 mmol), Palladium(II) acetate (6.26 mg, 0.03 mmol), [Reactants], 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (24.22 mg, 0.04 mmol) and Cesium carbonate (136 mg, 0.42 mmol) were suspended in dioxane (3 mL)nbsp;into a test tube.nbsp;The reaction was purged for 5 mins with nitrogen and then heated to 90 C for 18 hours with stirring.nbsp;The reaction was cooled to cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desirednbsp;crude product was eluted from the column using 7M NH3MeOH andnbsp;fractions were evaporated to dryness to afford crude product .The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-(5-cyano-2-(3-methoxy--1H-pyrazol-5-ylamino)pyridin-4-ylamino)-N-methylbenzamide (72.0 mg, 54.7 %) as a beige solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C#N)NC3=CC(=NN3C)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 54.7 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/07/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "43" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000228 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.04 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1N)C" + } + amount { + moles { + value: 0.0038 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3C#N)Cl" + } + amount { + moles { + value: 0.0019 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000228 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000152 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "6-chloro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-8-ylamino)nicotinonitrile (595 mg, 1.90 mmol), Palladium(II) acetate (34.2 mg, 0.15 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (132 mg, 0.23 mmol), 1,3-dimethyl-1H-pyrazol-4-amine (423 mg, 3.80 mmol) and Cesium carbonate (744 mg, 2.28 mmol) were suspended in dioxane (40 mL).nbsp;The reaction was purged for 5 mins with nitrogen and then heated to 90 C for 2 hour with stirring.nbsp;The reaction was cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desired crude product was eluted from the column using 7M NH3MeOH andnbsp;fractions were evaporated to dryness to afford crude product .The crude product was purified by preparative basic HPLC. Fractions containing the desired compound were evaporated to dryness to afford 6-(1,3-dimethyl-1H-pyrazol-4-ylamino)-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-8-ylamino)nicotinonitrile (54.0 mg, 7.33 %) as a beige solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC4=C3C(=O)N(CC4)C)C#N)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 7.33 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/21/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "45" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)[O-].[Na+]" + } + amount { + moles { + value: 0.00016 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.001 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1N)C" + } + amount { + moles { + value: 0.00032 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3C#N)Cl" + } + amount { + moles { + value: 0.00016 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 2e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.28e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "1,3-dimethyl-1H-pyrazol-4-amine (35.5 mg, 0.32 mmol), 6-chloro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-8-ylamino)nicotinonitrile (50 mg, 0.16 mmol)sodium phenolate (18.56 mg, 0.16 mmol),(R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (8.74 mg, 0.02 mmol) and diacetoxypalladium (2.87 mg, 0.01 mmol) were suspended in DME (1 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT. LCMS indicated 47% product, ~8% dimer, ~8% hydrolysed Starting material , Starting material 25% and an unknown 17% @ 2.66 and unknown 12% @ 0.77.Sample combined with en01521-027 and en01521-034, SCX\'d and sent to purification group. The crude product was purified by preparative basic HPLC. Fractions containing the desired compound were evaporated to dryness to afford 6-(1,3-dimethyl-1H-pyrazol-4-ylamino)-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-8-ylamino)nicotinonitrile (34.0 mg, 54.9 %) as a brownid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC4=C3C(=O)N(CC4)C)C#N)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 54.89 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/12/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "46" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00192 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1N)C" + } + amount { + moles { + value: 0.00319 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3C#N)Cl" + } + amount { + moles { + value: 0.0016 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 0.00016 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00016 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "1,3-dimethyl-1H-pyrazol-4-amine (355 mg, 3.19 mmol), 6-chloro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-8-ylamino)nicotinonitrile (500 mg, 1.60 mmol), Cesium carbonate (625 mg, 1.92 mmol), Palladium(II) acetate (28.7 mg, 0.13 mmol)and (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (87 mg, 0.16 mmol) were suspended in DME (10 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness. The crude product was handed to the purification group and purified by basic preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford 6-(1,3-dimethyl-1H-pyrazol-4-ylamino)-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-8-ylamino)nicotinonitrile (271 mg, 43.8 %) as a brown solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC4=C3C(=O)N(CC4)C)C#N)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 43.75 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/13/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "49" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00192 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1N)C" + } + amount { + moles { + value: 0.0032 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3C#N)Cl" + } + amount { + moles { + value: 0.0016 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 0.00016 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00016 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "6-chloro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-8-ylamino)nicotinonitrile (500 mg, 1.60 mmol), 1,3-Dimethyl-1H-pyrazol-4-ylamine (355 mg, 3.20 mmol) and Cesium carbonate (625 mg, 1.92 mmol), Palladium(II) acetate (28.7 mg, 0.13 mmol) and (R)-(-)-1-[(S)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (90 mg, 0.16 mmol) were suspended in DME (10 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT.nbsp;This was combined with reactions EN01370-84-87 and concentrated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM.nbsp;Mixed fractions were combined and re-columned. This prcess was repeated a further 3 times! quot;Purequot; fractions were combined and evaporated to dryness to afford 6-(1,3-dimethyl-1H-pyrazol-4-ylamino)-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-8-ylamino)nicotinonitrile (484 mg, 15.63 %) as a yellow solid (1.08g) - 100% by LCMS anean by TLC but the NMR is not great. Passed onto the purification group.The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the required product.200mg trial purification - resulted in 137mg pure - EN01370-88-1Rest of the material processed to give EN01370-88-2 (347mg and 177mg) " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC4=C3C(=O)N(CC4)C)C#N)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 15.63 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/24/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "50" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C1CCC2=NCCCN2CC1" + } + amount { + moles { + value: 5.09e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.001 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CC1C(=O)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000509 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1OC2=C(C(=CN=C2O1)Cl)N" + } + amount { + moles { + value: 0.00061 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 5.09e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" + } + amount { + moles { + value: 4.58e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 130.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.190 mL, 1.27 mmol) was added to a mixture of N-(4-chloropyridin-2-yl)cyclopropanecarboxamide (100 mg, 0.51 mmol), 6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-amine (105 mg, 0.61 mmol) and BIS(DIBENZYLIDENEACETONE)PALLADIUM(0) (26.3 mg, 0.05 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (29.4 mg, 0.05 mmol) in toluene (1 mL) in a microwave tube. The reaction was degased, purged with argon and heated to 130 C over a period of 7 hours in an oil bath. The mixture was diluted with dichloromethane, washed with water (emulsion), with brine, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 3% methanol in dichloromethane. The solvent was evaporated to dryness to afford N-(4-(6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-ylamino)pyridin-2-yl)cyclopropanecarboxamide (55.0 mg, 32.5 %) as a yellow solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CC1C(=O)NC2=NC=CC(=C2)NC3=C4C(=NC=C3Cl)OCO4" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 32.5 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/11/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "51" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0407 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.075 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CC1C(=O)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.0203 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1OC2=C(C(=CN=C2O1)Cl)N" + } + amount { + moles { + value: 0.0203 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00244 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00102 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "N-(4-chloropyridin-2-yl)cyclopropanecarboxamide (4 g, 20.34 mmol), 6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-amine (3.51 g, 20.34 mmol),nbsp;(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.412 g, 2.44 mmol), diacetoxypalladium (0.228 g, 1.02 mmol) and cesium carbonate (13.26 g, 40.68 mmol) were suspended in 1,4-dioxane (75 mL) and sealed into 5 microwave tubes. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT. The reaction mixture was diluted with EtOAc (250 mL) and washed with water (250 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford and orange gum.nbsp;The gum was dissolved in a little ether, then isohexane was added to precipitate N-(4-(6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-ylamino)pyridin-2-yl)cyclopropanecarboxamide (2.180 g, 32.2 %) as a e solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CC1C(=O)NC2=NC=CC(=C2)NC3=C4C(=NC=C3Cl)OCO4" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 32.21 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/24/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "52" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00814 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CC1C(=O)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.00407 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1OC2=C(C(=CN=C2O1)Cl)N" + } + amount { + moles { + value: 0.00407 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000488 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000203 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "N-(4-chloropyridin-2-yl)cyclopropanecarboxamide (0.8 g, 4.07 mmol), 6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-amine (0.702 g, 4.07 mmol),nbsp;(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.282 g, 0.49 mmol), diacetoxypalladium (0.046 g, 0.20 mmol) and cesium carbonate (2.65 g, 8.14 mmol) were suspended in 1,4-dioxane (15 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT. The reaction mixture was evaporated and partitioned between EtOAc (50 mL) and water (50 mL).nbsp;The mixture was filtered and the organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford N-(4-(6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-ylamino)pyridin-2-yl)cyclopropanecarboxamide (0.384 g, 28.4 %) as a white solid. Impure fractions were combined and purified by flash silicromatography, elution gradient 0 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford more crude material.nbsp;This material was triturated with DCM to afford a second batch of the material." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CC1C(=O)NC2=NC=CC(=C2)NC3=C4C(=NC=C3Cl)OCO4" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 28.37 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/17/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "55" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0127 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.018 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CC1C(=O)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.00509 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1OC2=C(C(=CN=C2O1)Cl)N" + } + amount { + moles { + value: 0.00509 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000559 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.0004 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of N-(4-chloropyridin-2-yl)cyclopropanecarboxamide (1 g, 5.09 mmol), 6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-amine (0.878 g, 5.09 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.324 g, 0.56 mmol), diacetoxypalladium (0.090 g, 0.40 mmol), cesium carbonate (4.14 g, 12.71 mmol) and dioxane (18 mL) was degased, purged (x3) with argon and heated to reflux over a period of 4 hours in an oil bath (110C). The reaction was complete. The reaction mixture was allowed to warm to room temperature diluted with water (25ml), a saturated solution of NH4Cl (35ml). Extraction with dichloromethane (x2), the organic was washed with a saturated aqueous solution of brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 2% methanol in dichloromethane. The solvent was evaporated, the product was diluted in dichloromethane. The solution was filtered through PTFE filter 0.45m, the filtrate was conceno dryness to afford N-(4-(6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-ylamino)pyridin-2-yl)cyclopropanecarboxamide (1.200 g, 70.9 %) as anbsp;white crystalline solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CC1C(=O)NC2=NC=CC(=C2)NC3=C4C(=NC=C3Cl)OCO4" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 70.91 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/17/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "56" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00814 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CC1C(=O)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.00407 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1OC2=C(C(=CN=C2O1)Cl)N" + } + amount { + moles { + value: 0.00407 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000488 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000203 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "N-(4-chloropyridin-2-yl)cyclopropanecarboxamide (0.8 g, 4.07 mmol), 6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-amine (0.702 g, 4.07 mmol),nbsp;(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.282 g, 0.49 mmol), diacetoxypalladium (0.046 g, 0.20 mmol) and cesium carbonate (2.65 g, 8.14 mmol) were suspended in 1,4-dioxane (15 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford N-(4-(6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-ylamino)pyridin-2-yl)cyclopropanecarboxamide (0.592 g, 43.7 %) as a white solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CC1C(=O)NC2=NC=CC(=C2)NC3=C4C(=NC=C3Cl)OCO4" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 43.73 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/27/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "58" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00742 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.025 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCN1CCNCC1" + } + amount { + moles { + value: 0.00742 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1C2=CC(=O)C3=C(O2)C(=CC=C3)C4=C5C(=C(C=C4)I)C6=CC=CC=C6S5" + } + amount { + moles { + value: 0.00371 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000742 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000742 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "8-(1-iododibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (2 g, 3.71 mmol), 2,2\'-BIS(DIPHENYLPHOSPHINO)-1,1\'-BINAPHTHYL (0.462 g, 0.74 mmol), CESIUM CARBONATE (3.62 g, 11.12 mmol) and PALLADIUM (II) ACETATE (0.166 g, 0.74 mmol) were weighed out in a flask and inerted with argon. toluene (25 ml) and 1-ethylpiperazine (0.942 ml, 7.42 mmol) were added and the mixture was degassed several times with argon. The reaction was stirred at 110 C (bath) for 2 hours.The reaction was incomplete. 2,2\'-BIS(DIPHENYLPHOSPHINO)-1,1\'-BINAPHTHYL (0.462 g, 0.74 mmol) and PALLADIUM (II) ACETATE (0.166 g, 0.74 mmol) were added, the reaction mixture was purged with argon, and the mixture was stirred at 110 C for 5 hours. Reaction was quite clean: Crude LCMS showed very little de-iodo by-product and starting material left.The reaction was diluted with dichloromethane and insolubles were removed by filtration. The filtrate was concentrated to dryness. The crude product was purified by flash chrphy on silica gel eluting with 0 to 5% methanol in dichloromethane. The solvent was evaporated, the resulting solid was stirred in diethyl ether (40 ml) for 2 days. The product was filtered to give a solid which was collected by filtration and dried under vacuum to give 8-(1-(4-ethylpiperazin-1-yl)dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (0.950 g, 48.7 %) as a pale beige solid.Melting point: 221-224CPurity check: 99%, Et2O: 0.06 molemole, H2O: 0.3 molemoleH NMR strength: 97% +- 3%nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCN1CCN(CC1)C2=C3C4=CC=CC=C4SC3=C(C=C2)C5=CC=CC6=C5OC(=CC6=O)N7CCOCC7" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 48.74 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/22/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "60" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 5.56e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.00025 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCN1CCNCC1" + } + amount { + moles { + value: 7.42e-05 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1C2=CC(=O)C3=C(O2)C(=CC=C3)C4=C5C(=C(C=C4)I)C6=CC=CC=C6S5" + } + amount { + moles { + value: 3.71e-05 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.71e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 9.27e-07 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 130.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "8-(1-iododibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (20 mg, 0.04 mmol), 1-ethylpiperazine (9.42 l, 0.07 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.145 mg, 3.71 mol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (0.849 mg, 0.93 mol) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (16.62 l, 0.11 mmol) were suspended in dioxane (250 l) and sealed into a microwave tube. The reaction was degased, purged with argon and heated to 130 C over a period of 45 minutes in the microwave reactor. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCN1CCN(CC1)C2=C3C4=CC=CC=C4SC3=C(C=C2)C5=CC=CC6=C5OC(=CC6=O)N7CCOCC7" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/16/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "61" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0155 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.2 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.129 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)Br)[N+](=O)[O-]" + } + amount { + moles { + value: 0.129 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.0155 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.0103 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;4-bromo-1-methoxy-2-nitrobenzene (30 g, 129.29 mmol), 1-(piperazin-1-yl)ethanone (16.57 g, 129.29 mmol), cesium carbonate (84 g, 258.59 mmol),diacetoxypalladium (2.322 g, 10.34 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (8.98 g, 15.52 mmol) in dioxane (200 mL) were degazed with nitrogen and stirred at 100C for 1 hour.nbsp;The reaction mixture was allowed to cool to room temperature, water (1000mL) was added and mixture was filtered on celite.nbsp;The aq. layer was extracted with CH2Cl2 (2X500mL). The organic layer was dried on MgSO4, filtered and concentrated to dryness to afford the crude product. This product was purified by flash chromatography on silica gel eluting with ethyl acetate - methanol (92-8), the solvents were evaporated to dryness to afford 1-(4-(4-methoxy-3-nitrophenyl)piperazin-1-yl)ethanone (10.80 g, 29.9 %)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)OC)[N+](=O)[O-]" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 29.91 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "12/18/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "62" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00931 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.12 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.0776 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)Br)[N+](=O)[O-]" + } + amount { + moles { + value: 0.0776 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00931 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00621 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "1-(piperazin-1-yl)ethanone (9.94 g, 77.58 mmol), Cesium carbonate (50.6 g, 155.15 mmol), XANTPHOS (5.39 g, 9.31 mmol) and Pd(OAc)2 (1.393 g, 6.21 mmol) were added to a stirred solution of 4-bromo-1-methoxy-2-nitrobenzene (18 g, 77.58 mmol) dissolved in dioxane (120 ml). The resulting suspension was heated to 120 C (bath) over a period of 1 hour. The reaction mixture was allowed to cool and the residual cesium carbonate was removed by filtration through a pad of Dicalite speed plus, washing with dichloromethane. The solvent was removed under reduced pressure to give a dark oil. PBO-02628-53-01 w= 45 gThe crude product in solution in DCM was added to a silica gel column and was eluted with methanol 0 to 20% in EtOAc (NOVASEP). Collected fractions to dryness to afford 1-(4-(4-methoxy-3-nitrophenyl)piperazin-1-yl)ethanone (17.96 g, 83 %) as a yellow solid. PBO-02628-53-02 nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)OC)[N+](=O)[O-]" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 82.89 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/25/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "63" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000776 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00646 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)Br)[N+](=O)[O-]" + } + amount { + moles { + value: 0.00646 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000776 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000517 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "4-bromo-1-methoxy-2-nitrobenzene (1.5 g, 6.46 mmol), 1-(piperazin-1-yl)ethanone (0.829 g, 6.46 mmol), CESIUM CARBONATE (4.21 g, 12.93 mmol), XANTPHOS (0.449 g, 0.78 mmol) and PdOAc2 (0.116 g, 0.52 mmol) were suspended in dioxane (20 ml) and sealed into a microwave tube. The reaction was heated to 120 C for 90 minutes in the microwave reactor and cooled to RT.nbsp;The reaction mixture was filtered through celite with ethyl acetate (50 mL).nbsp;The filtrate was evaporated to dryness.nbsp;The crude product was purified by flash silica chromatography in EtOAc. Pure fractions were evaporated to dryness to afford 1-(4-(4-methoxy-3-nitrophenyl)piperazin-1-yl)ethanone (0.022 g, 1.218 %) as a brown solid.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)OC)[N+](=O)[O-]" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 1.22 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/06/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "64" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000776 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00646 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)Br)[N+](=O)[O-]" + } + amount { + moles { + value: 0.00646 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000776 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000517 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "4-bromo-1-methoxy-2-nitrobenzene (1.5 g, 6.46 mmol) was added in one portion to 1-(piperazin-1-yl)ethanone (0.829 g, 6.46 mmol), CESIUM CARBONATE (4.21 g, 12.93 mmol), XANTPHOS (0.449 g, 0.78 mmol) and PdOAc2 (0.116 g, 0.52 mmol) in dioxane (20 ml) under nitrogen. The resulting mixture was stirred at 120 C for 3 hours.nbsp;The reaction mixture was filtered through celite and the fitrate evaporated to dryness. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 1-(4-(4-methoxy-3-nitrophenyl)piperazin-1-yl)ethanone (0.025 g, 1.385 %) as a brown oil. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)OC)[N+](=O)[O-]" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 1.38 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/08/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "65" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 9.61e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1N)C" + } + amount { + moles { + value: 0.0012 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" + } + amount { + moles { + value: 0.000801 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 9.61e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 6.41e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (250 mg, 0.80 mmol), 1,3-dimethyl-1H-pyrazol-4-amine (134 mg, 1.20 mmol), Sodium tert-butoxide (115 mg, 1.20 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (55.6 mg, 0.10 mmol) and BIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (58.7 mg, 0.06 mmol) were suspended in dioxane (15 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT. Reaction not complete by LCMS so more 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (55.6 mg, 0.10 mmol), BIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (58.7 mg, 0.06 mmol) and 1,3-dimethyl-1H-pyrazol-4-amine (134 mg, 1.20 mmol) were added and the reaction heated to 150 C for a further 30 minutes in the microwave reactor and cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness to afford crude as a tan gum. The sample was given to the purification group for purification by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford 2-(5-chloro-2-(1,3-dimethyl-1H-pyrazol-4-ylamino)pyridin-4-ylamino)-N-methoxybenzamide (44.3 mg, 14.30 %) as a tan solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)Cl)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 14.3 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/02/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "66" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00248 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1CNCC(N1)C" + } + amount { + moles { + value: 0.000248 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=CC(=C1)Br)NC2=NC=C(C(=N2)C3=CN=C4N3C=CC=C4)Cl" + } + amount { + moles { + value: 0.000248 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 9.94e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.97e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 140.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "N-(4-bromo-2-methoxyphenyl)-5-chloro-4-(imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-amine (107 mg, 0.25 mmol), 2,6-dimethylpiperazine (28.4 mg, 0.25 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (5.75 mg, 9.94 mol), diacetoxypalladium (1.116 mg, 4.97 mol) and cesium carbonate (162 mg, 0.50 mmol) were suspended in 1,4-dioxane (2 mL) . The reaction was purged with nitrogen and heated to 140 C for 6 hours in an oil bath. Control LCMS : no traces of expected " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1CN(CC(N1)C)C2=CC(=C(C=C2)NC3=NC=C(C(=N3)C4=CN=C5N4C=CC=C5)Cl)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/28/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "67" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000521 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.05 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)N)OC" + } + amount { + moles { + value: 0.00521 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN=C(N=C1C2=CN(C3=CC=CC=C32)S(=O)(=O)C4=CC=CC=C4)Cl" + } + amount { + moles { + value: 0.00521 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000521 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000261 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Cesium carbonate (2.55 g, 7.82 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.301 g, 0.52 mmol) and diacetoxypalladium (0.058 g, 0.26 mmol) were added to a stirred suspension of 3-(2-chloro-5-methylpyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (2 g, 5.21 mmol) and 1-(4-(4-amino-3-methoxyphenyl)piperazin-1-yl)ethanone (1.299 g, 5.21 mmol) in 1,4-dioxane (50 ml). The resulting suspension was degassed with argon and stirred at 90 C for 2 hours.After cooling, the mixture was filtered through a pad of Dicalite speed plus and washed with dichloromethane. The solvent were evaporated. PBO-01132-93-01The crude product was purified by flash chromatography on silica gel (Merck cartrige SVP D40 - SI60 16-40m - 90g) eluting with 0 up to 100% EtOAc in dichloromethane . The 1-(4-(3-methoxy-4-(5-methyl-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (1.760 g, 56.6 %) was obtained as a yellow oil. PBO-01132-93-02An impure batch wned. PBO-01132-93-03nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN=C(N=C1C2=CN(C3=CC=CC=C32)S(=O)(=O)C4=CC=CC=C4)NC5=C(C=C(C=C5)N6CCN(CC6)C(=O)C)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 56.61 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/11/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "70" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000289 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0018 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" + } + amount { + moles { + value: 0.000184 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1CC2=CC=C(C=C2)Br" + } + amount { + moles { + value: 0.000199 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 8.81e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 4.91e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "The aim of the reaction is optimization.Tris(dibenzylideneacetone)dipalladium(0) (4.5 mg, 4.91 mol) and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (5.1 mg, 8.81 mol) were dissolved in dioxane (1.8 mL) in a 10 mL Schlenk tube and activated at 100 C for 6 min under argon. Then 5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (51 mg, 0.18 mmol), 4-(4-bromobenzyl)morpholine (51 mg, 0.20 mmol) and Cesium carbonate (94 mg, 0.29 mmol) were added. It was degassed again and stirred at 100 C under argon.The reaction was followed by HPLC. After 26 h 85.5 % conversion was obtained. 20 % by-product formation was detected.Finally, the reaction mixture wa" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=CC=C(C=C4)CN5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/03/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "71" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CCC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0576 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.36 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" + } + amount { + moles { + value: 0.036 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1CC2=CC=C(C=C2)Br" + } + amount { + moles { + value: 0.037 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000648 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.00054 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Tris(dibenzylideneacetone)dipalladium(0) (0.494 g, 0.54 mmol) and9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (0.375 g, 0.65 mmol)nbsp;were dissolved in toluene (160 mL) in a 1 L reactor equipped with a condensor and activated at 100 C for 6 min under argon. Then 5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (9.98 g, 36 mmol), 4-(4-bromobenzyl)morpholine (9.48 g, 37 mmol), Sodium tert-pentoxide (6.34 g, 57.60 mmol) and toluene (200 mL) were added. The reaction mixture became sticky yellowish green. It was stirred at 100 C under argon. The reaction was followed by HPLC. After 3 h no conversion was obtained. The mixture was stirred overnight but the conversion did not move. Then the mixture was cooled to 50 C, Pd-complex (5 mol%) and Xantphos (6 mol%) as preactivated catalyst in toluene (100 ml) were added to the mixture, it was degassed carefully, then it was put under argon. Then the reaction mixture was heated at 100 C. After 1 h fas detected.The reaction mixture was cooled to room temperature, diluted with dichloromethane (600 mL), extracted with water (4*500 mL), washed with brine (1*500 mL) and dried over Na2SO4. Filtration and concentration afforded orange brown solid. This solid was slurried in EtOAc ( 50 mL) and stirred at reflux point (78 C) for 10 min. Then it was cooled to room temperature with stirring and filtered. The filtercake was washed with ini-pentane (80 mL). Orange filtercake was obtained which still had some impurity.The above obtained orange filtercake was slurried in EtOAc (80 mL) and stirred at 80 C for 30 min. Then it was cooled to room t emperature and the precipitation was filtered. Yellow fine powder was obtai" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=CC=C(C=C4)CN5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 53.72 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/09/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "72" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CCC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0741 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.3 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" + } + amount { + moles { + value: 0.0463 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1CC2=CC=C(C=C2)Br" + } + amount { + moles { + value: 0.0532 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00446 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.00186 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Tris(dibenzylideneacetone)dipalladium(0) (1.703 g, 1.86 mmol) and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (2.58 g, 4.46 mmol) were dissolved in toluene (50 ml) in a 500 mL two-necked round-bottomed flask equipped with a condensor and activated at 50 C for 40 min under argon. 5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (12.84 g, 46.30 mmol), 4-(4-bromobenzyl)morpholine (13.64 g, 53.25 mmol), Sodium tert-pentoxide (8.16 g, 74.09 mmol) and extra toluene (250 mL) were added. The total volume of the reaction mixture was deoxygenized carefully by switching vacuum-argon 10-times and heated to 110 C under argon. After 10 min the mixture turned into green. The reaction was monitored by HPLC, after 22 h only ca 65 %. The reactuion was stopped and the mixture was cooled to room temperature. Toluene was removed in vacuo. The residual was dissolved in dichloromethane ( 1.2 L) and extracted with water (2*1 L). The aqueous phase was extracted with EtOAc. The combined orange organic phases were filtered through a celitepad and concetrated in vacuo. Dark orange brown sticky gum was obtained which solidified over 2 weeks.This solid was slurried in EtOAc (60 mL) at reflux point for 1 h, then it was cooled to rt slowly with vigorous stirring. Filtration afforded a light yellow solid and an orange filtrate.0.5 g of the filtercake was purified by preparative HPLC, it afforded 303 mg light yellow solid which was mitted to PARD directly (EN01460-38-001).1.8 g of the filtercake was purified by preparative HPLC, it afforded 1.02 g light yellow solid and 1.015 g was mitted to PARD directly in a standard bascoded bottle (EN01460-38-002) (barcode: 30152995).The residual material was used for recrystallization studies in the RSL group." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=CC=C(C=C4)CN5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 6.31 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/02/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "80" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CCC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000294 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CCCCOC(=O)C" + } + amount { + volume { + value: 0.0018 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" + } + amount { + moles { + value: 0.000184 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1CC2=CC=C(C=C2)Br" + } + amount { + moles { + value: 0.000193 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 9.2e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 4.91e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Tris(dibenzylideneacetone)dipalladium(0) (4.5 mg, 4.91 mol) and 2-Dicyclohexylphosphino-2\',4\',6\'-triisopropylbiphenyl (4.38 mg, 9.20 mol) were dissolved in butyl acetate (1.8 mL) in a 10 mL Schlenk tube and activated at 100 C for 6 min under argon. Then 5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (51 mg, 0.18 mmol), 4-(4-bromobenzyl)morpholine (49.5 mg, 0.19 mmol) and Sodium tert-pentoxide (32.4 mg, 0.29 mmol) were added. It was degassed again and stirred at 100 C under argon.The reaction was followed by HPLC. After 4.5 h no conversion was observed. Hence the whole reaction mixture wa" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=CC=C(C=C4)CN5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/07/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "81" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CCC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 6.48e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.035 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" + } + amount { + moles { + value: 0.0036 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1CC2=CC=C(C=C2)Br" + } + amount { + moles { + value: 0.00378 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 6.48e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 5.4e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Tris(dibenzylideneacetone)dipalladium(0) (0.049 g, 54 mol) and9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (0.037 g, 0.06 mmol)nbsp;were dissolved in toluene (15 mL) in a 50 mL two-necked round-bottomed flask equipped with a condensor and activated at 100 C for 6 min under argon. Then 5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (0.998 g, 3.6 mmol), 4-(4-bromobenzyl)morpholine (0.968 g, 3.78 mmol), Sodium tert-pentoxide (0.634 g, 5.76 mmol) and toluene (20 mL) were added. The reaction mixture became sticky yellowish green maybe by addition of the base. It was degassed carefully and stirred at 100 C under argon. In 1 hour the sticky mixture turned from yellowish green into orange brown muddy mixture. The reaction was followed by HPLC. After 22 h 98 % conversion was obtained. Then it was cooled to rt and filtered. The obtained dark brown crapy filtercake was discarded. The brown filtrate was diluted with dichloromethane (80 mL), extracted 3*100 mL), washed with brine (1*100 mL) and dried over Na2SO4. Filtration and concentration afforded orange solid (1.400 g). To this orange solid EtOAcnbsp;(7 mL) was added and heat to 80 C. At 60 C it started to form light precipitation. Extra EtOAc (10 mL) was added and stirred at 80 C for 10 min. Then it was cooled to rt with a continuous stirring. The light precipitation was filtered off, washed with EtOAc (7 mL) and ini-pentane (15 mL), and dried in vacuo. Light yellow powder was o" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=CC=C(C=C4)CN5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 33.82 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/08/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "86" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CCC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.208 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 1.0 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" + } + amount { + moles { + value: 0.13 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1CC2=CC=C(C=C2)Br" + } + amount { + moles { + value: 0.136 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00234 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.00195 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Tris(dibenzylideneacetone)dipalladium(0) (1.786 g, 1.95 mmol) and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (1.354 g, 2.34 mmol)nbsp;were dissolved in toluene (40 mL) in a 100 mL two-necked round-bottomed flask equipped with a condensor and activated at 50 C for 30 min under argon. In a 2 L reactor 5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (36.0 g, 130 mmol), 4-(4-bromobenzyl)morpholine (34.8 g, 136 mmol), Sodium tert-pentoxide (22.91 g, 208.00 mmol) were dissolved in degassed toluene (960 mL) by heating at 100 C. The preactivated catalyst solution was added to the mixture. It was put under nitrogen atmosphere carefully and stirred at 100 C. The reaction was monitored by HPLC. After 20 h 38 % conversion was obtained. An extra batch of preactivated catalyst (3 %) in toluene (40 mL) was added and the mixture was stirred at 100 C under nitrogen. After 52 h 92 % conversion was detected.Then the reaction mixture was cooledture, diluted with DCM (8 L) and extracted with water (3*5L). The separated organic phase was washed with brine and dried over Na2SO4. Filtration and concentration afforded orange solid which was slurried in EtOAc (100 mL) and stirred at reflux point for 30 min. Then it was cooled to room temperature and filtered. Yellow filtercake was obtained which was washed with EtOAc (150 ml). It was reslurried in EtOAc (100 mL) and stirred at reflux point for 30 min. Then it was cooled to room temperature and filtered. The filtercake was washed with EtOAc (150 ml) and dried in vacuo. Light yellow fine powder was obtained." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=CC=C(C=C4)CN5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 79.28 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/16/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "87" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CCC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00146 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.0017 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" + } + amount { + moles { + value: 0.001 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1CC2=CC=C(C=C2)Br" + } + amount { + moles { + value: 0.0011 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 0.01 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "The aim of the reaction is only optimization and test. The reaction described below was carried out under argon atmosphere.Palladium(II) acetate (2.245 mg, 10.00 mol) and (R)-(-)-1-[(S)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (5.61 mg, 10.00 mol) were mixed in DME (0.2 mL) in a 1.4 ml vial under argon and stirred for 1 minute at room temperature.The orange pre-mixed Pd-catalyst solution were added to a 10 mL Schlenk-tube containing 4-(4-bromobenzyl)morpholine (0.282 g, 1.1 mmol) and Sodium tert-pentoxide (0.161 g, 1.46 mmol) in DME (1.5 mL). Finally, 5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (0.277 g, 1 mmol) was added and the bright orange reaction mixture was stirred at 90 C.The mixture turned from bright orange into bright yellow in 1 h. The reaction was followed by HPLC. No reaction took place, hence the mixture was di" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=CC=C(C=C4)CN5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/14/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "88" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000364 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C(=NN1C)C)N" + } + amount { + moles { + value: 0.000607 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C(F)(F)F)Cl" + } + amount { + moles { + value: 0.000303 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 4.85e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.43e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide (100 mg, 0.30 mmol), 1,3,5-trimethyl-1H-pyrazol-4-amine (76 mg, 0.61 mmol), cesium carbonate (119 mg, 0.36 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (28.1 mg, 0.05 mmol) and diacetoxypalladium (5.45 mg, 0.02 mmol) were suspended in dioxane (1.5 mL) and sealed into a tube. The reaction was degased, purged with nitrogen and heated to 100 C for 18 hours. Reaction was filtered. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford N-methyl-2-(5-(trifluoromethyl)-2-(1,3,5-trimethyl-1H-pyrazol-4-ylamino)pyridin-4-ylamino)benzamide (31.0 mg, 24.43 %) as a pale yellow solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C(=NN1C)C)NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NC)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 24.43 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/15/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "89" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00162 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.008 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1N)C" + } + amount { + moles { + value: 0.00162 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" + } + amount { + moles { + value: 0.00135 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 0.00014 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.4e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "1,3-dimethyl-1H-pyrazol-4-amine (180 mg, 1.62 mmol), 2-(2,5-dichloropyridin-4-ylamino)-N-methylbenzamide (400 mg, 1.35 mmol), Sodium t-Butoxide (156 mg, 1.62 mmol),(R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (73.8 mg, 0.14 mmol) and diacetoxypalladium (24.26 mg, 0.11 mmol) were suspended in DME (8 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT. Incomplete reaction, the reaction was heated to 150 C for a further 1 hour in the microwave reactor and cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH andnbsp;fractions were evaporated to dryness. The crude product was then purified by Basic prep HPLC, fractions containing the desired compound were evaporated to dryness to afford 2-(5-chloro-2-(1,3-dimethyl-1H-pyrazol-4-ylamino)pyridin-4-ylamino)-N-methylbenzamide (267 mg, 53.3 brown solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NC)Cl)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 53.31 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/06/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "90" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.002 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.008 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC1=C2C(=CC=C1)SC(=N2)N" + } + amount { + moles { + value: 0.0012 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)I" + } + amount { + moles { + value: 0.001 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.0001 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 3e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "4-methoxybenzo[d]thiazol-2-amine (0.216 g, 1.20 mmol), iodobenzene (0.112 mL, 1.00 mmol), XANTPHOS (0.058 g, 0.10 mmol), Pd2(dba)3 (0.027 g, 0.03 mmol) and SODIUM TERT-BUTOXIDE (0.192 g, 2.00 mmol) placed in a sealed reaction via under an atmosphere of nitrogen and heated at 90C for 1 hour. LCMS indicated mainly product, little SM. Cooled, diluted DCM and washed with water and brine. Org phase driedMgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with dichloromethane. Pure fractions were evaporated to dryness to afford 4-methoxy-N-phenylbenzo[d]thiazol-2-amine (0.039 g, 15.22 %) as an colorless solid. EN01327-44-1 (0.039 g, 0.15 mmol, 15.22 %)Not sure why yield so low, crude lcms looked fine. Reaction left for several days before working up." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=C2C(=CC=C1)SC(=N2)NC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 15.22 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/01/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "92" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0015 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC1CCNCC1" + } + amount { + moles { + value: 0.000499 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC2=NC=CC(=C2C=C1Cl)Cl" + } + amount { + moles { + value: 0.000449 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 4.99e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (5.60 mg, 0.02 mmol) was added in one portion to tert-butyl piperidin-4-ylcarbamate (100 mg, 0.50 mmol), 4,6-dichloroquinoline (89 mg, 0.45 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (28.9 mg, 0.05 mmol) and cesium carbonate (488 mg, 1.50 mmol) in DMA (5 mL). The resulting mixture was stirred at 150 C for 1 hour. LCMS analysis showed formation of a small amount of the desired product. The mixture was heated for a further 2 hours, after which time LCMS analysis showed loss of this small peak.Abandoned.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CN(CCC1N)C2=C3C=C(C=CC3=NC=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/22/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "93" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 3.02e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.001 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CC(C1)OC2=CC(=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000377 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC2=NC=C(N2C=C1)C3=NC(=NC=C3Cl)Cl" + } + amount { + moles { + value: 0.000377 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.02e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.51e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 105.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "3-(2,5-dichloropyrimidin-4-yl)imidazo[1,2-a]pyridine (100 mg, 0.38 mmol)i, itert-butyl 3-(4-amino-3-methoxyphenoxy)azetidine-1-carboxylate (111 mg, 0.38 mmol)i, iCESIUM CARBONATE (246 mg, 0.75 mmol)i ,idiacetoxypalladium (3.39 mg, 0.02 mmol)i and i9,9-DIMETHYL-4,5-BIS(DIPHENYLPHOSPHINO)XANTHENE (17.46 mg, 0.03 mmol)i iiwereii iisuspendedii in i1,4-dioxane (1 ml)i and degased with argon.The reactionnbsp;was heated from 60C to 105C for 3 hours.Doubt about the LCMS,deprotection of the BOC with TFA to confirm the dialkylation.iNo good pro" + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=C(C=CC(=C1)OC2CNC2)NC3=NC=C(C(=N3)C4=CN=C5N4C=CC=C5)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/22/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "94" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.135 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.25 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)N" + } + amount { + moles { + value: 0.0676 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.0676 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00203 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00135 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (0.303 g, 1.35 mmol) was added in one portion to a degassed mixture of 2,4-dichloropyridine (10 g, 67.57 mmol), aniline (6.29 g, 67.57 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.173 g, 2.03 mmol) and cesium carbonate (44.0 g, 135.14 mmol) in dioxane (250 mL) under argon. The resulting mixture was stirred at 100 C for 24 hours. The mixture was then cooled to room temperature, filtered and concentrated to dryness to give the crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-chloro-N-phenylpyridin-2-amine (7.72 g, 55.8 %) as a pale orange solid.nbsp;nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 55.82 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/04/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "96" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000364 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C(=CC=N1)N" + } + amount { + moles { + value: 0.000607 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C(F)(F)F)Cl" + } + amount { + moles { + value: 0.000303 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 4.85e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.43e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide (100 mg, 0.30 mmol), 1-methyl-1H-pyrazol-5-amine (58.9 mg, 0.61 mmol), cesium carbonate (119 mg, 0.36 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (28.1 mg, 0.05 mmol) and diacetoxypalladium (5.45 mg, 0.02 mmol) were suspended in dioxane (1.5 mL) and sealed into a tube. The reaction was degased, purged with nitrogen and heated to 100 C for 18 hours. Reaction was filtered. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford N-methyl-2-(2-(1-methyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)benzamide (62.0 mg, 52.4 %) [salt] as a pale orange solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C(F)(F)F)NC3=CC=NN3C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 52.37 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/12/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "97" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0168 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.08 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC=CC=C1N" + } + amount { + moles { + value: 0.014 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C(=CN=C1Cl)C(F)(F)F)I" + } + amount { + moles { + value: 0.014 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00224 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00112 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-chloro-4-iodo-5-(trifluoromethyl)pyridine (4.305 g, 14.00 mmol), 2-amino-N-methylbenzamide (2.103 g, 14.00 mmol), diacetoxypalladium (0.251 g, 1.12 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.296 g, 2.24 mmol) and cesium carbonate (5.47 g, 16.80 mmol) were mixed together in dioxane (80 mL). Reaction was degassed with argon and was stirred at 90 C overnight (15 hours) under argon.Reaction was filtered, washed with CH2Cl2 and filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 10 to 40% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford 2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide (3.39 g, 73.4 %) as a white crystalline solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C(F)(F)F)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 73.43 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/09/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "98" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0273 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.14 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC=CC=C1N" + } + amount { + moles { + value: 0.0228 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C(=CN=C1Cl)C(F)(F)F)I" + } + amount { + moles { + value: 0.0228 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00364 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00182 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-chloro-4-iodo-5-(trifluoromethyl)pyridine (7 g, 22.77 mmol), 2-amino-N-methylbenzamide (3.42 g, 22.77 mmol), diacetoxypalladium (0.409 g, 1.82 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.108 g, 3.64 mmol) and cesium carbonate (8.90 g, 27.32 mmol) were mixed together in dioxane (140 mL). Reaction was degassed with nitrogen and was stirred at 90 C overnight under nitrogen. Reaction was filtered, washed with CH2Cl2 and filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 10 to 50% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford 2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide (5.06 g, 67.4 %) as a pale yellow solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C(F)(F)F)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 67.4 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/10/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "99" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00195 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC=CC=C1N" + } + amount { + moles { + value: 0.00163 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C(=CN=C1Cl)C(F)(F)F)I" + } + amount { + moles { + value: 0.00163 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00026 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00013 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-chloro-4-iodo-5-(trifluoromethyl)pyridine (500 mg, 1.63 mmol), 2-amino-N-methylbenzamide (244 mg, 1.63 mmol), diacetoxypalladium (29.2 mg, 0.13 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (151 mg, 0.26 mmol) and cesium carbonate (636 mg, 1.95 mmol) were mixed together in dioxane (10 mL). Reaction was degassed with nitrogen and was stirred at 90 C overnight under nitrogen. Reaction was filtered, washed with CH2Cl2 and filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 10 to 50% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford 2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide (340 mg, 63.4 %) as a pale yellow solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C(F)(F)F)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 63.41 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/09/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "100" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00166 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCC(CC1)(CN=C(C2=CC=CC=C2)C3=CC=CC=C3)C(=O)N" + } + amount { + moles { + value: 0.00119 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1C(F)(F)F)Br" + } + amount { + moles { + value: 0.00119 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 5.34e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.56e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "tert-butyl 4-carbamoyl-4-((diphenylmethyleneamino)methyl)piperidine-1-carboxylate (500 mg, 1.19 mmol), 2-bromo-4-(trifluoromethyl)pyridine (268 mg, 1.19 mmol), and cesium carbonate (541 mg, 1.66 mmol) were suspended in dioxane (2 mL) . The reaction was purged with nitrogen for 10 minutes then 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (30.9 mg, 0.05 mmol) and palladium(II) acetate (7.99 mg, 0.04 mmol) were added. The reaction was heated at 90 C for 48 hours.The reaction was cooled to room temperature, diluted with DCM, filtered and concentrated.The crude product was purified by flash silica chromatography, elution gradient 0 to 40% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 4-((diphenylmethyleneamino)methyl)-4-(4-(trifluoromethyl)pyridin-2-ylcarbamoyl)piperidine-1-carboxylate (480 mg, 71.4 %) as a white solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCC(CC1)(CN=C(C2=CC=CC=C2)C3=CC=CC=C3)C(=O)NC4=NC=CC(=C4)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 71.42 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/16/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "102" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00347 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00301 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=CC=C1Br)[N+](=O)[O-]" + } + amount { + moles { + value: 0.00231 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000347 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000231 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "1-bromo-2-methyl-3-nitrobenzene (500 mg, 2.31 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (201 mg, 0.35 mmol) and cesium carbonate (1131 mg, 3.47 mmol) and diacetoxypalladium (52.0 mg, 0.23 mmol) were dissolved in toluene (10 mL)nbsp;and sealed into a microwave tube degazed and purged with argon. The reaction was heated to 100 C, over a period ofnbsp;12 hours. The reaction mixture was cooled down to room temperature, filtered and the residue was evaporated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 10% methanol in dichloromethane. The solvent was evaporated to dryness to afford 1-(4-(2-methyl-3-nitrophenyl)piperazin-1-yl)ethanone (600 mg, 98 %) as a solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=CC=C1[N+](=O)[O-])N2CCN(CC2)C(=O)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 98.46 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/10/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "103" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00695 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=C(C=CC(=C1)F)N" + } + amount { + moles { + value: 0.00348 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C(=CN=C1Cl)Cl)I" + } + amount { + moles { + value: 0.00365 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000209 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000139 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "palladium acetate (31.2 mg, 0.14 mmol) was added to 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (121 mg, 0.21 mmol), Cesium carbonate (2266 mg, 6.95 mmol), 2-amino-5-fluoro-N-methylbenzamide (585 mg, 3.48 mmol) and 2,5-dichloro-4-iodopyridine (1000 mg, 3.65 mmol) in dioxane (20 mL) under nitrogen. The resulting suspension was stirred at 80 C for 18hrs then cooled. Product appeared to be out of solution. Product and bis product suggested. Disappointing! The reaction mixture was evaporated to dryness and redissolved in EtOAc (100 mL), and washed sequentially with saturated Na2CO3 (50 mL), water (50 mL), and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford desired product as an beige solid.nbsp;nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CNC(=O)C1=C(C=CC(=C1)F)NC2=CC(=NC=C2Cl)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 13.27 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/12/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "104" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[K+]" + } + amount { + moles { + value: 0.00251 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1C#N)N" + } + amount { + moles { + value: 0.00151 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)NC(=O)C2=CN=C(C=C2)Cl" + } + amount { + moles { + value: 0.00126 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000251 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000126 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 50 mL round-bottomed flask a TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.115 g, 0.13 mmol),POTASSIUM TERT-BUTOXIDE (0.282 g, 2.51 mmol)and BINAP (0.157 g, 0.25 mmol) in dry 1,4-dioxane (10 mL) was mixed under N2.Followed by 6-chloro-N-cyclohexylnicotinamide (.300 g, 1.26 mmol) and 4-aminobenzonitrile (0.178 g, 1.51 mmol) was added and resulting mixture(dark brown) was heated at 100oC for 3 hrs.LCMS analysis showed the formation of required product.Reaction stopped,crude was passed through celite and washed with dioxane and finally with methanol.The filtrate was dried and dissolved in 3 ml DMSO for Waters MS Purification system.Pure fractions collected and concentrated.A White solid obtained as a product 6-(4-cyanophenylamino)-N-cyclohexylnicotinamide (0.040 g, 9.93 %).32 mg of above product was mitted for MGyrx2 projetct.LCMSNMR confirmed the product." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CCC(CC1)NC(=O)C2=CN=C(C=C2)NC3=CC=C(C=C3)C#N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 9.93 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/15/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "105" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000405 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.0025 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1N)C" + } + amount { + moles { + value: 0.000347 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C(F)(F)F)Cl" + } + amount { + moles { + value: 0.000289 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 3e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium(II) acetate (7.79 mg, 0.03 mmol), (R)-(-)-1-[(S)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (19.46 mg, 0.03 mmol), Cesium carbonate (0.032 mL, 0.40 mmol), 1,3-dimethyl-1H-pyrazol-4-amine (38.6 mg, 0.35 mmol) and 2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-N-methoxybenzamide (100 mg, 0.29 mmol) were suspended in DME (2.5 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness to afford crude product as a orange gum. The sample was given to the purification group to be purified by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford 2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N-methoxybenzamide (13.60 mg, 11.18 %) as a tum. The sample was not pure enough to register so will be re-made. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 11.18 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/13/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "106" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00201 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CC2=CC=CC=C2NC1" + } + amount { + moles { + value: 0.00134 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(N=C1Cl)Cl" + } + amount { + moles { + value: 0.00134 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000134 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 6.71e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2,4-dichloropyrimidine (200 mg, 1.34 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (78 mg, 0.13 mmol), Tris(dibenzylideneacetone)dipalladium(0) (61.5 mg, 0.07 mmol) and Cesium carbonate (656 mg, 2.01 mmol) was added to a microwave vial. toluene (2 mL) was added.nbsp;1,2,3,4-tetrahydroquinoline (179 mg, 1.34 mmol) was added. Heated to 120C in microwave oven for 90min. Crude filtered through celite and then added to prepHPLC. 30-70% acetonitrile in water. Pure fractions pooled and then freezedried over night. Yielded 1-(2-chloropyrimidin-4-yl)-1,2,3,4-tetrahydroquinoline (24.00 mg, 7.28 %)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CC2=CC=CC=C2N(C1)C3=NC(=NC=C3)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 7.28 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/02/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "107" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000425 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.0025 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1N)C" + } + amount { + moles { + value: 0.000364 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C(F)(F)F)Cl" + } + amount { + moles { + value: 0.000303 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 4e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium(II) acetate (8.17 mg, 0.04 mmol), (R)-(-)-1-[(S)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (20.40 mg, 0.04 mmol), Sodium tert-butoxide (0.052 mL, 0.42 mmol), 1,3-dimethyl-1H-pyrazol-4-amine (40.5 mg, 0.36 mmol) and 2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide (100 mg, 0.30 mmol) were suspended in DME (2.5 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness to afford 2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide (41.3 mg, 33.7 %) as a orange gum. The sample was given to the purification group to be purified by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford 2-(2-(1,3-dimethyl-1razol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide (41.3 mg, 33.7 %) as a yellow solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 33.67 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/02/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "108" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00113 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COC(=O)N1" + } + amount { + moles { + value: 0.000566 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1C#N)C2=CSC(=N2)Br" + } + amount { + moles { + value: 0.000377 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.77e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.64e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "4-(2-bromothiazol-4-yl)benzonitrile (100 mg, 0.38 mmol), 2-Oxazolidinone (49.3 mg, 0.57 mmol), diacetoxypalladium (5.93 mg, 0.03 mmol), cesium carbonate (369 mg, 1.13 mmol), water (10 l)nbsp;and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (21.82 mg, 0.04 mmol) were suspended in dioxane (2 mL), thoroughly degassed and sealed into a microwave tube and stirred at RT for 20 mins. The reaction was then heated to 150 C for 10 minutes in the microwave reactor and cooled to RT. Load of rubbish... ABAND" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1COC(=O)N1C2=NC(=CS2)C3=CC=C(C=C3)C#N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/30/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "111" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00116 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=C(C=C(C=C1)F)NC2=CC(=NC=C2Cl)Cl" + } + amount { + moles { + value: 0.000525 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1N)C.Cl.Cl" + } + amount { + moles { + value: 0.00105 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 8.4e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.2e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-(2,5-dichloropyridin-4-ylamino)-4-fluoro-N-methylbenzamide (165 mg, 0.53 mmol), 1,3-dimethyl-1H-pyrazol-4-amine dihydrochloride (193 mg, 1.05 mmol), cesium carbonate (376 mg, 1.16 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (48.6 mg, 0.08 mmol) and diacetoxypalladium (9.43 mg, 0.04 mmol) were suspended in dioxane (3 mL) and sealed into a tube. The reaction was degased, purged with nitrogen and heated to 100 C for 16 hours =gt; ireaction not complete. i(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine), diacetoxypalladium and cesium carbonate were added. The reaction was degased, purged with nitrogen and heated to 110 C for 4 hours =gt; ireaction still not complete, no progress ...iReaction was filtered, washed with CH2Cl2 and concentrated to dryness. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containcetic acid) and acetonitrile as eluent. The pure fractions were combined, basified with a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2. Organic layer was washed with brine, dried over MgSO4 and concentrated to dryness to afford 2-(5-chloro-2-(1,3-dimethyl-1H-pyrazol-4-ylamino)pyridin-4-ylamino)-4-fluoro-N-methylbenzamide (8.00 mg, 3.92 %) as a green dry film." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=C(C=CC(=C3)F)C(=O)NC)Cl)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 3.92 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/23/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "112" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00146 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1OC2=CC=CC(=C2O1)N" + } + amount { + moles { + value: 0.000729 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CC1C(=O)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000729 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 8.75e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.65e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "benzo[d][1,3]dioxol-4-amine (100 mg, 0.73 mmol), N-(4-chloropyridin-2-yl)cyclopropanecarboxamide (143 mg, 0.73 mmol), XANTPHOS (50.6 mg, 0.09 mmol), PALLADIUM(II) ACETATE (8.19 mg, 0.04 mmol) and CESIUM CARBONATE (475 mg, 1.46 mmol) were suspended in DMA (3mL) and sealed into a microwave tube. The reaction was heated to 150 C for 1.5 hours in the microwave reactor and cooled to RT.nbsp;LCMS showed completion.The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 0.35M NH3MeOH and pure fractions were evaporated to dryness to afford N-(4-(benzo[d][1,3]dioxol-4-ylamino)pyridin-2-yl)cyclopropanecarboxamidenbsp;as a brown oil. The crude product was purified by preparative HPLCnbsp;using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-(4-(benzo[d][1,3]dioxol-4-ylamino)pyridin-2-yl)cyclopropanecarmide (110 mg, 50.7 %) as a cream solid. nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CC1C(=O)NC2=NC=CC(=C2)NC3=C4C(=CC=C3)OCO4" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 50.74 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/09/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "113" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00223 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCNCC1" + } + amount { + moles { + value: 0.00168 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC=C(C=C1)OCC2=C(C=CC=N2)Br" + } + amount { + moles { + value: 0.00112 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000447 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000223 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of methyl 4-((3-bromopyridin-2-yl)methoxy)benzoate (360 mg, 1.12 mmol), Pd2dba3 (205 mg, 0.22 mmol), BINAP (278 mg, 0.45 mmol), cesium carbonate (728 mg, 2.23 mmol) and 1-methylpiperazine (168 mg, 1.68 mmol) in DMA (10 mL) was stirred at 100 C for overnight. Sat. NaHCO3 aq was added to the mixture, extracted with ethyl acetate three times, the combined organics were dried over anhydrous Na2SO4, filtered, the filtrate was conc. in vacuo, the residue was purified with ISCO (50% ethyl acetate in hexant to 100% ethyl acetate to 40% mthanol in ethyl acetate) to yield a brown oil as methyl 4-((3-(4-methylpiperazin-1-yl)pyridin-2-yl)methoxy)benzoate (245 mg, 64.2 %)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CCN(CC1)C2=C(N=CC=C2)COC3=CC=C(C=C3)C(=O)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 64.22 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/24/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "114" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00462 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN(C)[C@H]1CCNC1" + } + amount { + moles { + value: 0.00277 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C=C1Cl)Br)C#N" + } + amount { + moles { + value: 0.00231 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000462 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000231 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of 2-bromo-4-chlorobenzonitrile (500 mg, 2.31 mmol), (S)-N,N-dimethylpyrrolidin-3-amine (317 mg, 2.77 mmol), cesium carbonate (1505 mg, 4.62 mmol), tris(dibenzylideneacetone)dipalladium(0) (212 mg, 0.23 mmol) and BINAP (288 mg, 0.46 mmol) in toluene (15 mL) was stirred at 100 C for overnight. Conc. in vacuo, the residue was purified with ISCO (100% ethyl acetate to 30% methanol in ethyl acetate) to yield a light yellow solid as (S)-4-chloro-2-(3-(dimethylamino)pyrrolidin-1-yl)benzonitrile (400 mg, 69.3 %)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(C)[C@H]1CCN(C1)C2=C(C=CC(=C2)Cl)C#N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 69.34 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/29/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "115" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 1.01e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCC2=C(C1=O)C(=CC=C2)N" + } + amount { + moles { + value: 0.000202 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)Cl)C#N)C" + } + amount { + moles { + value: 0.000101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 1.01e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 5.05e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "8-amino-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (35.6 mg, 0.20 mmol), 4-chloro-6-(1,3-dimethyl-1H-pyrazol-4-ylamino)nicotinonitrile (25 mg, 0.10 mmol), diacetoxypalladium (1.133 mg, 5.05 mol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (5.84 mg, 10.09 mol) and cesium carbonate (39.5 mg, 0.12 mmol) were dissolved in dioxane (0.5 mL) and sealed into a microwave tube. nitrogen was let to bubble into the mixture then the reaction was heated to 100 C for 90 minutes. Crude LCMS showed the expected product P3 and no hydrolysis by-product at all like in uEN01775-20u !!The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. b10 days laterb, the fractions containing the desired compound were evaporated to dryness to afford impure 6-(11H-pyrazol-4-ylamino)-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-8-ylamino)nicotinonitrile (13.00 mg, 33.2 %): it has probably gone off after 10 days in solution (aqueous ammonium carbonate and acetonitrile)ENCOURAGING, THOUGH. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC4=C3C(=O)N(CC4)C)C#N)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 33.24 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/11/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "116" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=CC(=C1)N2CCOCC2)N" + } + amount { + moles { + value: 0.00076 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" + } + amount { + moles { + value: 0.000506 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 5.06e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.53e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-methoxy-4-morpholinoaniline (158 mg, 0.76 mmol), 2-(2,5-dichloropyridin-4-ylamino)-N-methylbenzamide (150 mg, 0.51 mmol),diacetoxypalladium (5.69 mg, 0.03 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (29.3 mg, 0.05 mmol) and cesium carbonate (330 mg, 1.01 mmol) were weighed out in a microwave vial and sealed. dioxane (3 mL) was added and argon was let to bubble for 5 minutes at rt. The resulting mixture was stirred at 110 C for 1 hour. The reaction mixture was allowed to cool to room temperature and concentrated in presence of decalite speed plus. The crude product was purified by flash chromatography on silica gel eluting with 0 to 4% methanol in ethyl acetateDCM (11). The solvent was evaporated to dryness. The foam was triturated in terbutyl methyl ether and the resulting precipitate was collected by filtration and washed with tBuOMe to afford 2-(5-chloro-2-(2-methoxy-4-morpholinophenylamino)pyridin-4-ylamino)-N-methylbenzamide (193 mg, 81 %) as a pale pink solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)NC3=C(C=C(C=C3)N4CCOCC4)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 81.43 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/23/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "117" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0159 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.025 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.0127 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=CC(=C1)F)Br" + } + amount { + moles { + value: 0.0106 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00127 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000635 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 200ml flask was added 1-bromo-4-fluoro-2-methylbenzene (2 g, 10.58 mmol) and TERT-BUTYL 1-PIPERAZINECARBOXYLATE (2.365 g, 12.70 mmol), CESIUM CARBONATE (5.17 g, 15.87 mmol) , BINAP (0.791 g, 1.27 mmol) 18-CROWN-6 (0.336 g, 1.27 mmol), followed by toluene (25 ml). Degass the mixture. TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.581 g, 0.63 mmol) was added. Heat at 110oC under nitrogen in an oil bath for overnight. The reaction mixture was diluted with ethyl acetate and filtered through celite. The Celite was washednbsp;with EtOAC. The EtOAC was concentrated down to give a brown oil.The crude product was purified by silica gel column(40g) and was eluted with 0% EtOACHexane -50% EtOACHexane.Yield: 0.5g Yellow oil. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=CC(=C1)F)N2CCN(CC2)C(=O)OC(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 16.05 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/20/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "118" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00545 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00436 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C=C1F)C(F)(F)F)Br" + } + amount { + moles { + value: 0.00363 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000436 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000218 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 100ml sealtube was added 1-bromo-4-fluoro-2-(trifluoromethyl)benzene (0.91 g, 3.63 mmol), CESIUM CARBONATE (1.775 g, 5.45 mmol), CESIUM CARBONATE (1.775 g, 5.45 mmol), BINAP (0.271 g, 0.44 mmol), TERT-BUTYL 1-PIPERAZINECARBOXYLATE (0.812 g, 4.36 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.200 g, 0.22 mmol) and 18-CROWN-6 (0.115 g, 0.44 mmol). Followed by 15mL toluene. The mixture was degassed by N2 bubbling for 15min. The reaction mixture was heated at 110oC under nitrogen in an oil bath for overnight. The reaction mixture was diluted with ethyl acetate and filtered through celite. The Celite was washednbsp;with EtOAC. The EtOAC was concentrated down to give a brown oil.The crude product was purified by silica gel column(40g) and was eluted with 0% EtOACHexane -25% EtOACHexane.Yield: 0.93g Yellow oil. .nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=C(C=C(C=C2)F)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 73.5 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/21/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "119" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "[O-]P(=O)([O-])[O-].[K+].[K+].[K+]" + } + amount { + moles { + value: 0.000291 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N1CC2CNCC(C1)O2" + } + amount { + moles { + value: 0.000213 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)Br)[N+](=O)[O-]" + } + amount { + moles { + value: 0.000194 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 3.1e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.94e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "1-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)ethanone (36.3 mg, 0.21 mmol), 4-bromo-1-methoxy-2-nitrobenzene (45 mg, 0.19 mmol), diacetoxypalladium (4.35 mg, 0.02 mmol), biphenyl-2-yldicyclohexylphosphine (10.88 mg, 0.03 mmol) and potassium phosphate (61.8 mg, 0.29 mmol) in DME (0.5 mL) were degassed with nitrogen and stirred at 80 C overnight =gt; ino product formed, degradationibiABANDONEDib" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)N1CC2CN(CC(C1)O2)C3=CC(=C(C=C3)OC)[N+](=O)[O-]" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/19/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "120" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[K+].[K+]" + } + amount { + moles { + value: 0.00147 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCC[C@@H](CO)N" + } + amount { + moles { + value: 0.00147 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C(=NC(=N1)N)Cl)CC2=CC=C(C=C2)CC#N" + } + amount { + moles { + value: 0.000733 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.33e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.67e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium(II) acetate (8.23 mg, 0.04 mmol) and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (42.4 mg, 0.07 mmol) were added to dioxane (3 mL) and the solution was stirred at room temperature for 10 minutes.nbsp;2-(4-((2-amino-4-chloro-6-methylpyrimidin-5-yl)methyl)phenyl)acetonitrile (200 mg, 0.73 mmol), (S)-(+)-2-Amino-1-pentanol (151 mg, 1.47 mmol) and POTASSIUM CARBONATE (203 mg, 1.47 mmol) were added and the mixture was heated at 100 C for 15 hours. LCMS showed no product and reaction not progressed." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCC[C@@H](CO)NC1=NC(=NC(=C1CC2=CC=C(C=C2)CC#N)C)N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/23/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "121" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[K+].[K+]" + } + amount { + moles { + value: 0.00146 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC[C@H]1CNC(=O)O1" + } + amount { + moles { + value: 0.00146 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C(=NC(=N1)/N=C/N(C)C)Cl)CC2=CC=C(C=C2)CC#N" + } + amount { + moles { + value: 0.000732 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.32e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.66e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium(II) acetate (8.22 mg, 0.04 mmol) and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (42.4 mg, 0.07 mmol) were added to dioxane (3 mL) and the solution was stirred at room temperature for 10 minutes.(E)-N\'-(4-chloro-5-(4-(cyanomethyl)benzyl)-6-methylpyrimidin-2-yl)-N,N-dimethylformimidamide (240 mg, 0.73 mmol),nbsp;(S)-5-ethyloxazolidin-2-one (169 mg, 1.46 mmol) and POTASSIUM CARBONATE (202 mg, 1.46 mmol) were added and the mixture was heated at 100 C for 1 hour. The solvent was evaporated under reduced pressure and the crude product was purified by flash silica chromatography, elution gradient 2 to 5% methanol in dichloromethane. Pure fractions were evaporated to dryness to afford (S,E)-N\'-(5-(4-(cyanomethyl)benzyl)-4-(5-ethyl-2-oxooxazolidin-3-yl)-6-methylpyrimidin-2-yl)-N,N-dimethylformimidamide (136 mg, 45.7 %) as a colorless solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC[C@H]1CN(C(=O)O1)C2=NC(=NC(=C2CC3=CC=C(C=C3)CC#N)C)/N=C/N(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 45.7 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/30/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "122" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000822 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0025 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=C(C=C(C=C1)F)N" + } + amount { + moles { + value: 0.000548 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C(=CN=C1Cl)Cl)I" + } + amount { + moles { + value: 0.000548 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 5.48e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.74e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (6.15 mg, 0.03 mmol) was added to a stirred suspension of 2,5-dichloro-4-iodopyridine (150 mg, 0.55 mmol), 2-amino-4-fluoro-N-methylbenzamide (92 mg, 0.55 mmol) (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (31.7 mg, 0.05 mmol) and cesium carbonate (268 mg, 0.82 mmol)nbsp;in 1,4-dioxane (2.5 mL) under nitrogen. The resulting suspension was stirred at 100 C for 16 hours.The mixture was cooled to RT; filtered the solvent was evaporated.The crude product was absorbed on silica gel and purified by flash chromatography on silica gel eluting with 20 to 80% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford 2-(2,5-dichloropyridin-4-ylamino)-4-fluoro-N-methylbenzamide (60.0 mg, 34.9 %) as anbsp;beige solid.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CNC(=O)C1=C(C=C(C=C1)F)NC2=CC(=NC=C2Cl)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 34.87 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/10/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "123" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00137 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0025 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=C(C=C(C=C1)F)N" + } + amount { + moles { + value: 0.001 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C(=CN=C1Cl)Cl)I" + } + amount { + moles { + value: 0.000913 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 9.13e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.56e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 140.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2,5-dichloro-4-iodopyridine (250 mg, 0.91 mmol), 2-amino-4-fluoro-N-methylbenzamide (169 mg, 1.00 mmol) diacetoxypalladium (10.25 mg, 0.05 mmol) (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (52.8 mg, 0.09 mmol) and cesium carbonate (446 mg, 1.37 mmol) were dissolved in 1,4-dioxane (2.5 mL) and sealed into a microwave tube. The reaction was degased, purged with nitrogen and heated to 140 C over a period of 30 minutes in the microwave reactor. The mixture was cooled to RT; filtered the solvent was evaporated.The crude product was absorbed on silica gel and purified by flash chromatography on silica gel eluting with 20 to 80% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford 2-(2,5-dichloropyridin-4-ylamino)-4-fluoro-N-methylbenzamide (175 mg, 61.0 %) as anbsp;beige solid.nbsp;nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CNC(=O)C1=C(C=C(C=C1)F)NC2=CC(=NC=C2Cl)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 61.03 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/15/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "124" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00695 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.04 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=C(C=C(C=C1)F)N" + } + amount { + moles { + value: 0.00348 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C(=CN=C1Cl)Cl)I" + } + amount { + moles { + value: 0.00365 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000209 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000139 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "palladium acetate (31.2 mg, 0.14 mmol) was added to 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (121 mg, 0.21 mmol), Cesium carbonate (2266 mg, 6.95 mmol), 2-amino-4-fluoro-N-methylbenzamide (585 mg, 3.48 mmol) and 2,5-dichloro-4-iodopyridine (1000 mg, 3.65 mmol) in dioxane (40 mL) under nitrogen. The resulting suspension was stirred at 80 C for 18hrs then cooled. Product and bis product suggested. Disappointing! The reaction mixture wasnbsp;evaporated to dryness and redissolved innbsp;EtOAc (150 mL), and washed sequentially with saturated NaHCO3 (2 x 100 mL), water (100 mL), and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered then evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford desired product as a yellow solid.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CNC(=O)C1=C(C=C(C=C1)F)NC2=CC(=NC=C2Cl)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 10.99 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/12/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "126" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000291 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N1CC2CNCC(C1)O2" + } + amount { + moles { + value: 0.000213 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)Br)[N+](=O)[O-]" + } + amount { + moles { + value: 0.000194 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 1.55e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.55e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "1-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)ethanone (36.3 mg, 0.21 mmol), 4-bromo-1-methoxy-2-nitrobenzene (45 mg, 0.19 mmol), diacetoxypalladium (3.48 mg, 0.02 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (8.98 mg, 0.02 mmol) and sodium 2-methylpropan-2-olate (28.0 mg, 0.29 mmol) in dioxane (0.5 mL) were degassed with nitrogen and stirred at 110 C for 4 hours =gt; isome product formed, by-products are major + degradationibiABANDONEDib" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)N1CC2CN(CC(C1)O2)C3=CC(=C(C=C3)OC)[N+](=O)[O-]" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/19/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "127" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00473 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00335 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CS(=O)(=O)C1=CC=C(C=C1)COC2=NC=C(C=N2)Br" + } + amount { + moles { + value: 0.003 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000161 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000169 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "5-bromo-2-(4-(methylsulfonyl)benzyloxy)pyrimidine (1.03 g, 3.00 mmol), tert-butyl piperazine-1-carboxylate (624.6 mg, 3.35 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (154.3 mg, 0.17 mmol),2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (100.0 mg, 0.16 mmol) andnbsp;sodium 2-methylpropan-2-olate (454.4 mg, 4.73 mmol) were mixed with toluene (20 mL). N2 was bubbled through the solvent for 15 minutes.The resulting mixture was stirred at 80 C for over night under N2.The reaction mixture was filtered through celite. The reaction mixture was evaporated to dryness and redissolved in EtOAc (75 mL), and washed sequentially with water (2x75 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(2-(4-(methylsulfonyl)benzyloxy)pyrimidin-5-yl)piperazine-1-carboxylate (1.6) as a white solid. The product was not pure! The crude product was purified by flash alumina chromatography, elution gradient 0 to 70% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(2-(4-(methylsulfonyl)benzyloxy)pyrimidin-5-yl)piperazine-1-carboxylate (1.664 %) as a white solid. The product was still not pure but was handed in for testing anyway, as 92% pure by NMR. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CN=C(N=C2)OCC3=CC=C(C=C3)S(=O)(=O)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 1.66 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/28/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "128" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00327 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.0024 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CS(=O)(=O)C1=CC=C(C=C1)COC2=NC=C(C=N2)Br" + } + amount { + moles { + value: 0.00218 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000109 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000109 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "5-bromo-2-(4-(methylsulfonyl)benzyloxy)pyrimidine (748.8 mg, 2.18 mmol), tert-butyl piperazine-1-carboxylate (447 mg, 2.40 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (100 mg, 0.11 mmol),2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (67.9 mg, 0.11 mmol) andnbsp;sodium 2-methylpropan-2-olate (315 mg, 3.27 mmol) were mixed with toluene (20 mL). N2 was bubbled through the solvent for 15 minutes.The resulting mixture was stirred at 80 C for over night under N2.The reaction mixture was filtered through celite. The reaction mixture was evaporated to dryness and redissolved in EtOAc (75 mL), and washed sequentially with water (2x75 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(2-(4-(methylsulfonyl)benzyloxy)pyrimidin-5-yl)piperazine-1-carboxylate (55.0 %) yellow solid. Was not pure and tailed on the coloumn. The crude product was purified by preparative HPLC (Phenomenex Gemini C18 110A (axia) column, 5 silica, 21 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.5% NH3 and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford as a white solid. The product crashed out on the HPLC coloumn and blocked the system, which gave bad recovery.Turns out the product is not stable. 2D TLC shows tailing of product.." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CN=C(N=C2)OCC3=CC=C(C=C3)S(=O)(=O)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 55.01 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/22/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "129" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00125 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.000864 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CS(=O)(=O)C1=CC=C(C=C1)COC2=NC=C(C=C2)Br" + } + amount { + moles { + value: 0.000754 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 7.76e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 5.58e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (48.3 mg, 0.08 mmol) was added in one portion to 5-bromo-2-(4-(methylsulfonyl)benzyloxy)pyridine (257.9 mg, 0.75 mmol), tert-butyl piperazine-1-carboxylate (160.9 mg, 0.86 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (51.1 mg, 0.06 mmol) and sodium 2-methylpropan-2-olate (120.1 mg, 1.25 mmol) in toluene (10 mL). N2 was bubbled through the solvent for 15 minutes.The resulting mixture was stirred at 80 C for over night under N2.The reaction mixture was filtered through celite. The reaction mixture was evaporated to dryness and redissolved in EtOAc (75 mL), and washed sequentially with water (2x75 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 70% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(6-(4-(methylsulfonyl)benzyloxy)pyridin-3-yl)piperazine-1-carboxylate.6 %) as a yellow solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CN=C(C=C2)OCC3=CC=C(C=C3)S(=O)(=O)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 42.6 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/21/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "130" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00222 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.008 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N1CCC2=C1C=CC(=C2)CCN3CCNCC3" + } + amount { + moles { + value: 0.00179 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)Br" + } + amount { + moles { + value: 0.00171 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.000171 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 8.55e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 95.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "0605 2009 14:53:56 +0200To ethyl 7-bromobenzofuran-2-carboxylate (0.460 g, 1.71 mmol) and 1-(5-(2-(piperazin-1-yl)ethyl)indolin-1-yl)ethanone (0.491 g, 1.79 mmol) (from EN02198-74) in dry degassed dioxane (8 mL) were added Cesium carbonate (0.724 g, 2.22 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-triisopropylbiphenyl (0.081 g, 0.17 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (0.078 g, 0.09 mmol) under argon and the reaction heated at 95C overnight. After cooling to rt, water and DCM were added and the layers separated. The aq phase was extracted with DCM (3x). The combined org phases were washed with water, dried (MgSO4), filtered and evaporated. The crude was purified by flash (SiO2; DCMMeOH 955) to give 0.485 g (61%) of the product as a yellow solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)N3CCN(CC3)CCC4=CC5=C(C=C4)N(CC5)C(=O)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 61.47 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/06/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "131" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000459 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N1CCC2=C1C=CC(=C2)CCN3CCNCC3" + } + amount { + moles { + value: 0.000371 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)Br" + } + amount { + moles { + value: 0.000353 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 3.53e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.77e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 95.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2204 2009 09:43:42 +0200To ethyl 7-bromobenzofuran-2-carboxylate (0.095 g, 0.35 mmol) and 1-(5-(2-(piperazin-1-yl)ethyl)indolin-1-yl)ethanone (0.101 g, 0.37 mmol) (from EN02198-74) in dry degassed dioxane (1.5 mL) were added Cesium carbonate (0.150 g, 0.46 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-triisopropylbiphenyl (0.017 g, 0.04 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (0.016 g, 0.02 mmol) under argon and the reaction heated at 95C for 5.5h. After cooling to rt, water and DCM were added and the layers separated. The aq phase was extracted with DCM (3x). The combined org phases were washed with water, dried (MgSO4), filtered and evaporated. The crude was purified by flash (SiO2; DCMMeOH 955) to give 0.105 g of the product as a yellow solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)N3CCN(CC3)CCC4=CC5=C(C=C4)N(CC5)C(=O)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 64.44 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/21/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "132" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0111 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.03 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CN(CCN1)CCC2=CC=CC=N2" + } + amount { + moles { + value: 0.0094 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)Br" + } + amount { + moles { + value: 0.00855 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.000855 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000427 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 95.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2705 2009 13:35:19 +0200To dry degassed dioxane (30 mL) were added ethyl 7-bromobenzofuran-2-carboxylate (2.30 g, 8.55 mmol) and 1-(2-(pyridin-2-yl)ethyl)piperazine (1.798 g, 9.40 mmol), Cesium carbonate (3.62 g, 11.11 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-triisopropylbiphenyl (0.407 g, 0.85 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (0.391 g, 0.43 mmol) under argon and the reaction heated at 95C for 4h. The reaction mixture was filtered and solvent evaporated. The material was purified by flash (SiO2; DCMMeOH 973) to give 0.620 g, but it was not pure enough (EN02198-94-001). A second flash was performed (SiO2; DCMMeOH 973) to give 0.540 g of the product as a yellow solid (EN02198-94-002). 100% pure according to HPLC.The reaction mixture was combined with the reaction mixture in EN02745-56 and hydrolysed. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)N3CCN(CC3)CCC4=CC=CC=N4" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 35.77 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/27/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "133" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0111 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.03 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CN(CCN1)CCC2=CC=CC=N2" + } + amount { + moles { + value: 0.00818 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)Br" + } + amount { + moles { + value: 0.00743 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.00104 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.00052 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 95.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "The reaction mixture of ethyl 7-bromobenzofuran-2-carboxylate (2.0 g, 7.43 mmol), 1-(2-(pyridin-2-yl)ethyl)piperazine (1.564 g, 8.18 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.476 g, 0.52 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (0.496 g, 1.04 mmol) and Cesium carbonate (3.63 g, 11.15 mmol) in dioxane (30 mL) (degassed with argon for 10 min) was heated at 95 C under argon for 5 h. After cooling, the reaction mixture was filtered and concentrated. The product was purified twice by isco, the first using DCM:MeOH (0-5%) and the second time using DCM:MeOH (0-3%). " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)N3CCN(CC3)CCC4=CC=CC=N4" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 18.97 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/27/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "134" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000483 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CN(CCN1)CCC2=CC=CC=N2" + } + amount { + moles { + value: 0.00039 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)Br" + } + amount { + moles { + value: 0.000372 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 3.72e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.86e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 95.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "0701 2009 12:44:11 +0100To ethyl 7-bromobenzofuran-2-carboxylate (0.100 g, 0.37 mmol) and 1-(2-(pyridin-2-yl)ethyl)piperazine (0.075 g, 0.39 mmol) in dry degassed dioxane (1.5 mL) were added Cesium carbonate (0.157 g, 0.48 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-triisopropylbiphenyl (0.018 g, 0.04 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (0.017 g, 0.02 mmol) under argon and the reaction heated at 95C on. All starting material consumed.nbsp;Water and DCM were added and the layers separated. The aq phase was extracted with DCM (3x). The combined org phases were washed with water, dried (MgSO4), filtered and evaporated. The crude was purified by flash (SiO2; DCMMeOH 955) to give 0.0661 g of the product as a pale yellow semisolid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)N3CCN(CC3)CCC4=CC=CC=N4" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 46.88 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/07/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "135" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00435 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.013 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CN(CCN1)CCC2=CC=CC=N2" + } + amount { + moles { + value: 0.00351 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)Br" + } + amount { + moles { + value: 0.00334 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.000334 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000167 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 95.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "1201 2009 15:21:58 +0100To ethyl 7-bromobenzofuran-2-carboxylate (0.900 g, 3.34 mmol) and 1-(2-(pyridin-2-yl)ethyl)piperazine (0.672 g, 3.51 mmol) in dry degassed dioxane (13 mL) were added Cesium carbonate (1.417 g, 4.35 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-triisopropylbiphenyl (0.159 g, 0.33 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (0.153 g, 0.17 mmol) under argon and the reaction heated at 95C on. All starting material consumed.nbsp;Water and DCM were added and the layers separated. The aq phase was extracted with DCM (3x). The combined org phases were washed with water, dried (MgSO4), filtered and evaporated. The crude was purified by flash chrom. (SiO2; DCMMeOH 955) to give EN02198-25-001:47.3 mg (fraction 12 from the flash) of the product as a pale yellow solid. This batch was mitted to test.EN02198-25-002:0.460 g (fractions 11 and 13-18 from the flash) of the product as a pale brown solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)N3CCN(CC3)CCC4=CC=CC=N4" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 39.97 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/12/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "136" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00725 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CN(CCN1)CCC2=CC=CC=N2" + } + amount { + moles { + value: 0.00585 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)Br" + } + amount { + moles { + value: 0.00557 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.000557 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000279 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 95.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "1702 2009 12:47:13 +0100To ethyl 7-bromobenzofuran-2-carboxylate (1.50 g, 5.57 mmol) and 1-(2-(pyridin-2-yl)ethyl)piperazine (1.120 g, 5.85 mmol) in dry degassed dioxane (20 mL) were added Cesium carbonate (2.361 g, 7.25 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-triisopropylbiphenyl (0.266 g, 0.56 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (0.255 g, 0.28 mmol) under argon and the reaction heated at 95C on. The reaction was allowed to reach rt. Starting material left1802 2009 14:51:20 +0100Additional2-Dicyclohexylphosphino-2\',4\',6\'-triisopropylbiphenyl (0.266 g, 0.56 mmol) andnbsp;Tris(dibenzylideneacetone)dipalladium(0) (0.255 g, 0.28 mmol) were added and the reaction stirred at 95C on. The reaction mixture was pooled with the reaction mixture in EN02198-44.nbsp;Water and DCM were added and the layers separated. The aq phase was extracted with DCM (3x). The combined org phases were washed with water, dried (Na2SO4), filtered and evaporated. The crude was puriflash chrom. (SiO2; DCMMeOH 955) to give 1.48 g (35% calculated from EN02198-44+45) of the product as a pale brown solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)N3CCN(CC3)CCC4=CC=CC=N4" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 69.5 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/17/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "138" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0133 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.03 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.0105 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)COC2=CN=C(C=C2)Cl" + } + amount { + moles { + value: 0.00953 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 9.53e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" + } + amount { + moles { + value: 9.53e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "BIS(DIBENZYLIDENEACETONE)PALLADIUM (0.055 g, 0.10 mmol) was added to tert-butyl piperazine-1-carboxylate (1.952 g, 10.48 mmol), 5-(benzyloxy)-2-chloropyridine (2.093 g, 9.53 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.059 g, 0.10 mmol) and sodium 2-methylpropan-2-olate (1.282 g, 13.34 mmol) in toluene (30 mL) at 20Cnbsp;under nitrogen. The resulting solution was stirred at 80 C for 16 hours then cooled to room temperature. The reaction mixture was filtered through celite, filtrate partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase was dried (Na2SO4), filtered and evaporated to give a brown gum. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(5-(benzyloxy)pyridin-2-yl)piperazine-1-carboxylate (2.420 g, 68.7 %) as a yellow solid. n" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=NC=C(C=C2)OCC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 68.75 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/23/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "139" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00628 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0175 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCC(CC1)CN" + } + amount { + moles { + value: 0.00236 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)OC(F)(F)F)C2=CN=C3N2N=C(C=C3)Cl.Cl" + } + amount { + moles { + value: 0.00157 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C1=CC=CC=C1C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 0.000471 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000157 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 100 mL round bottom flask was charged with a magnetic stir bar, toluene (17.45 mL), 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine hydrochloride (550 mg, 1.57 mmol) (EN02141-06), Pd2dba3 (144 mg, 0.16 mmol),nbsp;2\'-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (185 mg, 0.47 mmol),sodium tert-butoxide (604 mg, 6.28 mmol), and (1-methylpiperidin-4-yl)methanamine (302 mg, 2.36 mmol).nbsp;The mixture was degassed with argon, the vessel fitted with a reflux condenser, and then placed in an oil bath heated to 110 C with stirring for 16 h.nbsp;The mixture was cooled to rt, pre-absorbed onto silca gel (~ 10 g) and purified on silica gel (80 g) using MeOHDCM (1:3) as eluent to afford the title compound, .N-((1-methylpiperidin-4-yl)methyl)-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-amine (391 mg, 55.6 %) as an off white solid.nbsp;110 mg of this pure free base was dissolved in anhydrous MeOH and 32 uL of conc. H2SO4 were added.nbsp;The mixture was stirred for 10 min rt before being conc. in vacuo.nbsp;The crude solids were triturated with diethyl ether and collected via vacuum filtration to afford the title compound as its bis(bisulfate)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CCC(CC1)CNC2=NN3C(=NC=C3C4=CC(=CC=C4)OC(F)(F)F)C=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 55.56 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/12/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "141" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0295 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.1 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.00983 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=C(C2=CC(=C(C=C2N=C1)OCCOC)Br)NC3=C(C=C(C=C3)C)F" + } + amount { + moles { + value: 0.00983 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00314 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000786 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Reaction reference EN00057-06, EN02095-49, 67, 68, 74, 78, 90In a 50 mL round-bottomed flask was ethyl 6-bromo-4-(2-fluoro-4-methylphenylamino)-7-(2-methoxyethoxy)quinoline-3-carboxylate (4.6911 g, 9.83 mmol), Morpholine (0.857 mL, 9.83 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.720 g, 0.79 mmol), and rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (1.958 g, 3.14 mmol) in Dioxane (100 mL) to give a orange suspension.nbsp;The reaction mixture was heated and stirred at 80C (start 4pm).nbsp;After stirringheating overngiht, reaction is about 30% complete.nbsp;Add rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (1.958 g, 3.14 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.720 g, 0.79 mmol).nbsp;Continue heatingstirring.nbsp;After heating and stirring for another 24hr, reaction is about 85% complete with some starting material.nbsp;Add rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (1.958 g, 3.14 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.720 g, 0.79 mmol)sp;Continue heating and stirring.nbsp;Reaction complete after going another 24 hr.Cool reaction, and concentrate in vacuo (CIV).nbsp;Dissolve in DCM, and purify on ISCO; EtOAcHexanes, 0-100%, some product elutes at end of run.nbsp;Continue eluting column with MeOHDCM, 0-5%; more product elutes at 5%.nbsp;Combine all fractions containing product; 3.5475g isolated of an amber solid.nbsp;LC-MS and NMR indicate that it is a mixture of methyl and ethyl ester products." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=C(C2=CC(=C(C=C2N=C1)OCCOC)N3CCOCC3)NC4=C(C=C(C=C4)C)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 74.65 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/10/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "144" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[K+]" + } + amount { + moles { + value: 0.00033 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1CCOC1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@@H]1CN(CCN1)C(=O)OC(C)(C)C" + } + amount { + moles { + value: 0.0003 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)COC2=CC=C(C=C2)Br" + } + amount { + moles { + value: 0.0006 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" + } + amount { + moles { + value: 0.00033 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C.[Pd]" + } + amount { + moles { + value: 3e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of 1-(benzyloxy)-4-bromobenzene (158 mg, 0.60 mmol), (R)-tert-butyl 3-methylpiperazine-1-carboxylate (60.1 mg, 0.3 mmol), bis(tri-t-butylphosphine)palladium(0) (15.33 mg, 0.03 mmol) and potassium tert-butoxide (37.0 mg, 0.33 mmol) in THF (2 mL) was flushed with nitrogen and sealed into a microwave tube. The reaction was heated to 150 C for 20 minutes in the microwave reactor and cooled to RT.nbsp;The reaction mixture was filtered and the filtrate evaporated to dryness.nbsp;The residue was dissolved in MeOH (5mL) and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 0.35M NH3MeOH and pure fractions were evaporated to dryness.nbsp;The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-methylpiperazine-1-carboxylate (41.0 mg, 35.7 %) as a colourless oil that solidified on standing.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@@H]1CN(CCN1C2=CC=C(C=C2)OCC3=CC=CC=C3)C(=O)OC(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 35.73 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/23/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "145" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00045 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@@H]1CN(CCN1)C(=O)OC(C)(C)C" + } + amount { + moles { + value: 0.0003 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)COC2=CC=C(C=C2)Br" + } + amount { + moles { + value: 0.00036 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 2.4e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of (R)-tert-butyl 3-methylpiperazine-1-carboxylate (0.060 g, 0.3 mmol), 1-(benzyloxy)-4-bromobenzene (0.095 g, 0.36 mmol), palladium(II) acetate (6.74 mg, 0.03 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.015 g, 0.02 mmol) and sodium t-butoxide (0.043 g, 0.45 mmol) in toluene (2 mL) was flushed with nitrogen and sealed into a microwave tube. The reaction was heated to 150 C for 10 minutes in the microwave reactor and cooled to RT. Analysis by LCMS.nbsp;Only a small amount of the product could be detected (MH+ = 383, 5%).The reaction was not progressed further." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@@H]1CN(CCN1C2=CC=C(C=C2)OCC3=CC=CC=C3)C(=O)OC(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/23/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "147" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[K+]" + } + amount { + moles { + value: 0.00165 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1CCOC1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@@H]1CN(CCN1)C(=O)OC(C)(C)C" + } + amount { + moles { + value: 0.0015 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)COC2=CC=C(C=C2)Br" + } + amount { + moles { + value: 0.003 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" + } + amount { + moles { + value: 0.00015 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C.[Pd]" + } + amount { + moles { + value: 0.00015 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 75.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of 1-(benzyloxy)-4-bromobenzene (789 mg, 3.00 mmol), (R)-tert-butyl 3-methylpiperazine-1-carboxylate (300 mg, 1.5 mmol), bis(tri-t-butylphosphine)palladium(0) (77 mg, 0.15 mmol) and potassium tert-butoxide (185 mg, 1.65 mmol) in THF (10 mL) was flushed with nitrogen and heated to 75 C overnight.nbsp;A further 0.1eq of bis(tri-t-butylphosphine)palladium(0) (77 mg, 0.15 mmol) was added and the reaction was heated for a further 2.5 hours.nbsp;The solvent was evaporated and the residue dissolved in MeOH (10mL) and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 0.35M NH3MeOH and purified further by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-methylpiperazine-1-carboxylate (181 mg, 31.5 %) as an orange oil. nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@@H]1CN(CCN1C2=CC=C(C=C2)OCC3=CC=CC=C3)C(=O)OC(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 31.55 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/25/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "148" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00105 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@@H]1CN(CCN1)C(=O)OC(C)(C)C" + } + amount { + moles { + value: 0.00036 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)COC2=CC=C(C=C2)Br" + } + amount { + moles { + value: 0.0003 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 3e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of (R)-tert-butyl 3-methylpiperazine-1-carboxylate (0.072 g, 0.36 mmol), 1-(benzyloxy)-4-bromobenzene (0.079 g, 0.3 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.035 g, 0.06 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.027 g, 0.03 mmol) and sodium 2-methylpropan-2-olate (0.101 g, 1.05 mmol) in toluene (2 mL) was flushed with nitrogen and sealed into a microwave tube. The reaction was heated to 150 C for 10 minutes in the microwave reactor and cooled to RT. Only a small amount of the desired product was visible by LCMS. The reaction was not progressed further.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@@H]1CN(CCN1C2=CC=C(C=C2)OCC3=CC=CC=C3)C(=O)OC(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/20/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "149" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000595 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CCNCC1" + } + amount { + moles { + value: 0.000595 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C=C1Br)F)C#N" + } + amount { + moles { + value: 0.000595 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 2.97e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.97e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 160.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "4-bromo-2-fluorobenzonitrile (119 mg, 0.59 mmol), Piperidine (0.059 mL, 0.59 mmol), Palladium(II) acetate (6.68 mg, 0.03 mmol), dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (14.18 mg, 0.03 mmol) and sodium tert-butoxide (57.2 mg, 0.59 mmol) were suspended in toluene (4 mL) and tBuOH (0.800 mL) andnbsp;heated to 160C for 10 minutes in the microwave. LCMS indicated incomplete reaction, thus, the reaction mixture was heated to 160C for a further 20 minutes.nbsp;Still incomplete reaction however, the reaction mixture was diluted with EtOAc (10 mL), and washed sequentially with water (10 mL), and saturated brine (10 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane. A yellow oil (60mg) was isolated but NMR revealed this not be the desired product.No further work d" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CCN(CC1)C2=CC(=C(C=C2)C#N)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 49.37 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/23/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "151" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0171 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.04 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=CC=C1C2=CC3=CN=C(N=C3C(=C2)Cl)N" + } + amount { + moles { + value: 0.012 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C[C@H](C1=CC=C(C=C1)Br)NC(=O)OC(C)(C)C" + } + amount { + moles { + value: 0.0147 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000268 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000125 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 250 mL roundbottom flask was charged with 8-chloro-6-(pyridin-4-yl)quinazolin-2-amine (EN01547-76-1; 3.09 g, 12.04 mmol), (R)-tert-butyl 1-(4-bromophenyl)ethylcarbamate (EN01547-74-1; 4.42 g, 14.72 mmol), Pd2(dba)3 (114.4 mg, 2.1 mol % Pd), XantPhos (155.0 mg, 2.2 mol %), and Cs2CO3 (5.57 g, 17.10 mmol).nbsp;The flask was evacuated and backfilled with N2 (3x), and then anhydrous dioxane (40 mL) was added.nbsp;The mixture was allowed to stir at room temperature for ~5 minutes and was then heated under N2 in a 100 C oil bath.After heating overnight, LC-MS showed complete conversion of the starting material to the desired product (trace N-phenylated product).nbsp;A significant side product appeared to be present, derived from the starting aminoquinazoline that had undergone two Suzuki couplings in the previous step (see EN01547-76; MW=518.6).nbsp;The reaction was allowed to cool and was partitioned between EtOAc and H2O.nbsp;The aqueous layer was extracted with EtOAc, and the combined organics were concentrated under reduced pressure.nbsp;The crude material was purified by silica gel chromatography (Rf in EtOAc = 0.44) to give a yellow-orange solid.2.92 g (51%) of solid was collected.nbsp;A trace of EtOAc remained by NMR analysis despite being kept under high vacuum over the weekend." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@H](C1=CC=C(C=C1)NC2=NC=C3C=C(C=C(C3=N2)Cl)C4=CC=NC=C4)NC(=O)OC(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 50.96 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/04/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "152" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000563 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.136 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=CC(=N1)N2C=NC=N2)N" + } + amount { + moles { + value: 0.0282 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC(=O)N1CCC(CC1)OC2=C(C(=NC=N2)Cl)OC" + } + amount { + moles { + value: 0.0282 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)CN1CCN2CCN(P1N(CC2)CC(C)C)CC(C)C" + } + amount { + moles { + value: 0.000563 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000282 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Sodium tert-butoxide (8.28 mL, 67.61 mmol) was added portionwise to a mixture of 2-methyl-6-(1H-1,2,4-triazol-1-yl)pyridin-3-amine (4.94 g, 28.17 mmol) isopropyl 4-(6-chloro-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate (9.29 g, 28.17 mmol) and in dioxane (136 mL) at 18C over a period of 1 minute under nitrogen. The mixture was degassed by jecting to vacuum then nitrogen atmosphere (six times). Palladium(II) acetate (0.063 g, 0.28 mmol) and 2,8,9-Triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo{3.3.3}undecane (0.200 mL, 0.56 mmol) was added and the mixture degassed again. The resulting suspension was stirred at 90 C for 3 hours.nbsp;Palladium(II) acetate (0.126 g, 0.56 mmol)nbsp;and 2,8,9-Triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo{3.3.3}undecane (0.400 mL, 1.12 mmol) was added and the reaction stirred at 90 C for 5 hours. The reaction mixture was diluted with water (100 mL) then extracted with EtOAc (300 mL), and washed with saturated brine (100 mL). The aqueous was extEtOAc ( 100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography (330g column), elution gradient 0 to 10% EtOH in DCM (rising quickly to 5% then more slowly to 10%). Pure fractions were evaporated to dryness to afford impure isopropyl 4-(5-methoxy-6-(2-methyl-6-(1H-1,2,4-triazol-1-yl)pyridin-3-ylamino)pyrimidin-4-yloxy)piperidine-1-carboxylate, EN02029-80-P, as a yellow solid. The chromatography was repeated to give a slightly purer sample, EN02029-80-P2. This was triturated with Et2O (40 mL) to give a mobile solid which was filtered off and washed with Et2O (2 x 10 mL) then hexane (2 x 10 mL) to give a pale yellow solid, EN02029-80-solid 1. Analysis of this compound showed good purity so this mobile pale yellow solid was handed in as EN02029-80-01." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=CC(=N1)N2C=NC=N2)NC3=C(C(=NC=N3)OC4CCN(CC4)C(=O)OC(C)C)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 48.49 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/25/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "155" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 4e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N1CCN(CC1)C2=C(C=C(C(=C2)OC)N)OC" + } + amount { + moles { + value: 0.0005 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC2=NC=C(N2C=C1)C3=NC(=NC=C3Cl)Cl" + } + amount { + moles { + value: 0.0005 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 4e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "i3-(2,5-dichloropyrimidin-4-yl)imidazo[1,2-a]pyridine (132.5 mg, 0.50 mmol)iinbsp;ii1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethanone (140 mg, 0.50 mmol)ii ii(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (23.14 mg, 0.04 mmol)iinbsp;iicesium carbonate (244 mg, 0.75 mmol)ii iidiacetoxypalladium (4.49 mg, 0.02 mmol)ii were suspended in ii1,4-dioxane (4 ml)ii,degased with argon . The mixture was heated to ii80 Ciinbsp;for 2 hrs *i" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)N1CCN(CC1)C2=C(C=C(C(=C2)OC)NC3=NC=C(C(=N3)C4=CN=C5N4C=CC=C5)Cl)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/04/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "156" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 1.52e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC=CC=C1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CCNC1" + } + amount { + moles { + value: 0.000304 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)NC3=NC=C(C(=N3)C4=CN=C5N4C=CC(=C5)Cl)Cl)OC" + } + amount { + moles { + value: 0.000203 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 1.52e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 5.07e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 105.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "ipyrrolidine (0.025 mL, 0.30 mmol)ii was added to a suspension of ii1-(4-(4-(5-chloro-4-(7-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-ylamino)-3-methoxyphenyl)piperazin-1-yl)ethanone (104 mg, 0.20 mmol)iinbsp;in iidioxane (3.5 mL)ii, followed by iisodium 2-methylpropan-2-olate (58.5 mg, 0.61 mmol)ii, the mixturenbsp;was degassed by bubbling N2 through , thennbsp;a solutionnbsp;of pre-activated ( 50C 15 min ) solution in dioxannenbsp;(1 ml) of iidicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (7.26 mg, 0.02 mmol)ii ( Xphos) and iiTRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (4.65 mg, 5.07 mol)ii was added . iiThe brown-orange suspension was stirred atnbsp;ii105 Cii 1 hr ( trace of reaction ) iianisole (2 mL)ii w then overnight under nitrogen atmosphere : few of reaction observednbsp;from 1 hr to 16 hrs heatingii andnbsp;TBAC ( 25 mg ) were added and the heating was continued overnight no reactionnbsp;iinbsp;i" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)NC3=NC=C(C(=N3)C4=CN=C5N4C=CC(=C5)N6CCCC6)Cl)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/24/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "157" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000609 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0035 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CCNC1" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)NC3=NC=C(C(=N3)C4=CN=C5N4C=CC(=C5)Cl)Cl)OC" + } + amount { + moles { + value: 0.000203 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 6.09e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 3.04e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 95.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "ipyrrolidine (0.019 mL, 0.22 mmol)ii was added to a suspension of ii1-(4-(4-(5-chloro-4-(7-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-ylamino)-3-methoxyphenyl)piperazin-1-yl)ethanone (104 mg, 0.20 mmol)iinbsp;in iidioxane (3.5 mL)ii, followed by iisodium 2-methylpropan-2-olate (58.5 mg, 0.61 mmol)ii, the mixturenbsp;was degassed by bubbling N2 through , then ii2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (3.79 mg, 6.09 mol)ii and iiTRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (2.79 mg, 3.04 mol)ii were added . iiThe orange suspension was stirred atnbsp;ii95 Cii for 2 hours under nitrogen atmosphere : no reaction observediiThe same quantities of Binap and Pd2dba3 were added : 2 hours later ( no reaction ),nbsp;iipyrro5 mL, 1.01 mmol)i iwas added and the yellow orange mixture was heated at 100C overnight....no reaction iiWater ( 1ml) was added , solution, and the heating was continued :nbsp;mass pick 548, 549 appeared ( trce ? under SM pick ,Uplc, lcms2 acid conditions , trace of product) iiAn activated batch of Xantphos Pd2dba3 ( 1.51 Pd ) was prepared and added and the heating continued no evolution iiNot progressednbsp;isolationrecovery lateriinbsp;iinbsp;i" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)NC3=NC=C(C(=N3)C4=CN=C5N4C=CC(=C5)N6CCCC6)Cl)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/16/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "158" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0803 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.16 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=CC(=N1)S(=O)(=O)C)N" + } + amount { + moles { + value: 0.0318 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(N=CN=C1Cl)OC2CCN(CC2)C(=O)OC(C)C" + } + amount { + moles { + value: 0.0335 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)CN1CCN2CCN(P1N(CC2)CC(C)C)CC(C)C" + } + amount { + moles { + value: 0.000669 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000335 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Sodium tert-butoxide (9.83 mL, 80.31 mmol) was added portionwise to isopropyl 4-(6-chloro-5-methylpyrimidin-4-yloxy)piperidine-1-carboxylate (10.50 g, 33.46 mmol) and 2-methyl-6-(methylsulfonyl)pyridin-3-amine (5.92 g, 31.79 mmol) in dioxane (160 mL) at 18C over a period of 1 minute under nitrogen. The reaction was degassed with vacuum nitrogen (6 times) and 2,8,9-Triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo{3.3.3}undecane (0.238 mL, 0.67 mmol) and Palladium(II) acetate (0.075 g, 0.33 mmol) was added and the suspension was stirred at 90 C for a further 2 hours.nbsp;More 2,8,9-Triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo{3.3.3}undecane (0.238 mL, 0.67 mmol) and Palladium(II) acetate (0.075 g, 0.33 mmol) was added and the suspension was stirred at 90 C for a further another 2 hours before being allowed to cool and stirred at room temperature overnight.nbsp;The reaction was worked up with water (50 mL) and diluted with EtOAc (400 mL), and washed sequentially with water (100 mL) and sat (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography (330g column), elution gradient 0 to 50% EtOAc in DCM (rising quickly to 20% then more slowly to 50%). The impure fractions were collected and combined and purified again in exactly the same way. Pure fractions were evaporated to dryness to afford isopropyl 4-(5-methyl-6-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)pyrimidin-4-yloxy)piperidine-1-carboxylate, EN02029-72-solid-1, as a yellow solid. This solid was recrystallised from MeOH (~ 50 mL) and the resultant solid filtered off and washed with cold MeOH (2 x 5 mL), Et2O (2 x 5 mL) then isohexane (2 x 5 mL). The solid, EN02029-72-solid-2 was combined with the product from EN02029-67-01 and the whole sample was named EN02029-72-01 (8.39 g) and mitted to the collection." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(N=CN=C1OC2CCN(CC2)C(=O)OC(C)C)NC3=C(N=C(C=C3)S(=O)(=O)C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 54.09 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/12/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "159" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00185 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.00462 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=NC=C1Br)N" + } + amount { + moles { + value: 0.000925 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000111 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 9.25e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (20.76 mg, 0.09 mmol) was added to 5-bromopyridin-3-amine (160 mg, 0.92 mmol), morpholine (0.403 mL, 4.62 mmol) (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (64.2 mg, 0.11 mmol) and cesium carbonate (603 mg, 1.85 mmol) in dioxane (5 mL).nbsp;The resulting solution was stirred at 150 C in the microwave for 30 minutes. The major product was the dimer. Rection abandoned.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1COCCN1C2=CN=CC(=C2)N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/24/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "160" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00185 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.0462 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=NC=C1Br)N" + } + amount { + moles { + value: 0.000925 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000111 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 9.25e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (20.76 mg, 0.09 mmol) was added to 5-bromopyridin-3-amine (160 mg, 0.92 mmol), morpholine (4028 l, 46.24 mmol) (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (64.2 mg, 0.11 mmol) and cesium carbonate (603 mg, 1.85 mmol). The resulting suspension was stirred at 150 C for 30 minutes in a microwave. Reaction very messy but some product is visible.nbsp;Reaction abandoned.n" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1COCCN1C2=CN=CC(=C2)N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/28/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "162" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00107 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.008 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC(=NN1C(=O)OC(C)(C)C)N" + } + amount { + moles { + value: 0.000642 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC(C1=C(C=C(C=N1)F)F)NC2=C(C(=NC(=N2)Cl)N3CCOCC3)F" + } + amount { + moles { + value: 0.000535 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 4.82e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 3.21e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (27.9 mg, 0.05 mmol), 2-chloro-N-(1-(3,5-difluoropyridin-2-yl)ethyl)-5-fluoro-6-morpholinopyrimidin-4-amine (200 mg, 0.54 mmol), tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate (127 mg, 0.64 mmol) and cesium carbonate (349 mg, 1.07 mmol) were added to dioxane (8 mL).nbsp;The mixture was purged with nitrogen for 15 minutes.nbsp;Pd2(dba)3 (29.4 mg, 0.03 mmol) was added and the mixture heated at 110 C for 3h.nbsp;No sign of any reaction." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CC(=NN1)NC2=NC(=C(C(=N2)N3CCOCC3)F)NC(C)C4=C(C=C(C=N4)F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/23/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "163" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.019 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=C(C=C1)C" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCCN1" + } + amount { + moles { + value: 0.076 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CN=C1)Br" + } + amount { + moles { + value: 0.0127 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" + } + amount { + moles { + value: 0.000633 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000253 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 130.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 100 ml RBF, 3-bromopyridine (1.220 mL, 12.66 mmol) was taken in xylenes (20 mL). To this was added tris(dibenzylideneacetone)dipalladium(0) (0.232 g, 0.25 mmol), tri-t-butylphosphine (10%wt in Hexane) (1.281 g, 0.63 mmol) and sodium tert-butoxide (1.825 g, 18.99 mmol). Then piperazine (6.54 g, 75.95 mmol) was added to RM and the RM was then heated at 130 C for 5 hrs. The reaction was monitored by LCMS. It did not show formation of product. The RM was discarded. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CN(CCN1)C2=CN=CC=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/06/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "164" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00228 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.00638 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCC(CC1)CN" + } + amount { + moles { + value: 0.000857 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)OC(F)(F)F)C2=CN=C3N2N=C(C=C3)Cl.Cl" + } + amount { + moles { + value: 0.000571 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C1=CC=CC=C1C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 0.000171 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 5.71e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 50 mL round bottom flask was charged with a magnetic stir bar, toluene (6.376 mL), 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine hydrochloride (200 mg, 0.57 mmol), (1-methylpiperidin-4-yl)methanamine (110 mg, 0.86 mmol), 2\'-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (67.4 mg, 0.17 mmol), Pd2dba3 (52.3 mg, 0.06 mmol), and sodium tert-butoxide (220 mg, 2.28 mmol).nbsp;The mixture was degassed with argon, the vessel fitted with a reflux condenser, and then placed in an oil bath heated to 110 C with stirring for 16 h.nbsp;The mixture was cooled to rt, pre-absorbed onto silca gel (~ 20 g) and purified on silica gel (80 g) using MeOHDCM (1:3) as eluent to afford the title compound ~ 90 % pure.nbsp;This material was then dissolved in DMSO and purified via reverse phase HPLC waterMECN (5-gt;55%, 12 min) as eluent.nbsp;The pure fractions were collected and converted to the corresponding HCl salt to afford N-((1-methylpiperidin-4-yl)methyl)-3-(3-(trifluoromethoxy)phenyl)imi[1,2-b]pyridazin-6-amine (125 mg, 49.5 %) hydrochloride as a white solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CCC(CC1)CNC2=NN3C(=NC=C3C4=CC(=CC=C4)OC(F)(F)F)C=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 49.52 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/08/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "166" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.014 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.03 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.012 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)COC2=NC(=CC=C2)Br" + } + amount { + moles { + value: 0.01 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00015 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.0001 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Reagents split into 2 microwave tubes:-2-(benzyloxy)-6-bromopyridine (2.641 g, 10.00 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.092 g, 0.10 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.093 g, 0.15 mmol) ,morpholine (1.045 g, 12.00 mmol) and sodium t-butoxide (1.345 g, 14.00 mmol) were suspended in toluene (30 mL). Degassed with N2 for 5 mins and sealed into a microwave tube. The reaction was heated to 120 C for 10 minutes in the microwave reactor and cooled to RT. buWork-up*ubThe mixture was diluted with EtOAc and filtered through a short celite pad. The solution was then concentrated to dryness to give an orange viscous liquid (~4.7g).The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 4-(6-(benzyloxy)pyridin-2-yl)morpholine (2.350 g, 87 %) as a yellow oil. nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1COCCN1C2=NC(=CC=C2)OCC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 86.94 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/18/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "168" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000466 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C(=CC=N1)N" + } + amount { + moles { + value: 0.000466 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)Cl" + } + amount { + moles { + value: 0.00031 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 6.21e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 3.1e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "8-(2,5-dichloropyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (100 mg, 0.31 mmol), 1-methyl-1H-pyrazol-5-amine (60.3 mg, 0.62 mmol), sodium 2-methylpropan-2-olate (44.7 mg, 0.47 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (38.7 mg, 0.06 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (28.4 mg, 0.03 mmol) were suspended in dioxane (2 mL) and sealed into a microwave tube. The reaction was degased, purged with nitrogen and heated to 150 C over a period of 30 minutes in the microwave reactor. Reaction was filtered, washed with CH2Cl2 and concentrated to dryness. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 1% acetic acid) and acetonitrile as eluent. The fractions containing product were combined and basified with saturated aqueous solution ofnbsp;NaHCO3. Aqueous layer was extracted with CH2Cl2 (2x15 mL). Organic layer was washedh brine, dried over MgSO4 and concentrated to dryness to afford 8-(5-chloro-2-(1-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (57.0 mg, 48.0 %) as a yellow crystalline solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)NC4=CC=NN4C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 47.97 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/16/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "169" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000466 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C(=CC=N1)N" + } + amount { + moles { + value: 0.000466 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)Cl" + } + amount { + moles { + value: 0.00031 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 6.21e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 3.1e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "8-(2,5-dichloropyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (100 mg, 0.31 mmol), 1-methyl-1H-pyrazol-5-amine (60.3 mg, 0.62 mmol), sodium 2-methylpropan-2-olate (44.7 mg, 0.47 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (35.9 mg, 0.06 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (28.4 mg, 0.03 mmol) were suspended in dioxane (2 mL) and sealed into a microwave tube. The reaction was degased, purged with nitrogen and heated to 150 C over a period of 30 minutes in the microwave reactor. Reaction was filtered, washed with CH2Cl2 and concentrated to dryness. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 1% acetic acid) and acetonitrile as eluent. The fractions containing product were combined and basified with saturated aqueous solution ofnbsp;NaHCO3. Aqueous layer was extracted with CH2Cl2 (2x15 mL). Organic lawas washed with brine, dried over MgSO4 and concentrated to dryness to afford 8-(5-chloro-2-(1-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (52.0 mg, 43.8 %) as a pale purple crystalline solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)NC4=CC=NN4C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 43.76 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/16/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "170" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000466 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C(=CC=N1)N" + } + amount { + moles { + value: 0.000466 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)Cl" + } + amount { + moles { + value: 0.00031 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 6.21e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 3.1e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "8-(2,5-dichloropyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (100 mg, 0.31 mmol), 1-methyl-1H-pyrazol-5-amine (60.3 mg, 0.62 mmol), sodium 2-methylpropan-2-olate (44.7 mg, 0.47 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (38.7 mg, 0.06 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (28.4 mg, 0.03 mmol) were suspended in dioxane (2 mL) and sealed into a tube. The reaction was degased, purged with nitrogen and heated to 100 C for 1 hour. Reaction was filtered, washed with CH2Cl2 and concentrated to dryness. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford 8-(5-chloro-2-(1-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (32.0 mg, 26.9 %) as a white solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)NC4=CC=NN4C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 26.93 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/07/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "171" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000466 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C(=CC=N1)N" + } + amount { + moles { + value: 0.000466 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)Cl" + } + amount { + moles { + value: 0.00031 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 6.21e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 3.1e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 140.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "8-(2,5-dichloropyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (100 mg, 0.31 mmol), 1-methyl-1H-pyrazol-5-amine (60.3 mg, 0.62 mmol), sodium 2-methylpropan-2-olate (44.7 mg, 0.47 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (38.7 mg, 0.06 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (28.4 mg, 0.03 mmol) were suspended in dioxane (2 mL) and sealed into a microwave tube. The reaction was degased, purged with nitrogen and heated to 140 C for 5 minutes in the microwave reactor. Reaction was filtered, washed with CH2Cl2 and concentrated to dryness. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford 8-(5-chloro-2-(1-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (36.0 mg, 30.3 %) as an off-whiolid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)NC4=CC=NN4C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 30.3 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/08/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "172" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000372 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C(=CC=N1)N" + } + amount { + moles { + value: 0.000621 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)Cl" + } + amount { + moles { + value: 0.00031 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 4.97e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.48e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "8-(2,5-dichloropyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (100 mg, 0.31 mmol), 1-methyl-1H-pyrazol-5-amine (60.3 mg, 0.62 mmol), cesium carbonate (121 mg, 0.37 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (28.7 mg, 0.05 mmol) and diacetoxypalladium (5.57 mg, 0.02 mmol) were suspended in dioxane (2 mL) and sealed into a tube. The reaction was degased, purged with nitrogen and heated to 100 C for 12 hours. Reaction was filtered, washed with CH2Cl2 and concentrated to dryness. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford 8-(5-chloro-2-(1-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (83 mg, 69.8 %) as a grey solid.Sample was combined with EN01622-31,32,33,35,3,38,39amp;40. The crude product was purified by flash chromatography on silica gel eluting with 0 to 4% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford 8-(5-chloro-2-(1-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (218 mg, EN01622-42-02) as a pale pink foam." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)NC4=CC=NN4C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 69.85 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/09/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "173" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00712 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.018 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC" + } + amount { + moles { + value: 0.00356 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1C2=CC(=O)N3C=CC=C(C3=N2)C4=CC=CC5=C4SC6=C5C=C(C=C6)OS(=O)(=O)C(F)(F)F" + } + amount { + moles { + value: 0.00178 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 8.9e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 4.45e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "tert-butyl methylcarbamate (467 mg, 3.56 mmol) dissolved in dioxane (5ml) was added in one portion to 6-(2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)dibenzo[b,d]thiophen-2-yl trifluoromethanesulfonate (1000 mg, 1.78 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (40.8 mg, 0.04 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (51.5 mg, 0.09 mmol) and cesium carbonate (2321 mg, 7.12 mmol) in dioxane (18mL) at 110 C. The reaction flask was evacuated and blanketed with nitrogen 4X. The resulting suspension was stirred at 110 C for 3i ihoursi.nbsp;iThe crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOHDCM (5050) and pure fractions were evaporated to dryness to afford tert-butyl methyl(6-(2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)dibenzo[b,d]thiophen-2-yl)carbamate (771 mg, 80 %) as a yellow solid. Used crude in the next reaction see EN0198" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N(C)C1=CC2=C(C=C1)SC3=C2C=CC=C3C4=CC=CN5C4=NC(=CC5=O)N6CCOCC6" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 79.79 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/12/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "174" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00712 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.018 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC" + } + amount { + moles { + value: 0.00356 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1C2=CC(=O)N3C=CC=C(C3=N2)C4=CC=CC5=C4SC6=C5C=C(C=C6)OS(=O)(=O)C(F)(F)F" + } + amount { + moles { + value: 0.00178 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 8.9e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 4.45e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "tert-butyl methylcarbamate (467 mg, 3.56 mmol) dissolved in dioxane (5ml) was added in one portion to 6-(2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)dibenzo[b,d]thiophen-2-yl trifluoromethanesulfonate (1000 mg, 1.78 mmol) , TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (40.8 mg, 0.04 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (51.5 mg, 0.09 mmol) and cesium carbonate (2321 mg, 7.12 mmol) in degassed dioxane (18 mL), under nitrogen, at 110 C. The reaction flask was evacuated and blanketed with nitrogen 4X. The resulting suspension was stirred at 110 C for 3i ihours with complete reaction observed by LCMS.nbsp;After cooling, the mixture was partitioned between EtOAc (100mL) and water (50ml).nbsp;The organics were separated and dried (MgSO4) and evaporated to give the crude product, tert-butyl methyl(6-(2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)dibenzo[b,d]thiophen-2-yl)carbamate (950 mg, 98 %) which was combined with the crude product from EN02472-66 and (proceedure detailed on that page).mz (ES+) (M+H)+ = 543; HPLC tR= 2.91 min." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N(C)C1=CC2=C(C=C1)SC3=C2C=CC=C3C4=CC=CN5C4=NC(=CC5=O)N6CCOCC6" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 98.31 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/06/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "175" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0463 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.018 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC" + } + amount { + moles { + value: 0.0232 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1C2=CC(=O)N3C=CC=C(C3=N2)C4=CC=CC5=C4SC6=C5C=C(C=C6)OS(=O)(=O)C(F)(F)F" + } + amount { + moles { + value: 0.0116 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000579 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000289 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "tert-butyl methylcarbamate (3.04 g, 23.15 mmol) dissolved in dioxane (5ml) was added in one portion to 6-(2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)dibenzo[b,d]thiophen-2-yl trifluoromethanesulfonate (6.50g, 11.58 mmol) , TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.265 g, 0.29 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.335 g, 0.58 mmol) and cesium carbonate (15.09 g, 46.30 mmol) in degassed dioxane (18 mL), under nitrogen. The reaction flask was evacuated and blanketed with nitrogen 4X. iiThe resulting suspension was stirred at 110 C for 3i ihours with complete reaction observed by LCMS.nbsp;After cooling, the mixture was partitioned between EtOAc (500mL) and water (250ml).nbsp;The organics were separated and dried (MgSO4) and evaporated to give the crude product which was combined with the crude product from EN02472-66.nbsp;The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evapor to dryness to afford tert-butyl methyl(6-(2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)dibenzo[b,d]thiophen-2-yl)carbamate (5.61 g, 89 %) as a yellow solid. 1H NMR (400 MHz, CDCl3, 22C) d 1.48 (9H, s), 3.34 - 3.39 (7H, m), 3.54 - 3.59 (4H, m), 5.63 (1H, s), 6.99 - 7.05 (1H, m), 7.34 (1H, dd), 7.56 (2H, m), 7.72 (1H, d), 7.86 (1H, dt), 8.04 (1H, s), 8.16 (1H, dt), 9.04 (1H, m).mz (ES+) (M+H)+ = 543; HPLC tR= 2.89 min." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N(C)C1=CC2=C(C=C1)SC3=C2C=CC=C3C4=CC=CN5C4=NC(=CC5=O)N6CCOCC6" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 89.31 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/07/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "176" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00132 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=C(C=C1)C" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC(=CC=C1)OC2CCNCC2.Cl" + } + amount { + moles { + value: 0.000451 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC2=NN=C(N2C=C1Br)C(F)(F)F" + } + amount { + moles { + value: 0.000376 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 2.82e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" + } + amount { + moles { + value: 1.88e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "6-bromo-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.38 mmol), 4-(3-methoxyphenoxy)piperidine hydrochloride (110 mg, 0.45 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (17.56 mg, 0.03 mmol) and Sodium tert-butoxide (0.161 mL, 1.32 mmol) were suspended in xylenes (5 mL), then de-gassed and purged with nitrogen. Bis(dibenzylideneacetone)palladium (10.81 mg, 0.02 mmol) was added, and the mixture was sealed into a microwave tube. The reaction was heated to 100 C for 20 minutes in the microwave reactor and cooled to RT.nbsp;The reaction mixture was diluted with EtOAc (25 mL), and washednbsp;with water (25 mL). The organic layer was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 19 mm diameter, 100 mm length), using decreasinglyixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-(4-(3-methoxyphenoxy)piperidin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (45.0 mg, 30.5 %) as a white solid. nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=CC(=CC=C1)OC2CCN(CC2)C3=CN4C(=NN=C4C(F)(F)F)C=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 30.51 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/22/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "177" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=C(C=C1)C" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C(=CC=N1)CCOC2=CC=C(C=C2)C3CCNCC3" + } + amount { + moles { + value: 0.000244 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC2=NN=C(N2C=C1Br)C(F)(F)F" + } + amount { + moles { + value: 0.000244 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 1.83e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" + } + amount { + moles { + value: 1.22e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "6-bromo-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (65 mg, 0.24 mmol), 4-(4-(2-(1-methyl-1H-pyrazol-5-yl)ethoxy)phenyl)piperidine (112 mg, 0.24 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (11.41 mg, 0.02 mmol) and Sodium tert-butoxide (0.060 mL, 0.49 mmol) were suspended in xylenes (5 mL), then de-gassed and purged with nitrogen. Bis(dibenzylideneacetone)palladium (7.02 mg, 0.01 mmol) was added, and the mixture was sealed into a microwave tube. The reaction was heated to 110 C for 30 minutes in the microwave reactor and cooled to RT. The reaction mixture was diluted with EtOAc (25 mL), and washed with water (25 mL). The aqueous layer was extraced with further EtOAc (25 mL). The combined organic layers were purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness to afford crude product.nbsp;The crude product was purified by preparative HPLC (Waters XBridge Prep C18 Oolumn, 5 silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-(4-(4-(2-(1-methyl-1H-pyrazol-5-yl)ethoxy)phenyl)piperidin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (22.00 mg, 19.14 %) as a colourless gum. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1C(=CC=N1)CCOC2=CC=C(C=C2)C3CCN(CC3)C4=CN5C(=NN=C5C(F)(F)F)C=C4" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 19.14 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/16/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "178" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0013 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.05 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCCC1CO" + } + amount { + moles { + value: 0.0434 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C=C1Cl)Cl)I" + } + amount { + moles { + value: 0.0434 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00521 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000434 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 125.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "buProcedure:ubTo a flask was added 1,3-Dichloro-4-iodobenzene (5.89 mL, 43.41 mmol), piperidin-4-ylmethanol (5 g, 43.41 mmol), cesium carbonate (28.3 g, 86.83 mmol), 18-Crown-6 (1.377 g, 5.21 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.811 g, 1.30 mmol), and toluene (50 mL).nbsp;The mixture was stirred under nitrogen and Tris(dibenzylideneacetone)dipalladium(0) (0.398 g, 0.43 mmol) was added in one portion.nbsp;The resultant yellow mixture was heated with oil bath temperature set at 125C for 3 hours.nbsp;LCMS shows desired product as well as other impurities.nbsp;The reaction was cooled to room temperature.nbsp;Ethyl acetate (2 x 200 mL) was added and the resultant mixture was extracted with saturated aqueous sodium chloride (200 mL).nbsp;The organics were collected and dried over sodium sulfate.nbsp;Ethyl acetate (100 mL) and hexanes (100 mL) were added to the crude and insoluble material filltered off.nbsp;The filtrate was concentrated and chromatographed on ca gel (divided into 3 40 gram silica gel columns).nbsp;The columns were eluted with hexanes up to ethyl acetate:hexanes (up to 100%).nbsp;The desired product eluted between 40-60% ethyl acetate:hexanes.nbsp;Clean fractions were combined from all columns and concentrated to give EN01972-36-1 (2.47 g, 21.87% yield) as an orange oil.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CN(CCC1CO)C2=C(C=C(C=C2)Cl)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 21.87 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/06/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "179" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0013 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.05 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCCC1CO" + } + amount { + moles { + value: 0.0434 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C=C1Cl)Cl)I" + } + amount { + moles { + value: 0.0434 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00521 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000434 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 125.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "buProcedure:ubTo a flask was added 1,3-Dichloro-4-iodobenzene (5.89 mL, 43.41 mmol), piperidin-4-ylmethanol (5 g, 43.41 mmol), cesium carbonate (28.3 g, 86.83 mmol), 18-Crown-6 (1.377 g, 5.21 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.811 g, 1.30 mmol), and toluene (50 mL).nbsp;The mixture was stirred under nitrogen and Tris(dibenzylideneacetone)dipalladium(0) (0.398 g, 0.43 mmol) was added in one portion.nbsp;The resultant yellow mixture was heated with oil bath temperature set at 125C for 3 hours.nbsp;LCMS shows desired product as well as other impurities.nbsp;The reaction was cooled to room temperature.nbsp;Ethyl acetate (2 x 200 mL) was added and the resultant mixture was extracted with saturated aqueous sodium chloride (200 mL).nbsp;The organics were collected and dried over sodium sulfate.nbsp;The crude was placed in the freezer for several days.The crude was dissolved in 10% methanol:dichloromethane (200 mL) and preabsorbed onto silica gel.nbsp;mn chromatography was performed on silica gel eluting with hexanes up to ethyl acetate:hexanes (10%, 20%, 40%).nbsp;Desired product eluted at 40% ethyl acetate:hexanes.nbsp;Collected clean fractions and concentrated to give EN01972-57-1 (2.83 g, 25.06% yield) as an orange oil.nbsp;Put aside product due to shift in priorities of project." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CN(CCC1CO)C2=C(C=C(C=C2)Cl)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 25.06 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/27/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "180" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00098 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C=O" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN(C)CCN" + } + amount { + moles { + value: 0.0098 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)I" + } + amount { + moles { + value: 0.0049 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00098 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.00049 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 50 mL round-bottomed flask (t=g) was unsym-Dimethylethylenediamine (1.080 mL, 9.80 mmol), Iodobenzene (0.549 mL, 4.90 mmol), and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.449 g, 0.49 mmol)Cesium carbonate (2.396 g, 7.35 mmol) andCesium carbonate (2.396 g, 7.35 mmol)nbsp;were added. in DMF (10 mL) ([VOLUME]) to give a brown suspension. Reaction stirred over night at 100. no reaction." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(C)CCNC1=CC=CC=C1" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/14/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "181" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000447 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC1CNC1" + } + amount { + moles { + value: 0.000383 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=NC=CC(=C1)Br" + } + amount { + moles { + value: 0.000319 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 3.19e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 70.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of all the reactants in toluene was heated in a sealed vial at 70 oC overnight. According to LC-MS the reaction was completed and the product had been formed.Toluene was removed, water was added and the product was extracted with DCM. The organic phase was dried through phase separator and concentrated. The crude was used without further purification in the next step, EN01762-02." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC1CN(C1)C2=CC(=NC=C2)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 100.28 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/21/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "182" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00149 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.006 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC1CNC1" + } + amount { + moles { + value: 0.00128 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=NC=CC(=C1)Br" + } + amount { + moles { + value: 0.00106 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000106 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 5.32e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 70.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of all the reactants in toluene was heated in a sealed vial at 70 oC overnight. According to LC-MS the reaction was completed and the product had been formed.Toluene was removed, water was added and the product was extracted with DCM. The organic phase was dried through phase separator and concentrated." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC1CN(C1)C2=CC(=NC=C2)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 99.96 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/25/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "183" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 1.31e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.001 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCC2=C(C1=O)C(=CC=C2)N" + } + amount { + moles { + value: 0.000131 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" + } + amount { + moles { + value: 0.000131 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 1.31e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 6.54e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A suspension of 8-amino-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (23.06 mg, 0.13 mmol), N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (50 mg, 0.13 mmol), diacetoxypalladium (1.469 mg, 6.54 mol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (7.57 mg, 0.01 mmol) and cesium carbonate (85 mg, 0.26 mmol) was stirred at 80 C overnight under nitrogen. LCMS showed formation of more bis-arylation by-product than in uEN01775-08u (DMA under micorwaves conditions). The crude was combined with EN01775-08-01 and poured onto a silicagel column. The crude product was purified by flash chromatography eluting with 0 to 5% methanol in ethyl acetateDCM (11). The solvent was evaporated to dryness to afford a gummy film in the flask b(37mg: not that bad)b. it was scratched in diethyl ether (soluble) then after Et2O evaporation in a few drops of MeCN. A solid crashed out. The resulting solid was taken up into diethyl ether, collected by filtration and dried to af2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (19.00 mg, 33.7 %) as anbsp;white solid (a bit soluble in Et2O because some P1 remained in the Et2O filtrate).bnot the real yieldb" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC4=C3C(=O)N(CC4)C)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 33.74 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/10/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "184" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0209 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.12 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC=CC=C1N" + } + amount { + moles { + value: 0.0178 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" + } + amount { + moles { + value: 0.0105 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00105 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000523 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.606 g, 1.05 mmol), diacetoxypalladium (0.118 g, 0.52 mmol), 2-amino-N-methylbenzamide (2.67 g, 17.80 mmol) and N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (4 g, 10.47 mmol) were dissolved in dioxane (120 mL) and argon was let to bubble in the mixture for 5 minutes.cesium carbonate (6.82 g, 20.94 mmol) was added and argon was let to bubble in the mixture for 5 minutes. The reaction was stirred at 90 C for 2 hours. After taking 2 aliquotsd to check the reaction it turned from yello to grey. LCMS didn\'t show a complete clean reaction but it stopped.nbsp;The reaction mixture was allowed to cool to room temperature under stirring, diluted with dichloromethane, insoluble was removed by filtration and the filtrate was concentrated. The crude product was purified by flash chromatography on silica gel (150g) eluting with 0 to 5% methanol in ethyl acetateDCM (11). The solvent was evaporated to dryness, giving a gummym. 60 mL of tBuOMe was added and the resulting solution was stirred at rt for 15 minutes. The resulting precipitate was collected by filtration, washed with tBuOMe and dried to a constant weight to afford 2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide (3.60 g, 85 %) as a pale beige solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 85.04 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "12/02/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "185" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000132 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC=CC=C1N" + } + amount { + moles { + value: 0.00224 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" + } + amount { + moles { + value: 0.00132 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000132 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 6.58e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (76 mg, 0.13 mmol) and diacetoxypalladium (14.77 mg, 0.07 mmol) were dissolved in dioxane (15 mL) and argon was let to bubble in the mixture for 5 minutes. 2-amino-N-methylbenzamide (336 mg, 2.24 mmol), N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (503 mg, 1.32 mmol) and cesium carbonate (858 mg, 2.63 mmol) were added and the reaction was heated to 90 C, over a period of 90 minutes under nitrogen. LCMS didn\'t show a complete clean reaction (as Cs2CO3 got stuck on the flask). Vigourous stirring was applied and theaction was heated to 90 C, over a period of 90 minutes under nitrogen. Crude LCMS was as expected.nbsp;The reaction mixture was allowed to cool to room temperature under stirring, diluted with dichloromethane and decalite speed + was added. The mixture was concentrated and the crude product was purified by flash chromatography on silica gel eluting with 0 to 5% methanol in ethyl acetateDCM (11). Tnt was evaporated to dryness, giving a gummy foam of P1 (490mg). A bit of diethyl ether then a lot of pentane were added to obtain a solid, which was dried under vacuum at 50C to afford 2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide (450 mg, 77 %) as an yellow solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 76.94 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/30/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "186" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 1.31e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.001 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC=CC=C1N" + } + amount { + moles { + value: 0.000262 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" + } + amount { + moles { + value: 0.000131 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 1.31e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 6.54e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-amino-N-methylbenzamide (39.3 mg, 0.26 mmol), N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (50 mg, 0.13 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (7.57 mg, 0.01 mmol), diacetoxypalladium (1.469 mg, 6.54 mol) and cesium carbonate (85 mg, 0.26 mmol) were dissolved in dioxane (1 mL) and sealed into a microwave tube. Argon was let to bubble in the mixture for 5 minutes. The reaction was heated to 90 C, over a period of 90 minutes. LCMS showed complete and pretty clean reaction. The reaction mixture was allowed to cool to room temperature under stirring, diluted with dichloromethane and decalite speed + was added. The mixture was concentrated and the crude product was purified by flash chromatography on silica gel eluting with 0 to 5% methanol in ethyl acetateDCM (11). The solvent was evaporated to dryness, a bit of diethyl ether was added in order to crystallised but it didn\'t work. So it was concentrated again to afford 2-(2-(1,3-dimethyl-1H-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide (50.0 mg, 94 %) as anbsp;brown dry film." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 94.49 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/26/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "187" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00353 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.15 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=C(C=CC=C1OC)N" + } + amount { + moles { + value: 0.053 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" + } + amount { + moles { + value: 0.0353 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00353 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00177 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A suspension of 2-amino-6-methoxy-N-methylbenzamide (9.55 g, 52.99 mmol), N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (13.5 g, 35.33 mmol), diacetoxypalladium (0.397 g, 1.77 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.044 g, 3.53 mmol) and cesium carbonate (20.72 g, 63.59 mmol) in dioxane (150 mL) was degassed with argon, which was also let to bubble for 10 minutes then stirred at 100 C overnight (yellow-ish dense suspension turning grey lighter). The reaction mixture was allowed to cool to rt, the insolubles were removed by filtration, washed with EtOAc and the filtrate was concentrated. (Insolubles~25g, which seemed to contain very little P1 by TLC and LCMS).The crude product (24.5g) was purified by flash chromatography on silica gel eluting with 0 to 5% methanol in ethyl acetatenbsp;(pure AcOEt to remove by-product coming from overreaction). The solvent was evaporated to dryness to afford a foam (12.5g) which was dissolved in dichloroane (100ml). The resulting crystalline precipitate was collected by filtration, washed with dichloromethane. The filtrate was concentrated down, taken up into DCM and a second crop was collected by filtration, which was combined with the first batch and dried to a constant weight to afford 2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-6-methoxy-N-methylbenzamide (11.51 g, 75.0 %) as anbsp;white crystalline solid.The filtrate was concentrated to dryness, taken up into DCM and collected by filtration to give a second sample EN02972-35-02 (0.41 g, 0.944 mmol, 2.67 %)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=C(C(=CC=C3)OC)C(=O)NC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 75.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/25/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "188" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0068 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.3 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=C(C=CC=C1OC)N" + } + amount { + moles { + value: 0.102 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" + } + amount { + moles { + value: 0.068 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.0068 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.0034 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a stirred solution of N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (26 g, 68.04 mmol) and 2-amino-6-methoxy-N-methylbenzamide (18.39 g, 102.06 mmol) in dioxane (300 mL) is added cesium carbonate (39.9 g, 122.47 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (3.94 g, 6.80 mmol) and diacetoxypalladium (0.764 g, 3.40 mmol).Mixture was degassed 3 times with N2 and heated to 100C overnight. LCMS crude seems OK.Reaction was cooled to room temperature then salts were filtered and the filtrate concentrated to afford a crude compound which was purified on silica, eluting with 5% MeOH in AcOEt.Solvent were evaporated to afford a gum which finished by crystallize in 100mL of CH2Cl2.Solid was filtered and dried to a constant weight to afford 2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-6-methoxy-N-methylbenzamide (17.30 g, 58.5 %) as a white crystalline product.1H NMR, purity check OK, 98%purity." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=C(C(=CC=C3)OC)C(=O)NC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 58.53 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/17/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "189" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 3.93e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=C(C=CC=C1OC)N" + } + amount { + moles { + value: 0.000785 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" + } + amount { + moles { + value: 0.000393 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.93e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.96e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A suspension of [Reactants], N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (150 mg, 0.39 mmol), diacetoxypalladium (4.41 mg, 0.02 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (22.71 mg, 0.04 mmol) and cesium carbonate (256 mg, 0.79 mmol) in dioxane (2 mL) was degassed with argon then stirred at 100 C for 2 hours sealed in a microwave vial. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford impure product EN01775-26-01. The impure product was repurified by flash chromatography on silica gel eluting with 0 to 5% methanol in ethyl acetateDCM (11) - spillage occurred when collecting. The solvent was evaporated to dryness to afford 110mg ofoam, which was triturated in tBuOMe. The resulting precipitate was collected by filtration and dried to a constant weight to afford [Products] as anbsp;white solid EN01775-26-02 (81 mg, 0.186 mmol, 47.5 %)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=C(C(=CC=C3)OC)C(=O)NC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 47.5 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/07/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "190" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000688 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.037 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=C(C=CC=C1OC)N" + } + amount { + moles { + value: 0.0138 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" + } + amount { + moles { + value: 0.00688 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000688 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000344 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A suspension of [Reactants], N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (2.63 g, 6.88 mmol), diacetoxypalladium (0.077 g, 0.34 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.398 g, 0.69 mmol) and cesium carbonate (4.48 g, 13.77 mmol) in dioxane (37 mL) was degassed with argon then stirred at 100 C for 3 hours . The reaction mixture was concentrated to dryness, diluted with ethyl acetate (80 ml), washed with water (1 x 50 ml), brine, dried over magnesium sulfate and concentrated to afford an oil.The crude product was purified by flash chromatography on silica gel eluting with AcOet pure to remove impurities then 3 to 8% methanol in ethyl acetate. The solvent was evaporated to dryness to afford a foam which was dissolved in dichloromethane ( 12ml ).A solid was formed after a few minutes, which was filtered, dried .A white solid was obtained 2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-6-methoxmethylbenzamide (1.570 g, 52.5 %)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=C(C(=CC=C3)OC)C(=O)NC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 52.51 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/20/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "191" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 3.93e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCOC2=CC=CC(=C2C1=O)N" + } + amount { + moles { + value: 0.000785 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" + } + amount { + moles { + value: 0.000393 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.93e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.96e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A suspension of 6-amino-4-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (151 mg, 0.79 mmol), N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (150 mg, 0.39 mmol), diacetoxypalladium (4.41 mg, 0.02 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (22.71 mg, 0.04 mmol) and cesium carbonate (256 mg, 0.79 mmol) innbsp;dioxane (2 mL) was degassed with argon then stirred at 100 C for 2 hours sealed in a microwave vial. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford impure product EN01775-27-01. The impure product was repurified by flash chromatography on silica gel eluting with 0 to 5% methanol in ethyl acetateDCM (11). The solvent was evated to dryness to afford 118mg of a sticky foam, which was triturated in a mixture of tBuOMe and pentane (~30-40% of tBuOMe). The mixture was concentrated down to get a light white foam, which could be handled." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=C4C(=CC=C3)OCCN(C4=O)C)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 54.21 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/07/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "192" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00015 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)N" + } + amount { + moles { + value: 0.0002 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=NC(=C1Br)Cl)Cl" + } + amount { + moles { + value: 0.0001 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 7.5e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.5e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "BINAP (4.67 mg, 7.50 mol) and Pd2dba3 (2.289 mg, 2.50 mol) were dissolved in dioxane (1ml) and flushed with nitrogen. 3-bromo-2,6-dichloropyridine (0.023 g, 0.1 mmol), aniline (0.018 mL, 0.20 mmol) and sodium tert-butoxide (0.014 g, 0.15 mmol) were weight in another flask and flushed with nitrogen. The ligand-Pd mixture was joined and the reaction mixture was stirred at 100C over night. Detection of the reaction was done by LCMS. LCMS showed the completion of the reation. the 3-bromo-2,6-dichloropyridine as well as the aniline were gone, but no desired product was detected. NMR verified the observations. The products have not been ide" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=C(N=C(C=C2)Cl)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/29/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "193" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "[O-]P(=O)([O-])[O-].[K+].[K+].[K+]" + } + amount { + moles { + value: 2.6e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N" + } + amount { + moles { + value: 0.000625 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=C(N=C1Cl)Cl)C(=O)O" + } + amount { + moles { + value: 0.000521 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 2.6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Reagents were mixed in a 25 mL round bottom flask and flushed well with nitrogen -nbsp;heated at 100 C for 16 h. The mixture looked dark black. Could not detect any starting material or product!It was discarded." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC1=NC(=CC(=C1)C(=O)O)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/12/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "194" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0027 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C(=CC=N1)N" + } + amount { + moles { + value: 0.00162 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.00135 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00027 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000135 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 105.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (124 mg, 0.14 mmol) was added in one portion to 2,4-dichloropyridine (200 mg, 1.35 mmol), 1-methyl-1H-pyrazol-5-amine (158 mg, 1.62 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (156 mg, 0.27 mmol), and cesium carbonate (881 mg, 2.70 mmol) in 1,4-dioxane (20 mL) under nitrogen. The resulting mixture was stirred at 105C for 2 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (50 mL), and washed with water (50 mL). The organic layer was filtered using phase separating paper and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-chloro-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine (66.0 mg, 23.41 %) as a yellow oil which solidified on standing. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1C(=CC=N1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 23.41 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/09/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "195" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 7.97e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C(=CC=N1)N" + } + amount { + moles { + value: 0.000743 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.000676 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.97e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.74e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 200.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;2,4-dichloropyridine (100mg, 0.68 mmol), 1-methyl-1H-pyrazol-5-amine (72.2 mg, 0.74 mmol) and cesium carbonate (330 mg, 1.01 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (46.1 mg, 0.08 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (25.06 mg, 0.03 mmol) were suspended in 1,4-dioxane (5 mL) and sealed into a microwave tube. The reaction was heated to 200C for 1 hour in the microwave reactor and cooled to RT. The reaction mixture was evaporated to dryness and redissolved in DCM (20 mL), and washed with water (20 mL). The organic layer was filtered with phase separating paper and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-chloro-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine (14.00 mg, 9.93 %) as a yellow oil which solidified on standing. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1C(=CC=N1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 9.93 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/11/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "196" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0101 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.075 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C(=CC=N1)N" + } + amount { + moles { + value: 0.00743 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.00676 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000797 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000274 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 105.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (251 mg, 0.27 mmol) was [AP-added] to 2,4-dichloropyridine (1000mg, 6.76 mmol), 1-methyl-1H-pyrazol-5-amine (722 mg, 7.43 mmol), cesium carbonate (3302 mg, 10.14 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (461 mg, 0.80 mmol) in 1,4-dioxane (75 mL) warmed to 105C over a period of 21 hours under nitrogen. The reaction mixture was evaporated to dryness and redissolved in DCM (50 mL), and sequentially with water (25 mL). The organic layer was filtered using phase separating paper and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-chloro-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine (710 mg, 50.4 %) as a brown oil. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1C(=CC=N1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 50.36 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/12/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "197" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0101 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.06 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C(=CC=N1)N" + } + amount { + moles { + value: 0.0101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.00676 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000797 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000274 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 130.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (251 mg, 0.27 mmol) was added in one portion to 2,4-dichloropyridine (1000mg, 6.76 mmol), 1,3-dimethyl-1H-pyrazol-5-amine (826 mg, 7.43 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (461 mg, 0.80 mmol) and sodium tert-butoxide (974 mg, 10.14 mmol) in 1,4-dioxane (60 mL) warmed to 130C over a period of 10 minutes under nitrogen. The resulting mixture was stirred at 130C for 20 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (150 mL).nbsp;Solids were filtered off by suction and the filtrate sequently washed withnbsp;water (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 4% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-chloro-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine (802 mg, 56.9 %) as a yellow oil which crystallised on standi" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1C(=CC=N1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 56.88 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/23/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "198" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.101 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.5 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C(=CC=N1)N" + } + amount { + moles { + value: 0.101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.0676 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00405 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.00135 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 130.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (1.238 g, 1.35 mmol) was added in one portion to 2,4-dichloropyridine (10g, 67.57 mmol), 1-methyl-1H-pyrazol-5-amine (7.22 g, 74.33 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.346 g, 4.05 mmol) and sodium tert-butoxide (9.74 g, 101.36 mmol) in 1,4-dioxane (500 mL) warmed to 130C over a period of 10 minutes under nitrogen. The resulting mixture was stirred at 130 C for 24 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (300 mL), and washed with water (125 mL).nbsp;The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 4% MeOH in DCM. Pure fractions were evaporated to dryness to afford EN01861-14-01 (2.93 g, 20.8 %) as a yellow crystalline solid. EN01861-14-01 (2.93 g) was combined with EN01861-09-01 (2.63g) to give EN01861-14-02 (5.56 g) as a yellow crystalline p" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1C(=CC=N1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 60.25 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/30/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "199" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00203 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C(=CC=N1)N" + } + amount { + moles { + value: 0.00149 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.00135 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00016 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 5.47e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 105.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (50.1 mg, 0.05 mmol) was added in one portion to 2,4-dichloropyridine (200 mg, 1.35 mmol), 1-methyl-1H-pyrazol-5-amine (144 mg, 1.49 mmol), cesium carbonate (660 mg, 2.03 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (93 mg, 0.16 mmol) in 1,4-dioxane (20 mL) warmed to 105C over a period of 24 hours under nitrogen. The reaction mixture was evaporated to dryness and redissolved in DCM (20 mL), and washed with water (25 mL). The organic layer filtered using phase separating paper and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-chloro-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine (171 mg, 60.5 %) as a yellow crystalline solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1C(=CC=N1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 60.54 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/11/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "200" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.101 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.35 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C(=CC=N1)N" + } + amount { + moles { + value: 0.0743 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.0676 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00405 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.00135 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 105.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (1.238 g, 1.35 mmol) was added in one portion to 2,4-dichloropyridine (10g, 67.57 mmol), 1-methyl-1H-pyrazol-5-amine (7.22 g, 74.33 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.346 g, 4.05 mmol) and cesium carbonate (33.0 g, 101.36 mmol) in 1,4-dioxane (350 mL) warmed to 105C over a period of 20 hours under nitrogen. The reaction mixture was evaporated to dryness and redissolved in DCM (250 mL), and washed with water (200 mL) The organic layer was filtered using phase separating paper and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM.nbsp;Relavent fractions were repurified by flash silica chromatography, elution gradient 0 to 5% MeOH in EtOAc. Pure fractions were evaporated to dryness to afford 4-chloro-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine (2.91 g, 20.66 %) as a yellow crystalline solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1C(=CC=N1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 20.66 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/16/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "202" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 4e-06 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)N" + } + amount { + moles { + value: 0.00012 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=NC(=C1I)Cl)Cl" + } + amount { + moles { + value: 0.0001 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 4e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "The reaction vessel was charged with nitrogen,nbsp;BINAP (2.491 mg, 4.00 mol) and diacetoxypalladium (0.898 mg, 4.00 mol) were dilutet in toluene (2 ml) and flushed with nitrogen.2,6-dichloro-3-iodopyridine (0.027 g, 0.1 mmol), aniline (10.96 l, 0.12 mmol) and cesium carbonate (0.163 g, 0.50 mmol) were weight in another flask and flushed with nitrogen. The Pd-BINAP mixture was joined and the reaction mixture was warmed to 120 C and stirred over night. The reaction was monitored using LCMS. No product could " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=C(N=C(C=C2)Cl)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/10/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "203" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[K+].[K+]" + } + amount { + moles { + value: 8e-06 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.001 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)N" + } + amount { + moles { + value: 0.00012 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=NC(=C1I)Cl)Cl" + } + amount { + moles { + value: 0.0001 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 8e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Biphenyl-2-yldicyclohexylphosphine (2.80 mg, 8.00 mol) and diacetoxypalladium (0.898 mg, 4.00 mol) were dilutet in dioxane (1 ml) and flushed with nitrogen. 2,6-dichloro-3-iodopyridine (0.027 g, 0.1 mmol), aniline (10.96 l, 0.12 mmol) and potassium carbonate (0.276 g, 2.00 mmol) were weight in another flask and flushed with nitrogen. The ligand-Pd mixture was joined and the reaction mixture was stirred at 120C over night. The reaction was monitored by LCMS and TLC. No desired product could be obtained and the starting materi" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=C(N=C(C=C2)Cl)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/14/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "206" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0015 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)N" + } + amount { + moles { + value: 0.005 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=NC(=C1I)Cl)Cl" + } + amount { + moles { + value: 0.001 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 7.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "The reaction was carried out under nitrogen. Two runs using the same amount of starting material (2,6-dichloro-3-iodopyridine (274 mg, 1 mmol)) and the same conditions were started and carried out as described in the following.BINAP (46.7 mg, 0.08 mmol) and Pd2(dba)3 (22.89 mg, 0.03 mmol)nbsp;were given into a nitrogen charged reaction vessel and dissolved in dioxane (10ml). 2,6-dichloro-3-iodopyridine (274 mg, 1 mmol), aniline (0.457 ml, 5.00 mmol) and sodium tert-butoxide (144 mg, 1.50 mmol) were weight in another flask and flushed with nitrogen. The prepared ligand-Pd mixture was added and the reaction mixture was heated at 100C over night. The reaction was monitored using TLC and LCMS. After the reaction was completed,nbsp;the dioxane was evapurated and both reaction vessels containing the same reaction-mixture were combined. The crude was solved in DCM, filtered through a silica plug and it followed a water work up using sodium bicarbonate (5 %), brine and water. The organic p was dried over sodium sulfate and concentrated to yield a dark brown oil. NMR showed the desired product, as well as the bis-addition of aniline.The crude product was purified by reverse-phase preparative HPLC. Column: Kromasil C8. Eluent: A: MeCN, B: H2OMeCNCH3COOH, 9550.2. Gradient: The A fraction was increased from 30 % to 70 % over 40 minutes. Flow: 70 mLmin.The relevant fractions (6-9) were concentrated and freeze dried to yield 220.3 mg (46%) a brown oil." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=C(N=C(C=C2)Cl)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 92.14 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/01/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "207" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.007 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC1CCNCC1" + } + amount { + moles { + value: 0.005 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC(=CC=C1)Br" + } + amount { + moles { + value: 0.005 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.0005 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.0005 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "All chemicals were mixed in a 50 mL round bottom flask. The solids were degassed and placed under nitrogen. Toluene was added and the mixture was stirred at 100C for 24 h. Cooled and filtered. The filtrate was concentrated under vacuum. Crude product was mainly starting material but some product had been formed. The product was purified by silica gel chromatography using 1-4% methanolDCM. Product was slightly more polar than starting material bromide. There was obtained 230 mg of the desired product as a solid. HNMR and LC MS ok." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC1CCN(CC1)C2=CC=CC(=C2)C(=O)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 13.76 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/28/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "208" + } + identifiers { + type: NAME + details: "reaction type" + value: "9.7.39 [Other functional group interconversion] Chloro to amino" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000912 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.028 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N" + } + amount { + moles { + value: 0.012 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1F)Cl" + } + amount { + moles { + value: 0.0114 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000912 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000456 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-chloro-4-fluoropyridine (1.5 g, 11.40 mmol), tert-butyl carbamate (1.403 g, 11.97 mmol), CESIUM CARBONATE (7.43 g, 22.81 mmol) ,TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (0.418 g, 0.46 mmol) and 9,9-DIMETHYL-4,5-BIS(DIPHENYLPHOSPHINO)XANTHENE (0.528 g, 0.91 mmol) were suspended in 1,4-dioxane (28 ml) ,degased with argon andnbsp;heated to 90 C for 4 hours.After cooling the reaction wasnbsp;quenched with waternbsp;and extracted with ethyl acetate ( x 2 ). The combined organic phasesnbsp;were washed with waternbsp;, a saturated aqueous solution of brine , dried over magnesium sulfate , concentrated thennbsp;purified bynbsp;preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The product was diluted in DCM (5 mL) and was added TFA (1.00 mL). After 15 minutes, the volatiles were evaporatehe residue was treated with aq NH3 30% and reevaporated." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1F)N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 25.34 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/21/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "211" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "[O-]P(=O)([O-])[O-].[K+].[K+].[K+]" + } + amount { + moles { + value: 9.96e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0045 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)CN(C)C1=CC(=C(C=C1)N)OC" + } + amount { + moles { + value: 0.0011 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN2C(=CN=C2C(=C1)F)C3=NC(=NC=C3Cl)Cl" + } + amount { + moles { + value: 0.000996 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 9.96e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.98e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A microwave tube was charged with diacetoxypalladium (11.18 mg, 0.05 mmol), potassium phosphate (529 mg, 2.49 mmol),2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (62.0 mg, 0.10 mmol), 3-(2,5-dichloropyrimidin-4-yl)-8-fluoroimidazo[1,2-a]pyridine (282 mg, 1.00 mmol) purged with nitrogen. Dioxane (4.5 ml) was added followed by tert-butyl 2-((4-amino-3-methoxyphenyl)(methyl)amino)acetate (292 mg, 1.10 mmol). The resulting suspension was purged again andnbsp;was heated at 100 C for 1h30.After cooling, the mixture was filtered through a pad of Dicalite speed plus and washed with dichloromethane. The solvent were evaporated. PBO-01970-51-01The crude product was purified by flash chromatography on silica gel (Merck cartridge SVF D26 - SI60 15-40m - 30g) eluting with 0 up to 50% EtOAc in petroleum ether. Collected fractions worated to afford tert-butyl 2-((4-(5-chloro-4-(8-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-ylamino)-3-methoxyphenyl)(methyl)amino)acetate (220 mg, 43.1 %) as a clear yellow solid. PBO-01970-51-02" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)CN(C)C1=CC(=C(C=C1)NC2=NC=C(C(=N2)C3=CN=C4N3C=CC=C4F)Cl)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 43.05 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/05/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "213" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00308 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=C(C=CC=C1OC)N" + } + amount { + moles { + value: 0.00265 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C(=CN=C1Cl)C(F)(F)F)I" + } + amount { + moles { + value: 0.00257 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000411 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000206 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-chloro-4-iodo-5-(trifluoromethyl)pyridine (790 mg, 2.57 mmol), 2-amino-6-methoxy-N-methylbenzamide (477 mg, 2.65 mmol), diacetoxypalladium (46.2 mg, 0.21 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (238 mg, 0.41 mmol) and cesium carbonate (1005 mg, 3.08 mmol) were mixed together in dioxane (15 mL). Reaction was degassed with argon and was stirred at 90 C overnight under argon.Reaction was filtered, washed with CH2Cl2 and filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford 2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-6-methoxy-N-methylbenzamide (590 mg, 63.8 %) as a white foam." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CNC(=O)C1=C(C=CC=C1OC)NC2=CC(=NC=C2C(F)(F)F)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 63.83 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/23/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "214" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00164 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.008 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=C(C=CC=C1OC)N" + } + amount { + moles { + value: 0.00137 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C(=CN=C1Cl)C(F)(F)F)I" + } + amount { + moles { + value: 0.00137 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000219 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000109 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-chloro-4-iodo-5-(trifluoromethyl)pyridine (420 mg, 1.37 mmol), 2-amino-6-methoxy-N-methylbenzamide (246 mg, 1.37 mmol), diacetoxypalladium (24.54 mg, 0.11 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (126 mg, 0.22 mmol) and cesium carbonate (534 mg, 1.64 mmol) were mixed together in dioxane (8 mL). Reaction was degassed with argon and was stirred at 90 C overnight (15 hours) under argon.Reaction was filtered, washed with CH2Cl2 and the filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 10 to 30% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford 2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-6-methoxy-N-methylbenzamide (325 mg, 66.1 %) as a white solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CNC(=O)C1=C(C=CC=C1OC)NC2=CC(=NC=C2C(F)(F)F)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 66.13 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/08/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "215" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0273 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.075 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=C(C=CC=C1OC)N" + } + amount { + moles { + value: 0.0239 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C(=CN=C1Cl)C(F)(F)F)I" + } + amount { + moles { + value: 0.0228 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00364 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00182 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;2-chloro-4-iodo-5-(trifluoromethyl)pyridine (7 g, 22.77 mmol), 2-amino-6-methoxy-N-methylbenzamide (4.31 g, 23.91 mmol), diacetoxypalladium (0.409 g, 1.82 mmol) (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.108 g, 3.64 mmol) and cesium carbonate (8.90 g, 27.32 mmol) were suspended in dioxane (75 ml). Argon was let to bubble into the dark purple blurred solution and the reaction mixture was heated to at 90 C for 24h. (yellow suspension when temperature reached 70C).The reaction mixture was allowed to cool to room temperature, diluted with DCM (some drop of MeOH) and filtered. Silica gel was added and solents were evaporated to afford the crude, which was purified twice* by flash chromatography on silica gel eluting with 10 to 60% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford 2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-6-methoxy-N-methylbenzamide (7.00 g, 85 %) as an yellow f" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CNC(=O)C1=C(C=CC=C1OC)NC2=CC(=NC=C2C(F)(F)F)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 85.46 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/05/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "216" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00125 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.00312 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC1=CC(=CN=C1)I" + } + amount { + moles { + value: 0.000625 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.12e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "morpholine (0.272 mL, 3.12 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (43.4 mg, 0.07 mmol), tert-butyl 5-iodopyridin-3-ylcarbamate (200 mg, 0.62 mmol), diacetoxypalladium (7.01 mg, 0.03 mmol) andnbsp;cesium carbonate (407 mg, 1.25 mmol) were suspended in 1,4-dioxane (4 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness to afford the boc protected product.nbsp;HCl in dioxane (4M, 5mL) was added to the product . The resulting suspension was stirred at room temperature for 3 hours. The product was evaporated to dryness to afford crude product.nbsp;The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH plus 1% aqueous ammonia in DCM. Pure fractions were evaporated to drynes afford 5-morpholinopyridin-3-amine (31.0 mg, 27.7 %) as a cream solid. nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1COCCN1C2=CN=CC(=C2)N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 27.69 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/30/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "218" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00154 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(N=C1N)Cl" + } + amount { + moles { + value: 0.000772 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C=C1CO)Br)F" + } + amount { + moles { + value: 0.000772 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 9.26e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.86e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (8.67 mg, 0.04 mmol) was added to 2-chloropyrimidin-4-amine (100 mg, 0.77 mmol), (3-bromo-4-fluorophenyl)methanol (158 mg, 0.77 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (53.6 mg, 0.09 mmol) and cesium carbonate (503 mg, 1.54 mmol) in 1,4-dioxane (4 mL) . The resulting suspension was stirred at 150 C in the microwave for 30 minutes. None of the desired material was visible by LCMS. Reaction abandoned.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC(=C(C=C1CO)NC2=NC(=NC=C2)Cl)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/06/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "219" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CCC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000469 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)C(F)(F)F" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: " CC(C)(C(=O)OC)N" + } + amount { + moles { + value: 0.000427 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC=C(C=C1)Br" + } + amount { + moles { + value: 0.000469 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CCCCP(C12CC3CC(C1)CC(C3)C2)C45CC6CC(C4)CC(C6)C5" + } + amount { + moles { + value: 1.71e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.19e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 180.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "1-bromo-4-methoxybenzene (0.060 mL, 0.47 mmol), methyl 2-amino-2-methylpropanoate (0.05 g, 0.43 mmol), sodium 2-methylbutan-2-olate (0.052 g, 0.47 mmol), diacetoxypalladium (2.68 mg, 0.01 mmol) and methyl 2-(4-methoxyphenylamino)-2-methylpropanoate (0.00 g) was added to a microwave vial. (TRIFLUOROMETHYL)-BENZENE (0.5 mL) was used as solvent (1-1.2 mLmmol amine). The mixture was heated in microwave at 180 for 60min. No conversion of startingmaterial was obser" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C(=O)OC)NC1=CC=C(C=C1)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "12/19/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "220" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000854 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)C(F)(F)F" + } + amount { + volume { + value: 0.0004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: " CC(C)(C(=O)OC)N" + } + amount { + moles { + value: 0.000427 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1C(F)(F)F)Cl" + } + amount { + moles { + value: 0.000512 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CCCCP(C12CC3CC(C1)CC(C3)C2)C45CC6CC(C4)CC(C6)C5" + } + amount { + moles { + value: 4.27e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.13e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 180.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "1-chloro-4-(trifluoromethyl)benzene (0.068 mL, 0.51 mmol),nbsp;methyl 2-amino-2-methylpropanoate (0.05 g, 0.43 mmol),BUTYLDI-1-ADAMANTYLPHOSPHINE (0.015 g, 0.04 mmol), sodium 2-methylpropan-2-olate (0.082 g, 0.85 mmol) and diacetoxypalladium (4.79 mg, 0.02 mmol) was added to a microwave vial. (TRIFLUOROMETHYL)-BENZENE (0.5 mL) was used as solvent, before use the solvent was bubbled with nitrogen (1-1.2 mLmmol amine). The mixture was bubbled with nitrogen before the vial was sealed. The mixture was heated in microwave at 180 for 60min.. The mixture was heated in microwave at 180 for 60min. No conversion of startingmaterial was obser" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C(=O)OC)NC1=CC=C(C=C1)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/28/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "221" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00171 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: " CC(C)(C(=O)OC)N" + } + amount { + moles { + value: 0.00171 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=C(C=C1)Cl" + } + amount { + moles { + value: 0.00142 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CCCCP(C12CC3CC(C1)CC(C3)C2)C45CC6CC(C4)CC(C6)C5" + } + amount { + moles { + value: 5.69e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.85e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A flask was loaded with diacetoxypalladium (6.39 mg, 0.03 mmol), BUTYLDI-1-ADAMANTYLPHOSPHINE (0.020 g, 0.06 mmol), sodium 2-methylpropan-2-olate (0.164 g, 1.71 mmol) andnbsp;methyl 2-amino-2-methylpropanoate (0.2 g, 1.71 mmol). The flask was evacuated and backfilled and toluene (5ml) and 1-chloro-4-methylbenzene (0.168 ml, 1.42 mmol) was added.The mixture was stirred for 20h at 120. No conversion of startingmaterial was observed." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CC=C(C=C1)NC(C)(C)C(=O)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/28/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "222" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.024 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.075 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)N)C(C)C" + } + amount { + moles { + value: 0.0176 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" + } + amount { + moles { + value: 0.016 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00144 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000961 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (5 g, 16.02 mmol), 1-isopropyl-3-methyl-1H-pyrazol-5-amine (2.453 g, 17.62 mmol) and cesium carbonate (7.83 g, 24.03 mmol) were suspended in 1,4-dioxane (75 mL). Nitrogen was bubbled through mixture for 15 minutes. (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.834 g, 1.44 mmol) and diacetoxypalladium (0.216 g, 0.96 mmol) were added and flask was purged with nitrogen (x3). Mixture was stirred at reflux overnight.Reaction was allowed to cool to room temperature, filtered, washed with CH2Cl2MeOH (91, 60 mL). Silica (63-200 m) was added to the filtrate and mixture was concentrated to dryness. The crude product was purified by flash chromatography (dry loading) on silica gel eluting with 1 to 6% methanol in dichloromethane. The solvent was evaporated to dryness to afford 2-(5-chloro-2-(1-isopropyl-3-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-N-methoxybenzamide (3.35 g, 50.4 %) as a dark green foam =gt; icontains CH2Cl2 anOH.i EtOAc (10 mL) was added and mixture was stirred at room temperature for 5 hours. The resulting solid was filtered, washed with cold EtOAc and dried under high vacuum at 50C overnight to afford 2-(5-chloro-2-(1-isopropyl-3-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-N-methoxybenzamide (2.41 g, 36.3 %) as a pale yellow solid =gt; icrystalline powder under polarized light microscopyi" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)Cl)C(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 86.67 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/30/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "223" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.135 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.3 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)N)C(C)C" + } + amount { + moles { + value: 0.108 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" + } + amount { + moles { + value: 0.0897 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00807 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00538 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a stirred solution of 2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (28 g, 89.70 mmol) in 1,4-dioxane (300 mL) were added 1-isopropyl-3-methyl-1H-pyrazol-5-amine (14.98 g, 107.64 mmol), cesium carbonate (43.8 g, 134.55 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4.67 g, 8.07 mmol) and diacetoxypalladium (1.208 g, 5.38 mmol)Mixture was degassed 3 times with N2 and heated to reflux overnight: OK.Reaction was cooled down, then filtered, salts were washed with 500mL of a 9010 solution of CH2Cl2MeOH and the filtrate was concentrated.Residue was then dissolved in CH2Cl2MeOH, adsorbed on silica and purified by chromatography, eluting with 7% of MeOH in CH2Cl2.Solvent were concentrated and the solid obtained was stirred in 300mL of AcOEt for 3h.product was filtered, washed with AcOEt and dried on vacuum at 50C for the we.1H NMR indicates the presence of 7% of AcOEt...Need to dissolve the product in EtOH, then concentrato dryness and stirred with 500mL of water for 3h.Solid was filtered, washed with water and dried on vacuum overnight at 50C to afford 2-(5-chloro-2-(1-isopropyl-3-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-N-methoxybenzamide (21.50 g, 57.8 %) as a white powder.Purity-check OK." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)Cl)C(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 57.77 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/07/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "224" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000961 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)N)C(C)C" + } + amount { + moles { + value: 0.00128 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" + } + amount { + moles { + value: 0.000641 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000128 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" + } + amount { + moles { + value: 9.61e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (200 mg, 0.64 mmol), 1-isopropyl-3-methyl-1H-pyrazol-5-amine (178 mg, 1.28 mmol) and sodium 2-methylpropan-2-olate (92 mg, 0.96 mmol) were suspended in 1,4-dioxane (3 mL). Nitrogen was bubbled through mixture for 10 minutes. (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (74.1 mg, 0.13 mmol) and BIS(DIBENZYLIDENEACETONE)PALLADIUM(0) (55.3 mg, 0.10 mmol) were added and tube was sealed. Mixture was stirred at reflux overnight. Reaction was allowed to cool to room temperature, filtered, washed with CH2Cl2MeOH (91, 10 mL) and concentrated to dryness. The crude product was purified by flash chromatography (dry loading) on silica gel eluting with 1 to 5% methanol in dichloromethane. The solvent was evaporated to dryness to afford 2-(5-chloro-2-(1-isopropyl-3-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-N-methoxybenzamide (97 mg, 36.5 %) as a pink foam." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)Cl)C(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 36.49 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/25/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "225" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00192 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)N)C(C)C" + } + amount { + moles { + value: 0.00128 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" + } + amount { + moles { + value: 0.000641 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 6.41e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.2e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (200 mg, 0.64 mmol), 1-isopropyl-3-methyl-1H-pyrazol-5-amine (178 mg, 1.28 mmol) and cesium carbonate (626 mg, 1.92 mmol) were suspended in 1,4-dioxane (3 mL). Nitrogen was bubbled through mixture for 10 minutes. 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (39.9 mg, 0.06 mmol) and diacetoxypalladium (7.19 mg, 0.03 mmol) were added and tube was sealed. Mixture was stirred at reflux overnight. Reaction was allowed to cool to room temperature, filtered, washed with CH2Cl2MeOH (91, 10 mL) and concentrated to dryness. The crude product was purified by flash chromatography (dry loading) on silica gel eluting with 1 to 5% methanol in dichloromethane. The solvent was evaporated to dryness to afford 2-(5-chloro-2-(1-isopropyl-3-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-N-methoxybenzamide (125 mg, 47.0 %) as a pink foam =gt; icontaminated by a few BINAP or BINAP by-productsi" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)Cl)C(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 47.02 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/25/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "226" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00192 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)N)C(C)C" + } + amount { + moles { + value: 0.00128 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" + } + amount { + moles { + value: 0.000641 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000192 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 9.61e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (200 mg, 0.64 mmol), 1-isopropyl-3-methyl-1H-pyrazol-5-amine (178 mg, 1.28 mmol) and cesium carbonate (626 mg, 1.92 mmol) were suspended in 1,4-dioxane (3 mL). Nitrogen was bubbled through mixture for 10 minutes. 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (120 mg, 0.19 mmol) and diacetoxypalladium (21.58 mg, 0.10 mmol) were added and tube was sealed. Mixture was stirred at reflux overnight. Reaction was allowed to cool to room temperature, filtered, washed with CH2Cl2MeOH (91, 10 mL) and concentrated to dryness. The crude product was purified by flash chromatography (dry loading) on silica gel eluting with 1 to 5% methanol in dichloromethane. The solvent was evaporated to dryness to afford 2-(5-chloro-2-(1-isopropyl-3-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-N-methoxybenzamide (98 mg, 36.9 %) as a pink foam =gt; iimpure, contains BINAP or BINAP by-productsi" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)Cl)C(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 36.87 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/25/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "227" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000961 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)N)C(C)C" + } + amount { + moles { + value: 0.00128 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" + } + amount { + moles { + value: 0.000641 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 4.81e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.2e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (200 mg, 0.64 mmol), 1-isopropyl-3-methyl-1H-pyrazol-5-amine (178 mg, 1.28 mmol) and cesium carbonate (313 mg, 0.96 mmol) were suspended in 1,4-dioxane (3 mL). Nitrogen was bubbled through mixture for 10 minutes. (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (27.8 mg, 0.05 mmol) and diacetoxypalladium (7.19 mg, 0.03 mmol) were added and tube was sealed. Mixture was stirred at reflux overnight =gt; iincomplete reactioni. Reaction was heated for a further 7 hours =gt; ino evolutioni. More Pd(OAc)2 and Xantphos were added, mixture was degassed with nitrogen and heated at reflux overnight =gt; icompletei.Reaction was allowed to cool to room temperature, filtered, washed with CH2Cl2MeOH (91, 10 mL) and concentrated to dryness. The crude product was purified by flash chromatography (dry loading) on silica gel eluting with 1 to 5% methanol in dichloromethane. The solvent was evaporated to dryness to afford 2-(5-chloro-2-(1-isopropyl-3-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-N-methoxybenzamide (90 mg, 33.9 %) as a pink foam." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)Cl)C(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 33.86 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/25/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "228" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00192 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)N)C(C)C" + } + amount { + moles { + value: 0.000705 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" + } + amount { + moles { + value: 0.000641 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 6.41e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.2e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (200 mg, 0.64 mmol), 1-isopropyl-3-methyl-1H-pyrazol-5-amine (98 mg, 0.70 mmol) and cesium carbonate (626 mg, 1.92 mmol) were suspended in 1,4-dioxane (3 mL). Nitrogen was bubbled through mixture for 10 minutes. 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (39.9 mg, 0.06 mmol) and diacetoxypalladium (7.19 mg, 0.03 mmol) were added and tube was sealed. Mixture was stirred at reflux overnight. Reaction was allowed to cool to room temperature, filtered, washed with CH2Cl2MeOH (91, 10 mL). Silica (63-200 m) was added to the filtrate and mixture was concentrated to dryness. The crude product was purified by flash chromatography (dry loading) on silica gel eluting with 1 to 5% methanol in dichloromethane. The solvent was evaporated to dryness to afford 2-(5-chloro-2-(1-isopropyl-3-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-N-methoxybenzamide (120 mg, 45.1 %) as a pale beige foam =gt; icontaminated by a few BINAP or BINAP by-productsi" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)Cl)C(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 45.14 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/25/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "229" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00192 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)N)C(C)C" + } + amount { + moles { + value: 0.000961 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" + } + amount { + moles { + value: 0.000641 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 6.41e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.2e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (200 mg, 0.64 mmol), 1-isopropyl-3-methyl-1H-pyrazol-5-amine (134 mg, 0.96 mmol) and cesium carbonate (626 mg, 1.92 mmol) were suspended in 1,4-dioxane (3 mL). Nitrogen was bubbled through mixture for 10 minutes. 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (39.9 mg, 0.06 mmol) and diacetoxypalladium (7.19 mg, 0.03 mmol) were added and tube was sealed. Mixture was stirred at reflux overnight. Reaction was allowed to cool to room temperature, filtered, washed with CH2Cl2MeOH (91, 10 mL). Silica (63-200 m) was added to the filtrate and mixture was concentrated to dryness. The crude product was purified by flash chromatography (dry loading) on silica gel eluting with 1 to 5% methanol in dichloromethane. The solvent was evaporated to dryness to afford 2-(5-chloro-2-(1-isopropyl-3-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-N-methoxybenzamide (127 mg, 47.8 %) as a pale beige foam =gt; icontaminated by a few BINAP or BINAP by-productsi" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)Cl)C(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 47.78 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/25/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "231" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000682 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0043 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)N)C(C)C" + } + amount { + moles { + value: 0.00091 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" + } + amount { + moles { + value: 0.000455 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 9.1e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" + } + amount { + moles { + value: 6.82e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "dioxane (4.3 mL) was added to 2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (142 mg, 0.45 mmol), 1-isopropyl-3-methyl-1H-pyrazol-5-amine (127 mg, 0.91 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (52.6 mg, 0.09 mmol), BIS(DIBENZYLIDENEACETONE)PALLADIUM (39.2 mg, 0.07 mmol) and sodium 2-methylpropan-2-olate (65.6 mg, 0.68 mmol) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT.nbsp;Reaction mixture from EN042315 was combined and filtered through a PTFE cup to remove insoluble precipitate, washed filter with dioxane and combined filtrates were purified by ion exchange chromatography, using an 25g SCX-2 column. The desired product was eluted from the column using 7M NH3MeOH and product fractions were evaporated to dryness to afford crude product (457 mg).nbsp;The crude product was purified by flash silica (40g grace) chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporateddryness to afford 2-(5-chloro-2-(1-isopropyl-3-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-N-methoxybenzamide (175 mg, 93 %) as a beige solid. nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)Cl)C(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 92.72 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/28/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "233" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00475 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.3 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=C(N=C(C=N1)Cl)N" + } + amount { + moles { + value: 0.0791 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CS(=O)(=O)C1=CC=C(C=C1)Br" + } + amount { + moles { + value: 0.0791 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00475 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00237 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 85.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "1-bromo-4-(methylsulfonyl)benzene (18.6 g, 79.12 mmol) then cesium carbonate (33.5 g, 102.85 mmol) were successively added to a solution of 6-chloropyrazin-2-amine (10.25 g, 79.12 mmol) in 1,4-dioxane (300 ml). The mixture was purged with nitrogen, then (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.75 g, 4.75 mmol) and diacetoxypalladium (0.533 g, 2.37 mmol) were added, the mixture was purged with nitrogen then heated to 85C for 3 hours. After cooling the mixture was diluted with ethylacetate (300 mL), filtered, the solid washed with ethyl acetate (2x100 mL). Filtrate was washed with water (500 mL) =gt; iemulsion, 100 mL of brine were added to help separation of layers.i Organics were washed with brine and dried over MgSO4. Crude product (28g) was purified by flash chromatography on silica gel (solid deposit) eng with 1 to 4% methanolic ammonia (7 N) in dichloromethane =gt; ino separation !! crude was flushedi. The solvent was evaporated to dryness to afford crude product (22g). It was recrystallised from EtOAc (~450 mL) to afford 6-chloro-N-(4-(methylsulfonyl)phenyl)pyrazin-2-amine (14.00 g, 62.4 %, EN03787-21-01) as a white crystalline solid =gt; ipurity = 91%, contains 6.9% EtOAci. Silica (63-200 m) was added to filtrate and it was concentrated to dryness to be purified by flash chromatography on silica gel eluting with 1 to 4% methanolic ammonia (7 N) in dichloromethane =gt; iagain, no separation !! iFractions containing product were combined and concentrated to dryness. Residue (4.3g) was recrystallised from EtOAc (~70 mL) to afford 6-chloro-N-(4-(methylsulfonyl)phenyl)pyrazin-2-amine (1.80 g, 8.0 %, EN03787-21-02) as a white crystalline solid =gt; ipurity = 91%, contains 6.5% EtOAc.ibiHMS6ib" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CS(=O)(=O)C1=CC=C(C=C1)NC2=CN=CC(=N2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 70.39 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/10/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "234" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000758 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C(F)(F)F)Cl" + } + amount { + moles { + value: 0.000303 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C(=N1)C(F)(F)F)N.Cl" + } + amount { + moles { + value: 0.000607 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 4.85e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.43e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide (100 mg, 0.30 mmol), 1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride (122 mg, 0.61 mmol), cesium carbonate (247 mg, 0.76 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (28.1 mg, 0.05 mmol) and diacetoxypalladium (5.45 mg, 0.02 mmol) were suspended in dioxane (1.5 mL) and sealed into a tube. The reaction was degased, purged with nitrogen and heated to 100 C for 18 hours. Reaction was filtered. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford N-methyl-2-(2-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)benzamide (84 mg, 60.4 %) as a yellow crystne solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C(F)(F)F)NC3=CN(N=C3C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 60.42 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/20/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "236" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000885 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN" + } + amount { + moles { + value: 0.000885 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=NC=C1Br)C(F)(F)F" + } + amount { + moles { + value: 0.000442 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 1.33e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C(Cl)(Cl)Cl.[Pd].[Pd]" + } + amount { + moles { + value: 8.85e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 130.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "3-bromo-5-(trifluoromethyl)pyridine (100 mg, 0.44 mmol), methylamine 2 M in THF (0.442 mL, 0.88 mmol), and cesium carbonate (202 mg, 0.62 mmol) were suspended in dioxane (3 mL) . The reaction was purged with nitrogen for 30 minutes then 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (7.68 mg, 0.01 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0)-CHLOROFORM ADDUCT (9.16 mg, 8.85 mol) were added. The reaction was heated at 130 c for 30mins. No REACTION ABANDONED" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CNC1=CN=CC(=C1)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/30/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "237" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000885 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN.Cl" + } + amount { + moles { + value: 0.000885 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=NC=C1Br)C(F)(F)F" + } + amount { + moles { + value: 0.000442 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 1.33e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C(Cl)(Cl)Cl.[Pd].[Pd]" + } + amount { + moles { + value: 8.85e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 130.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "3-bromo-5-(trifluoromethyl)pyridine (100 mg, 0.44 mmol), methylamine hydrochloride (59.8 mg, 0.88 mmol), and cesium carbonate (490 mg, 1.50 mmol) were suspended in dioxane (3 mL) . The reaction was purged with nitrogen for 30 minutes then 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (7.68 mg, 0.01 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0)-CHLOROFORM ADDUCT (9.16 mg, 8.85 mol) were added. The reaction was heated to 130 C in a CEM microwave for 1 hour. No Product formed.Aband" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CNC1=CN=CC(=C1)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/02/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "238" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 3e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.001 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNC(=O)C1" + } + amount { + moles { + value: 0.000499 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=CC(=C1)Cl)[N+](=O)[O-]" + } + amount { + moles { + value: 0.000499 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of tert-butyl 3-oxopiperazine-1-carboxylate (100 mg, 0.50 mmol), 4-chloro-2-methoxy-1-nitrobenzene (94 mg, 0.50 mmol), cesium carbonate (244 mg, 0.75 mmol),nbsp;(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (17.34 mg, 0.03 mmol) and diacetoxypalladium (4.48 mg, 0.02 mmol) was dried for 15 min under HV. Degassed dioxane (1,0-1,2 ml) was added and the resulting mixture was stirred at 90c for 16 hours under inert atmosphere. TLC showed consumption of both SM and new spot (UV active). Reaction combined with EN02378-08 (same TLC profile).LC-MS of crude: EN02378-07-01Extraction: AE2M Na2CO3 sol. Purification by chromatography: eluent AEhexane 2080 to 6040. bIsolated: m= 240 mgb; orange foam. FLA 02378-07-02: 1H NMR, LC-MS: OK. Estimated yield: 68%." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(C(=O)C1)C2=CC(=C(C=C2)[N+](=O)[O-])OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 68.39 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "12/02/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "240" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000337 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.017 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNC(=O)C1" + } + amount { + moles { + value: 0.00749 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=CC(=C1)Cl)[N+](=O)[O-]" + } + amount { + moles { + value: 0.00749 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000337 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.00019 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of tert-butyl 3-oxopiperazine-1-carboxylate (1500 mg, 7.49 mmol), 4-chloro-2-methoxy-1-nitrobenzene (1405 mg, 7.49 mmol),cesium carbonate (3417 mg, 10.49 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (195 mg, 0.34 mmol)nbsp;and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (174 mg, 0.19 mmol)was dried for 15 min under HV. Degassed dioxane (17 ml) was added and the resulting mixture was stirred at 90C for 16 hours under inert atmosphere. Work-up and purification: see EN02378-07-02. tert-butyl 4-(3-methoxy-4-nitrophenyl)-3-oxopiperazine-1-carboxylate (2640 mg, 100 %) was isolated as an orange foam. FLA 02378-10-01: 1H NMR, LC-MS: OK." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(C(=O)C1)C2=CC(=C(C=C2)[N+](=O)[O-])OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 100.3 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "12/04/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "241" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0157 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.1 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.0157 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COCCOC1=CC(=CC(=C1)[N+](=O)[O-])I" + } + amount { + moles { + value: 0.0121 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000362 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000604 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;diacetoxypalladium (0.136 g, 0.60 mmol)nbsp;was added to a stirred mixture ofnbsp;1-iodo-3-(2-methoxyethoxy)-5-nitrobenzene (3.9 g, 12.07 mmol), morpholine (1.373 mL, 15.69 mmol)nbsp;and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.225 g, 0.36 mmol) and cesium carbonate (11.80 g, 36.21 mmol)nbsp;dissolved in toluene (100 mL) over a period of 5 minutes, degased and under argon. The resulting mixture was heatednbsp;at 110 C for 4 hours.The toluene was evaporated , water ( 50ml) was added and the mixture was extracted with ethyle acetate, dried over MgSO4, filtered and asorbed on silica gel.The crude product was purified by flash chromatography on silica gel eluting with 1 to 4% methanol in dichloromethane. The solvent was evaporated to dryness to afford 4-(3-(2-methoxyethoxy)-5-nitrophenyl)morpholine (0.550 g, 16.14 %) as anbsp;orange solid.( starting material unreacted : 2 .5g)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "COCCOC1=CC(=CC(=C1)[N+](=O)[O-])N2CCOCC2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 16.14 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/01/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "242" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0101 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.08 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.0101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COCCOC1=CC(=CC(=C1)[N+](=O)[O-])I" + } + amount { + moles { + value: 0.00774 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000774 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000387 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (0.087 g, 0.39 mmol) was added to a stirred mixture ofnbsp;1-iodo-3-(2-methoxyethoxy)-5-nitrobenzene (2.5 g, 7.74 mmol), cesium carbonate (7.56 g, 23.21 mmol) and morpholine (0.880 mL, 10.06 mmol) and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.482 g, 0.77 mmol) dissolved in toluene (80 mL) and dioxane (20 mL) over a period of 10 minutes, degased and under argon. The resulting suspensionnbsp;was heated at 110 C for 15 hours.Solvents were evaporated and the mixture was adsorbed with ammoniamethanol 7N on silica gel.The crude product was purified by flash chromatography on silica gel eluting with 40 to 60% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford 4-(3-(2-methoxyethoxy)-5-nitrophenyl)morpholine (2.000 g, 92 %) as anbsp;orange solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COCCOC1=CC(=CC(=C1)[N+](=O)[O-])N2CCOCC2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 91.56 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/03/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "243" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0901 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.25 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.039 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COCCOC1=CC(=CC(=C1)[N+](=O)[O-])I" + } + amount { + moles { + value: 0.03 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.003 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.0015 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "The diacetoxypalladium (0.337 g, 1.50 mmol) was added to a stirred mixture ofnbsp;1-iodo-3-(2-methoxyethoxy)-5-nitrobenzene (9.7 g, 30.02 mmol), cesium carbonate (29.3 g, 90.07 mmol) and morpholine (3.41 mL, 39.03 mmol) and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (1.869 g, 3.00 mmol) dissolved in toluene (200 mL) and dioxane (50 mL) The reaction was degased, purged with argon and heated at 110 C for 15 hours. The mixture was diluted with dichloromethane (250ml) the salts were fitered, the filtrate was concentrated.The crude product was purified by flash chromatography on silica gel eluting with 0 to 15% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford 4-(3-(2-methoxyethoxy)-5-nitrophenyl)morpholine (4.50 g, 53.1 %) as anbsp;orange solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COCCOC1=CC(=CC(=C1)[N+](=O)[O-])N2CCOCC2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 53.1 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/23/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "244" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00148 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.006 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC" + } + amount { + moles { + value: 0.00148 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1C2=CC(=O)C3=C(O2)C(=CC=C3)C4=CC=CC5=C4SC6=C5C=C(C=C6)OS(=O)(=O)C(F)(F)F" + } + amount { + moles { + value: 0.000369 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 1.85e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 9.23e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 140.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "6-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thiophen-2-yl trifluoromethanesulfonate (207.4 mg, 0.37 mmol), tert-butyl methylcarbamate (194 mg, 1.48 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (10.69 mg, 0.02 mmol) and cesium carbonate (481 mg, 1.48 mmol) were suspended in dioxane (6 mL) and sealed into a microwave tube. The reaction was heated to 140 C for 1 hour in the microwave reactor and cooled to RT. The reaction mixture was filtered then silica gel (2 g) added.nbsp;The mixture was concentrated iin vacuoi to yield a white powder which was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford tert-butyl methyl(6-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thiophen-2-yl)carbamate (70.0 mg, 34.9 %) as a white solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N(C)C1=CC2=C(C=C1)SC3=C2C=CC=C3C4=CC=CC5=C4OC(=CC5=O)N6CCOCC6" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 34.93 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/16/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "246" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00694 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0173 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC" + } + amount { + moles { + value: 0.0026 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1C2=CC(=O)C3=C(O2)C(=CC=C3)C4=CC=CC5=C4SC6=C5C=C(C=C6)OS(=O)(=O)C(F)(F)F" + } + amount { + moles { + value: 0.00173 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 8.67e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 4.34e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A solution of tert-butyl methylcarbamate (341 mg, 2.60 mmol) in dioxane (17.300 ml) was added to a stirred mixture of 6-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thiophen-2-yl trifluoromethanesulfonate (974 mg, 1.73 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (39.7 mg, 0.04 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (50.2 mg, 0.09 mmol) and cesium carbonate (2261 mg, 6.94 mmol). The resulting mixture was stirred under nitrogen at 110 C for 18 hours. The reaction mixture was poured into water (100 mL) and EtOAc (100 mL). Methanol addition was required to aid separation of layers. b[would vac off dioxane in future]b. The aqueous was further extracted with EtOAc (2 x 50 mL) and DCM (50 mL), all with the aid of methanol for layer separation. The combined organics were washed with saturated brine solution (still formed emulsions), dried over MgSO4 and concentrated under reduced pressure.The crude product was purified by flash silica chromatography, elutgradient 0 to 4% 7M NH3MeOH in DCM. Pure fractions were evaporated to dryness to afford tert-butyl methyl(6-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thiophen-2-yl)carbamate (630 mg, 66.9 %) as a yellow solid. This was taken through to the next step at 85% pure, with no further purification.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N(C)C1=CC2=C(C=C1)SC3=C2C=CC=C3C4=CC=CC5=C4OC(=CC5=O)N6CCOCC6" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 66.94 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/31/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "247" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000712 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.00178 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC" + } + amount { + moles { + value: 0.000267 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1C2=CC(=O)C3=C(O2)C(=CC=C3)C4=CC=CC5=C4SC6=C5C=C(C=C6)OS(=O)(=O)C(F)(F)F" + } + amount { + moles { + value: 0.000178 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 8.9e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 4.45e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A solution of tert-butyl methylcarbamate (35.0 mg, 0.27 mmol) in dioxane (1.781 ml) was added to a stirred mixture of 6-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thiophen-2-yl trifluoromethanesulfonate (100 mg, 0.18 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (4.08 mg, 4.45 mol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (5.15 mg, 8.90 mol) and cesium carbonate (232 mg, 0.71 mmol). The resulting mixture was stirred under nitrogen at 110 C for 3 hours. The cooled reaction mixture was diluted with methanol and the residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH andnbsp;evaporated to dryness to afford tert-butyl methyl(6-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thiophen-2-yl)carbamate (97 mg, 100 %) as a orange residue. 100% assumed and this was progressed to the next stage with no further purification." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N(C)C1=CC2=C(C=C1)SC3=C2C=CC=C3C4=CC=CC5=C4OC(=CC5=O)N6CCOCC6" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 100.38 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/12/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "248" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000776 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00646 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)Br)[N+](=O)[O-]" + } + amount { + moles { + value: 0.00646 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000776 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000517 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;diacetoxypalladium (0.116 g, 0.52 mmol)nbsp;was added to a stirred mixture ofnbsp;4-bromo-1-methoxy-2-nitrobenzene (1.5 g, 6.46 mmol), 1-(piperazin-1-yl)ethanone (0.829 g, 6.46 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.449 g, 0.78 mmol) and cesium carbonate (4.21 g, 12.93 mmol) dissolved in dioxane (10 mL) , degased and under argon. The resulting suspensionnbsp;was stirred at 120 C for 2 hours.At 25C, the mixture was filtered and evaporated under reduce pressure.The mixture was adsorbed on silica gel.The crude product was purified by flash chromatography on silica gel eluting with 1 to 5% methanol in ethyle acetate. The solvent was evaporated to dryness to afford 1-(4-(4-methoxy-3-nitrophenyl)piperazin-1-yl)ethanone (1.400 g, 78 %) as anbsp;orange so" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)OC)[N+](=O)[O-]" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 77.54 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/07/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "249" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0155 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.3 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.129 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)Br)[N+](=O)[O-]" + } + amount { + moles { + value: 0.129 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.0155 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.0103 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;diacetoxypalladium (2.322 g, 10.34 mmol)nbsp;was added to a stirred suspension ofnbsp;4-bromo-1-methoxy-2-nitrobenzene (30 g, 129.29 mmol), 1-(piperazin-1-yl)ethanone (16.57 g, 129.29 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (8.98 g, 15.52 mmol) and cesium carbonate (84 g, 258.59 mmol) dissolved in dioxane (300 mL) , degasednbsp;and under argon. The resulting suspension was stirred at 120 C for 2 hours.At 25C, the mixture was filtered and adsorbed on silica gel .The crude product was purified by flash chromatography on silica gel eluting with 1 to 5% methanol in ethyle acetate. The solvent was evaporated to dryness to afford 1-(4-(4-methoxy-3-nitrophenyl)piperazin-1-yl)ethanone (31.0 g, 86 %) as anbsp;orange so" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)OC)[N+](=O)[O-]" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 85.85 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/08/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "250" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00314 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.13 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CONC(=O)C1=CC=CC=C1N" + } + amount { + moles { + value: 0.0534 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" + } + amount { + moles { + value: 0.0314 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00314 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00157 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.817 g, 3.14 mmol), diacetoxypalladium (0.353 g, 1.57 mmol), 2-amino-N-methoxybenzamide (8.87 g, 53.39 mmol), N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (12 g, 31.40 mmol) and cesium carbonate (20.46 g, 62.81 mmol) were weighed out in a round bottom flask. dioxane (130 mL) was added and argon was let to bubble in the mixture for 10 minutes. The suspension was stirred at 100 C overnight. The reaction mixture was allowed to cool to room temperature under stirring, diluted with ethyl acetate and the insolubles were removed by filtration, washed with EtOAc and the filtrate was concentrated. (Insolubles~19g).The crude product (30g) was purified by flash chromatography on silica gel eluting with 0 to 5% methanol in ethyl acetate. The solvent was evaporated to dryness, giving a gummy foam EN02972-52-01 (15 g, 35.7 mmol, 114 %): not pure. It was repurified by flash chromatography on silica gel eluting with 0 t methanol in ethyl acetate. The solvent was evaporated to dryness to give to batches: one pure EN02972-52-02 (12 g, 28.5 mmol, 91 %), one less pure EN02972-52-03 (0.8 g, 1.903 mmol, 6.06 %).The foam EN02972-52-02 (12 g, 28.5 mmol, 91 %) was dissolved in hot EtOH (12mL). Crystallisation occurred. The resulting crystalline solid was collected by filtration and dried to a constant weight to afford EN02972-52-04 (8.7 g, 19.04 mmol, 60.6 %) as a white crystalline solid. Its filtrate was combined with EN02972-52-03 (0.8 g, 1.903 mmol, 6.06 %) and vacced down. The solid was taken up into EtOH, collected by filtration to give a second crop as a white solid EN02972-52-05 (1.88 g, 4.47 mmol, 14.24 %)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 74.87 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/17/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "251" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000523 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.06 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CONC(=O)C1=CC=CC=C1N" + } + amount { + moles { + value: 0.0089 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" + } + amount { + moles { + value: 0.00523 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000523 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000262 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.303 g, 0.52 mmol), diacetoxypalladium (0.059 g, 0.26 mmol), 2-amino-N-methoxybenzamide (1.479 g, 8.90 mmol), N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (2 g, 5.23 mmol) and cesium carbonate (3.41 g, 10.47 mmol) were weighed out in a round bottom flask. dioxane (60 mL) was added and argon was let to bubble in the mixture for 10 minutes. The suspension was stirred at 100 C overnight. The reaction mixture was allowed to cool to room temperature under stirring, diluted with dichloromethane and methanol, silicagel was added and the mixture was concentrated. The crude product was purified by flash chromatography on silica gel (150g) eluting with 0 to 5% methanol in ethyl acetateDCM (11). The solvent was evaporated to dryness, giving a gummy foam. 35 mL of tBuOMe was added and the resulting solution was stirred at rt for 3 hours. The resulting precipitate was collected by filtration, washed with tBuOMe and dried tconstant weight to afford EN02430-89-01 (1.53 g, 3.64 mmol, 69.5 %) as a white solid, which was contained DCM and EtOAc. It was taken up into a minimum of MeCN, heated to 100C and MeCN was added until complete solubilisation. The solution was filtered and left to cool to rt overnight. The crystallized product was collected by filtration and dried to constant weight under high vacuum (7.10-2mbar) at 50C for 1h, to give EN02430-89-02 (1.2 g, 2.63 mmol, 50.2 %) as a crystalline white solid. The filtrate was concentrated, triturated in MeCN and the resulting solid was collected by filtration to give EN02430-89-03 (0.2 g, 0.476 mmol, 9.09 %) - a second crop - as a white solid.1g of EN02430-89-02 (1.2 g, 2.63 mmol, 50.2 %), EN02430-89-03 (0.2 g, 0.476 mmol, 9.09 %) amp; EN02430-89-04 (48 mg, 0.114 mmol, 2.182 %) were combined, stirred in boiling water (100 mL) for 10 minutes, cooled down, collected by filtration and dried under vacuum (7.10-2mbar) at 50C in presence give EN02430-89-05 (1.1 g, 2.56 mmol, 49.0 %)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 48.99 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/20/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "252" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 5.89e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC=CC(=C1C(=O)NOC)N" + } + amount { + moles { + value: 0.000667 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" + } + amount { + moles { + value: 0.000393 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 5.89e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.53e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (34.1 mg, 0.06 mmol), diacetoxypalladium (7.93 mg, 0.04 mmol), 2-amino-N,6-dimethoxybenzamide (131 mg, 0.67 mmol), N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (150 mg, 0.39 mmol) and cesium carbonate (256 mg, 0.79 mmol) were weighed out in a wave vial, sealed and dioxane (5 mL) was added. Argon was let to bubble in the mixture for 5 minutes. The reaction was stirred at 90 C overnight. The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane and MeOH, silica gel was added and the mixture was concentrated. The crude product was purified by flash chromatography on silica gel (25g) eluting with 0 to 5% methanol in ethyl acetateDCM (11). The solvent was evaporated to dryness. The residue was triturated in diethyl ether (gummy in tBuOMe) and the resulting precipitate was collected by filtration, washed with diethyl ether and dried to a constant weight to afford 2-(2-(1,3-dimethrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (131 mg, 74.1 %) as a off-white solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=C(C(=CC=C3)OC)C(=O)NOC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 74.09 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/20/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "253" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00327 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.13 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=C(C=CC=C1OC)N" + } + amount { + moles { + value: 0.0491 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)I)C(F)(F)F)C" + } + amount { + moles { + value: 0.0327 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00327 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00164 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A suspension of 2-amino-6-methoxy-N-methylbenzamide (8.84 g, 49.07 mmol), N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (12.5 g, 32.71 mmol), diacetoxypalladium (0.367 g, 1.64 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.893 g, 3.27 mmol) and cesium carbonate (19.18 g, 58.88 mmol) in dioxane (130 mL) was degassed with argon, which was also let to bubble for 10 minutes then stirred at reflux for 6h. The reaction mixture was allowed to cool to rt, the insolubles were removed by filtration, washed with EtOAc and the filtrate was concentrated. (Insolubles~23g).The crude product (20g) was purified by flash chromatography on silica gel eluting with 0 to 5% methanol in ethyl acetate. The solvent was evaporated to dryness to afford a foam (7.9g) which was taken up into dichloromethane (40ml) (no time to get dissolved, it crashed out very quickly) and sonicated for 5 minutes. The resulting precipitate was collected by filtration, washed with dichloromethane and dried under vacuum at 50C to a constant weight to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-6-methoxy-N-methylbenzamide (6.53 g, 46.0 %) as anbsp;white solid.The filtrate was concentrated to dryness (residue weight: 700mg), taken up into DCM and collected by filtration to give a second sample EN02972-51-02 (0.36 g, 0.829 mmol, 2.53 %)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=C(C(=CC=C3)OC)C(=O)NC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 45.95 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/15/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "254" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0072 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.3 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=C(C=CC=C1OC)N" + } + amount { + moles { + value: 0.108 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)I)C(F)(F)F)C" + } + amount { + moles { + value: 0.072 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.0072 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.0036 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 95.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-amino-6-methoxy-N-methylbenzamide (19.45 g, 107.95 mmol), N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (27.5 g, 71.97 mmol) (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4.16 g, 7.20 mmol) diacetoxypalladium (0.808 g, 3.60 mmol) and cesium carbonate (42.2 g, 129.54 mmol) were suspended in dioxane (300 mL). The reaction was degased, purged with argon sereval times and heated to 95 C overnight. The reaction mixture was allowed to cool to rt, the insolubles were removed by filtration, washed with EtOAc and the filtrate was concentrated.The resulting residue was triturated with dichloromethane (150 ml), filtered, washed with DCM to give EN03299-47-01 (8.5 g, 19.57 mmol, 27.2 %)The filtrate was purified by flash chromatography on silica gel eluting with AcOEt and 5% methanol in ethyl acetate. Solvent were evaporated. The resulting precipitate was collected by filtration, washed with dichloromethane and dried to afford EN03299-47-02 (4.5 g, 10.36l, 14.39 %).Not enought combined with uEN03299-49u" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=C(C(=CC=C3)OC)C(=O)NC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 41.58 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/30/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "255" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000724 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000483 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1C2=C(N=C(C=C2)Cl)OC(CN1C)C3CC3" + } + amount { + moles { + value: 0.000483 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 2.41e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.21e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "8-chloro-2-cyclopropyl-4,5-dimethyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (122 mg, 0.48 mmol), 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (99 mg, 0.48 mmol), Pd2dba3 (11.05 mg, 0.01 mmol), BINAP (15.03 mg, 0.02 mmol) and SODIUM TERT-BUTOXIDE (69.6 mg, 0.72 mmol) were weighed in to a microwave vial, the vial was capped and flushed with argon. toluene (4 mL) was added and the mixture was heated to 100C in a microwaver apparatus for 2 h. The cooled reaction mixture was diluted with dichloromethane and filtered. The mixture was concentrated and purified by column chromatography on Silica, using gradient elution with increasing concentration of methanol, from 0 to 8 %, in dichloromethane to give a mixture of the two diastereomers. This was then jected to diastereo and enantio separation to give 31 mg of isomer 1, 32.6 mg of isomer 2, 29 mg of isomer 3 and 29.7 mg of isomer 4 of 2-cyclopropyl-N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4,5-dimethyl-2,3,4,5-tetrahydropyrido[f][1,4]oxazepin-8-amine (Total Yield 122.3 mg, 60 %)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1C2=C(N=C(C=C2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)OC(CN1C)C5CC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 15.27 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/12/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "256" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0669 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.14 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCCN1" + } + amount { + moles { + value: 0.287 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" + } + amount { + moles { + value: 0.0478 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00478 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.00119 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "sodium 2-methylpropan-2-olate (6.43 g, 66.88 mmol) was added to 1-(benzyloxy)-4-bromo-2-fluorobenzene (13.43 g, 47.77 mmol) and piperazine (24.69 g, 286.64 mmol) in toluene (140 mL). The resulting mixture was bubbled with nitrogen for 10 minutes then 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (2.97 g, 4.78 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (1.094 g, 1.19 mmol) were added and the mixture was stirred at 110 C for 20 hours.nbsp;The reaction mixture was cooled to room temperature then fitered through celite and the filter cake washed with ethyl acetate (500 mL).nbsp;The filtrate was evaporated to give crude product.nbsp;The crude product was purified by flash silica chromatography, elution gradient 0 to 20% MeOH in DCM. Pure fractions were evaporated to dryness to afford 1-(4-(benzyloxy)-3-fluorophenyl)piperazine (9.80 g, 71.6 %) as a solid. nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CN(CCN1)C2=CC(=C(C=C2)OCC3=CC=CC=C3)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 71.64 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "12/05/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "258" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000712 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.001 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)CN1CCOCC1" + } + amount { + moles { + value: 0.000214 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1C2=CC(=O)N3C=CC=C(C3=N2)C4=CC=CC5=C4SC6=C5C=C(C=C6)OS(=O)(=O)C(F)(F)F" + } + amount { + moles { + value: 0.000178 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 8.9e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 4.45e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A solution of 6-(2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)dibenzo[b,d]thiophen-2-yl trifluoromethanesulfonate (100mg, 0.18 mmol) in dry dioxane (1 ml) was added to a stirred mixture of N-methyl-2-morpholinoacetamide (33.8 mg, 0.21 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (4.08 mg, 4.45 mol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (5.15 mg, 8.90 mol) and cesium carbonate (232 mg, 0.71 mmol) in dry dioxane (1 ml) . The resulting mixture was stirred under nitrogen at 110 C for 3 hours.nbsp;UPLC analysis showed no appreciable product only hydrolysis of the triflate - not isolated , reaction abandonned" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(C1=CC2=C(C=C1)SC3=C2C=CC=C3C4=CC=CN5C4=NC(=CC5=O)N6CCOCC6)C(=O)CN7CCOCC7" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/23/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "259" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "[O-]P(=O)([O-])[O-].[K+].[K+].[K+]" + } + amount { + moles { + value: 1.12e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.001 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)CN1CCOCC1" + } + amount { + moles { + value: 0.000224 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1C2=CC(=O)N3C=CC=C(C3=N2)C4=CC=CC5=C4SC6=C5C=C(C=C6)OS(=O)(=O)C(F)(F)F" + } + amount { + moles { + value: 0.000112 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 1.12e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.12e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a microwave vial, under nitrogen, at room temperature, a solution of 6-(2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)dibenzo[b,d]thiophen-2-yl trifluoromethanesulfonate (63 mg, 0.11 mmol) in dry toluene (1 mL) was added to a stirred mixture of N-methyl-2-morpholinoacetamide (35.5 mg, 0.22 mmol), Tripotassium phosphate (47.6 mg, 0.22 mmol), rac BINAP (6.99 mg, 0.01 mmol) and Palladium(II) acetate (2.52 mg, 0.01 mmol) in . The resulting mixture was heated in a Biotage Optimiser Microwave reactor under nitrogen at 100 C for 3 hours.nbsp;UPLC of the reaction showed no indication of the desired compound - not isolated - reaction abandonned.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(C1=CC2=C(C=C1)SC3=C2C=CC=C3C4=CC=CN5C4=NC(=CC5=O)N6CCOCC6)C(=O)CN7CCOCC7" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/31/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "260" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000955 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000597 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC(=NC2=C1CN(CC(O2)C3=NC(=CS3)C)C)Cl" + } + amount { + moles { + value: 0.000597 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 2.99e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.49e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "8-chloro-4,6-dimethyl-2-(4-methylthiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (185 mg, 0.60 mmol), 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (122 mg, 0.60 mmol), Pd2dba3 (13.67 mg, 0.01 mmol), BINAP (18.59 mg, 0.03 mmol) and SODIUM TERT-BUTOXIDE (92 mg, 0.96 mmol) were weighed into a microwave vial. toluene (5 mL) was added and the vial was capped and flushed with argon. The mixture was heated to 100C in a microwave apparatus for 2 h. The reaction mixture was diluted with dichloromethane and filtered. The solvents were evaporated and the residue was purified by column chromatography on Silica using a gradient of increasing concentration of methanol, from 0 to 8 %, in dichloromethane to give 163 mg og the title product . The enantiomers were separated by HPLC using a chiral stationary phase to give enantiomer 1 of N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4,6-dimethyl-2-(4-methylthiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (66.3 mg, 23.25 %d enantiomer 2 of N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4,6-dimethyl-2-(4-methylthiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (65.2 mg, 22.86 %)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CC(=NC2=C1CN(CC(O2)C3=NC(=CS3)C)C)NC4=NC(=C(C=C4)C5=CN(N=C5)C)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 22.86 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/10/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "263" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[K+]" + } + amount { + moles { + value: 0.00926 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C=O" + } + amount { + volume { + value: 0.00926 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCNCC1" + } + amount { + moles { + value: 0.0231 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)NC1=CN=C(C=N1)Br" + } + amount { + moles { + value: 0.00463 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" + } + amount { + moles { + value: 0.00926 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 9.26e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "1-methylpiperazine (2.318 g, 23.14 mmol), N-(5-bromopyrazin-2-yl)acetamide (1 g, 4.63 mmol), tri-tert-butylphosphine (1.873 g, 9.26 mmol), tris(dibenzylideneacetone)dipalladium (0.085 g, 0.09 mmol) and potassium 2-methylpropan-2-olate (1.039 g, 9.26 mmol) were suspended in DMF (9.26 ml) and sealed into a microwave tube. The reaction was heated to 120 C for 40 minutes in the microwave reactor and cooled to RT. The mixture was diluted with methanol and acidified with HCl, then the solution was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness to afford N-(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)acetamide (0.866 g, 80 %) as a dark oil. Used without further purification. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)NC1=CN=C(C=N1)N2CCN(CC2)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 79.51 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/24/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "264" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00203 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CN=C1)N" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000122 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000101 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;pyridin-3-amine (95 mg, 1.01 mmol), 2,4-dichloropyridine (0.151 mL, 1.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (70.4 mg, 0.12 mmol) and cesium carbonate (660 mg, 2.03 mmol) were stirred in dioxane (5 mL).nbsp;The mixture was purged with nitrogen for 10 minutes.nbsp;Palladium(II) acetate (22.76 mg, 0.10 mmol) was added and the mixture heated at 100 C for 2h.nbsp;The mixture was cooled, filtered and concentrated.nbsp;The crude product was purified by flash silica chromatography, eluting gradient 5-45% EtOAc in isohexane. Fractions were evaporated to dryness and purified by flash silica chromatography, eluting at 35% EtOAc in isohexanenbsp;to afford 4-chloro-N-(pyridin-3-yl)pyridin-2-amine (107 mg, 51.5 %) as a cream powder." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC(=CN=C1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 51.48 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/29/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "266" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00201 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.001 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC(=NC2=C1CN(CC(O2)C3CCCO3)C)Cl" + } + amount { + moles { + value: 0.001 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 5.02e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.51e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (205 mg, 1.00 mmol), Pd2(dba)3 (22.99 mg, 0.03 mmol), BINAP (31.3 mg, 0.05 mmol) and SODIUM TERT-BUTOXIDE (193 mg, 2.01 mmol) were placed in a round bottomed flask. The flask was stoppered with a septum and flushed with argon. To this was added a solution of 8-chloro-4,6-dimethyl-2-(tetrahydrofuran-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (284 mg, 1.00 mmol) in toluene (5 mL) and the resulting mixture was heated to 100C for 5 h. The reaction mixture was diluted with dichloromethane and filtered, and the solvent was evaporated. The residue was purified by column chromatography on Silica using gradient elution with increasing concentration of methanol, from 0 to 8 %, in dichloromethane to give a mixture of the two diastereoisomers. The major isomer was precipitated from methanol once and from ethanol twice to give 45 mg of Isomer 1 of N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4,6-dimethyl-2-(tetrahydrofuran-2-yl)-2,3,4,5-tetrropyrido[3,2-f][1,4]oxazepin-8-amine (45 mg, 10 %) as a single diastereoisomer of unknown stereochemistry. The rest of the material was purified by HPLC to give Isomer 1 (115.7 mg, 25.6 %) and Isomer 2 (39 mg, 8.6 %) of N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4,6-dimethyl-2-(tetrahydrofuran-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CC(=NC2=C1CN(CC(O2)C3CCCO3)C)NC4=NC(=C(C=C4)C5=CN(N=C5)C)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 35.51 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/28/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "267" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00856 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.06 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CN(CCN1)CC2=CC=CC=C2" + } + amount { + moles { + value: 0.00673 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC(=O)C2=C(O1)C(=CC(=C2)OC)Br" + } + amount { + moles { + value: 0.00611 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000734 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000306 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Tris(dibenzylideneacetone)dipalladium(0) (0.280 g, 0.31 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.457 g, 0.73 mmol), ethyl 8-bromo-6-methoxy-4-oxo-4H-chromene-2-carboxylate (2 g, 6.11 mmol), 1-benzylpiperazine (1.169 mL, 6.73 mmol) and cesium carbonate (2.79 g, 8.56 mmol) were heated under argon to 80 C in toluene (60 mL) overnight.nbsp;The reaction mixture was allowed to cool.nbsp;Ethylacetate was added and the organic mixture was filtered.nbsp;The filtrate was evaporated onto Silica gel.nbsp;The crude product was added to a silica gel column and was eluted with MeOHDCM 0-5%.1H NMR in CDCl3 is consistent with desired productMSnbsp;(m+1) = 423.HPLC Peak RT = 3.38 minutes is product.nbsp;Purity = 63%." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC(=O)C2=C(O1)C(=CC(=C2)OC)N3CCN(CC3)CC4=CC=CC=C4" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 48.39 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/24/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "268" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[K+]" + } + amount { + moles { + value: 0.00094 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.000805 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC(=CC(=C1NC(=O)CC(C)(C)C)C)Br" + } + amount { + moles { + value: 0.000671 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C1=CC=CC=C1C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 6.86e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 3.39e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Exemplar cmpd from H. Lundbeck WO2007090409, though employing slightly different Buchwald-Hartwig coupling conditions.Tris(dibenzylidenacetone)dipalladium(0) (31 mg, 0.03 mmol) and 2\'-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (27 mg, 0.07 mmol) were stirred in anhydrous toluene (3 mL) for 15 minutes under an argon (g) sparge. To the stirring soluntion was added the N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (200 mg, 0.67 mmol) and morpholine (0.070 mL, 0.80 mmol) neat, followed by the potassium tert-butoxide (1M in THF) (0.94 mL, 0.94 mmol) via syringe. The mixture was then heated in a sealed vessel to 80 C for 18hrs before cooling to ambint temperature. The mixture was filtered thru a 0.7uM GMF. The resultant crude solution was ject to flash chromatorgraphy (SiO2 - 12 g; gradient elution: 100% hexanes for 1 minute then 0% - 80% EtOAcHexane over 13 minutes at 30 mLmin) via detection with UV light at 254nm. The appropriate fractions were then stirred overolorizing carbon (Norit neutral), filtered thru Celite and concentrated to afford the N-(2,6-dimethyl-4-morpholinophenyl)-3,3-dimethylbutanamide (130 mg, 63.7 %) as a off-white solid that appears to benbsp;~90% purity by 1H NMR (CDCl3), though TLC and LCMS reveal one peak. The resultant solid was ject to flash chromatorgraphy (basic alumina - 24 g; gradient elution: 5% EtOAcHexane for 1.5 minutes then 5% - 100% EtOAcHexane over 11 minutes at 30 mLmin) via detection with UV light at 254nm to afford the N-(2,6-dimethyl-4-morpholinophenyl)-3,3-dimethylbutanamide (130 mg, 63.7 %) again what appears to be ~90% purity by 1H NMR (CDCl3), though TLC and LCMS reveal one peak. Aliqout was provided to X. Ye for SFC analysis wherein all conditions examined reveal only one peak (attached). 1H NMR analysis in DMSO reveals one clean cmpd. Forming rotamers in CDCl3 with difference exagerated in the morpholino -CH2-N-CH2- protons." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CC(=CC(=C1NC(=O)CC(C)(C)C)C)N2CCOCC2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 63.67 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/14/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "269" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[K+]" + } + amount { + moles { + value: 0.00094 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.000804 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC(=CC(=C1NC(=O)CC2CCCC2)C)Br" + } + amount { + moles { + value: 0.00067 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C1=CC=CC=C1C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 6.86e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 3.39e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Exemplar cmpd from H. Lundbeck WO2007090409, though employing slightly different Buchwald-Hartwig coupling conditions.Tris(dibenzylidenacetone)dipalladium(0) (31 mg, 0.03 mmol) and 2\'-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (27 mg, 0.07 mmol) were stirred in anhydrous toluene (3 mL) for 15 minutes under an argon (g) sparge. To the stirring soluntion was added the N-(4-bromo-2,6-dimethylphenyl)-2-cyclopentylacetamide (208 mg, 0.67 mmol) and morpholine (0.070 mL, 0.80 mmol) neat, followed by the potassium tert-butoxide (1M in THF) (0.94 mL, 0.94 mmol) via syringe. he mixture was then heated in a sealed vessel to 80 C for 18hrs before cooling to ambint temperature. The mixture was filtered thru a 0.7uM GMF. The resultant crude solution was ject to flash chromatorgraphy (SiO2 - 12 g; gradient elution: 100% hexanes for 1 minute then 0% - 85% EtOAcHexane over 14 minutes at 30 mLmin) via detection with UV light at 254nm. The appropriate fractions were then stirred over lorizing carbon (Norit neutral), filtered thru Celite and concentrated to afford the 2-cyclopentyl-N-(2,6-dimethyl-4-morpholinophenyl)acetamide (47.0 mg, 22.17 %) as a white solid in 90% purity by 1H NMR (CDCl3), though TLC and LCMS reveal one peak. The resultant solid was ject to flash chromatorgraphy (basic alumina - 24 g; gradient elution: 5% EtOAcHexane for 1.5 minutes then 5% - 100% EtOAcHexane over 11 minutes at 30 mLmin) via detection with UV light at 254nm to afford 2-cyclopentyl-N-(2,6-dimethyl-4-morpholinophenyl)acetamide (28.0 mg, 13.21 %) again what appears to be ~80% purity by 1H NMR (CDCl3), though TLC and LCMS reveal one peak. Aliqout was provided to X. Ye for SFC analysis wherein all conditions examined reveal only one peak (attached). 1H NMR analysis in DMSO reveals one cmpd. Forming rotamers in CDCl3 with difference exagerated in the morpholino -CH2-N-CH2- protons." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CC(=CC(=C1NC(=O)CC2CCCC2)C)N3CCOCC3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 13.21 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/14/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "270" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00478 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.025 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@@H]1CNCCN1C(=O)OC(C)(C)C" + } + amount { + moles { + value: 0.00358 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=CC(=C1)Br)OCC2=CC=CC=C2" + } + amount { + moles { + value: 0.00341 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000136 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000102 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Tonbsp;(R)-tert-butyl 2-methylpiperazine-1-carboxylate (0.717 g, 3.58 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.094 g, 0.10 mmol) and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.085 g, 0.14 mmol) andnbsp;Sodium tert-butoxide (0.459 g, 4.78 mmol) was added a solution of 1-(benzyloxy)-4-bromo-2-methoxybenzene (1 g, 3.41 mmol) in Toluene (25 mL).nbsp;The reaction was heated to 80 C for 18 hours. the reaction was allowed to cool to room temperature and diluted with dcm (50 ml). This was washed with water (2 x 50 ml), dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The crude product was dissolved in hydrochloric acid solution in methanol (4N, 20 ml) and stirred at room temprature overnight. The solvent was removed under reduced pressure.The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness to afford (R)-1-(4-(benzylo3-methoxyphenyl)-3-methylpiperazine (0.429 g, 40.3 %) as a yellow gum. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@@H]1CN(CCN1)C2=CC(=C(C=C2)OCC3=CC=CC=C3)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 40.26 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/11/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "271" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 3.93e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCONC(=O)C1=CC=CC=C1N" + } + amount { + moles { + value: 0.000667 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)I)C(F)(F)F)C" + } + amount { + moles { + value: 0.000393 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.93e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.96e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (22.71 mg, 0.04 mmol), diacetoxypalladium (4.41 mg, 0.02 mmol), 2-amino-N-ethoxybenzamide (120 mg, 0.67 mmol), N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (150 mg, 0.39 mmol) and cesium carbonate (256 mg, 0.79 mmol) were weighed out in a wave vial, sealed and dioxane (4 mL) was added. Reaction was degassed with nitrogen. The reaction was stirred at 90 C for 12 hours =gt; iincomplete (~90% conversion)i. A few Pd(OAc)2, Xantphos and Cs2CO3 were added. Reaction was degassed with nitrogen and stirred at 90C for 2 hours =gt; icomplete.i The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane and MeOH and silica (40-63 m) was added. Mixture was concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 0 to 4% methanol in dichloromethane. Solvent was evaporated to afford product as a pale yellow foam. This wEt2O, petroleum ether was added and the resulting precipitate was sonicated for 10 minutes. Solid was filtered and dried under high vacuum to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N-ethoxybenzamide (127 mg, 74.5 %) as a white solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C(F)(F)F)NC3=CC(=NN3C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 74.48 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/13/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "272" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 3.93e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C(=C1)C(=O)NOCCO)N" + } + amount { + moles { + value: 0.000667 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)I)C(F)(F)F)C" + } + amount { + moles { + value: 0.000393 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.93e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.96e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (22.71 mg, 0.04 mmol), diacetoxypalladium (4.41 mg, 0.02 mmol), 2-amino-N-(2-hydroxyethoxy)benzamide (131 mg, 0.67 mmol), N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (150 mg, 0.39 mmol) and cesium carbonate (256 mg, 0.79 mmol) were weighed out in a wave vial, sealed and dioxane (4 mL) was added. Reaction was degassed with nitrogen. The reaction was stirred at 90 C for 12 hours =gt; iincomplete (~85% conversion)i. A few Pd(OAc)2, Xantphos and Cs2CO3 were added. Reaction was degassed with nitrogen and stirred at 90C for 2 hours =gt; ialmost complete.i The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane and MeOH and silica (40-63 m) was added. Mixture was concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 0 to 12% methanol in ethyl acetate. Solvent was evaporated to afford product as a yellow riturated in Et2O and petroleum ether and the resulting precipitate was sonicated for 10 minutes. Solid was filtered and dried under high vacuum to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N-(2-hydroxyethoxy)benzamide (86 mg, 48.6 %) as a yellow solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOCCO)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 48.64 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/13/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "273" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 9.1e-06 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=N1)C2=CC=C(C=C2)N" + } + amount { + moles { + value: 1.82e-05 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 1.82e-05 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 1.82e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.82e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A solution of (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (5.00 mg, 0.02 mmol) and 4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (3.17 mg, 0.02 mmol) in DME (.5 mL) was added via a syringe to a capped microwave vial containing PALLADIUM(II) ACETATE (0.409 mg, 1.82 mol), 2-(DICYCLOHEXYLPHOSPHINO)BIPHENYL (0.638 mg, 1.82 mol), CESIUM CARBONATE (8.89 mg, 0.03 mmol) and KI (1.511 mg, 9.10 mol) under an argon atmosphere. The resulting mixture was heated to 100C in a microwavwe apparatus for 1 h and analyzed by LCMS." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=N1)C2=CC=C(C=C2)NC3=NC4=C(CN(C[C@H](O4)C5=CC=CC=C5)C)C=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/16/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "275" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 2.73e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=N1)C2=CC=C(C=C2)N" + } + amount { + moles { + value: 1.82e-05 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 1.82e-05 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 1.82e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.82e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A solution of (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (5.00 mg, 0.02 mmol) and 4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (3.17 mg, 0.02 mmol) in DME (.5 mL) was added via a syringe to a capped microwave vial containing PALLADIUM(II) ACETATE (0.409 mg, 1.82 mol), 2-(DICYCLOHEXYLPHOSPHINO)BIPHENYL (0.638 mg, 1.82 mol) and CESIUM CARBONATE (8.89 mg, 0.03 mmol) under an argon atmosphere. The resulting mixture was heated to 100C in a microwave apparatus for 1 h and analyzed by LCMS. No " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=N1)C2=CC=C(C=C2)NC3=NC4=C(CN(C[C@H](O4)C5=CC=CC=C5)C)C=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/16/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "276" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[K+]" + } + amount { + moles { + value: 2.73e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=N1)C2=CC=C(C=C2)N" + } + amount { + moles { + value: 1.82e-05 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 1.82e-05 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 1.82e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.82e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A solution of (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (5.00 mg, 0.02 mmol) and 4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (3.17 mg, 0.02 mmol) in DME (0.5 mL) was added via a syringe to a capped microwave vial containing PALLADIUM(II) ACETATE (0.409 mg, 1.82 mol), 2-(DICYCLOHEXYLPHOSPHINO)BIPHENYL (0.638 mg, 1.82 mol) and KOtBu (3.06 mg, 0.03 mmol) under an argon atmosphere. The resulting mixture was heated to 100C in a microwavwe apparatus for 1 h and analyzed by LCMS. No " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=N1)C2=CC=C(C=C2)NC3=NC4=C(CN(C[C@H](O4)C5=CC=CC=C5)C)C=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/16/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "277" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 2.73e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=N1)C2=CC=C(C=C2)N" + } + amount { + moles { + value: 1.82e-05 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 1.82e-05 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 1.82e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.82e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A solution of (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (5.00 mg, 0.02 mmol) and 4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (3.17 mg, 0.02 mmol) in DME (.5 mL) was added via a syringe to a capped microwave vial containing PALLADIUM(II) ACETATE (0.409 mg, 1.82 mol), XANTPHOS (1.053 mg, 1.82 mol) and CESIUM CARBONATE (8.89 mg, 0.03 mmol) under an argon atmosphere. The resulting mixture was heated to 100C in a microwavwe apparatus for 1 h and analyzed by LCMS. No " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=N1)C2=CC=C(C=C2)NC3=NC4=C(CN(C[C@H](O4)C5=CC=CC=C5)C)C=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/16/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "278" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 2.73e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=N1)C2=CC=C(C=C2)N" + } + amount { + moles { + value: 1.82e-05 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 1.82e-05 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 1.82e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 9.1e-07 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A solution of (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (5.00 mg, 0.02 mmol) and 4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (3.17 mg, 0.02 mmol) in DME (.5 mL) was added via a syringe to a capped microwave vial containing Pd2(dba)3 (0.833 mg, 0.91 mol), 2-(DICYCLOHEXYLPHOSPHINO)BIPHENYL (0.638 mg, 1.82 mol) and Cs2CO3 (8.89 mg, 0.03 mmol) under an argon atmosphere. The resulting mixture was heated to 100C in a microwavwe apparatus for 1 h and analyzed by LCMS. No " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=N1)C2=CC=C(C=C2)NC3=NC4=C(CN(C[C@H](O4)C5=CC=CC=C5)C)C=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/16/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "279" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.005 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1CCOC1" + } + amount { + volume { + value: 0.036 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCCN1" + } + amount { + moles { + value: 0.0125 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC2=C(C=C(O2)C(=O)N)C(=C1)Br" + } + amount { + moles { + value: 0.0025 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00025 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000125 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 70.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "The crude product from EN03731-54-001, 4-bromobenzofuran-2-carboxamide (0.600 g, 2.5 mmol), was dissolved in THF (18 mL) and water (18.00 mL). To this mixture were added piperazine (1.077 g, 12.50 mmol), Cesium carbonate (1.629 g, 5.00 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.114 g, 0.13 mmol) and rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.156 g, 0.25 mmol) and the reaction was heated at 70 C over night.2010-04-13 No product was detected. The reaction mixture was filtered and solvents were removed in vacuo. The residue was partitioned between methylene chloride and water. The organic layer was washed with 1M HCl(aq), dired with sodium sulfate, filtered, concentrated and purified by flash chromatography(Isolute Si 70g, methylene chloride: methanol; 97:3). No product could be detectedisolated." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CN(CCN1)C2=C3C=C(OC3=CC=C2)C(=O)N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/12/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "280" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00204 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.000926 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C(=CC=C1)Br)[N+](=O)[O-]" + } + amount { + moles { + value: 0.000926 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000185 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 9.26e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "tert-butyl piperazine-1-carboxylate (172 mg, 0.93 mmol) and 1-bromo-3-methyl-2-nitrobenzene (0.124 mL, 0.93 mmol), were added to a stirred solution of diacetoxypalladium (20.78 mg, 0.09 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (107 mg, 0.19 mmol) and cesium carbonate (664 mg, 2.04 mmol) dissolved in dioxane (3 mL). The resulting solution was stirred at 80 C under nitrogen overnight.The reaction mixture was filtered, dried under vaccum.nbsp;The crude product was purified by flash chromatography on silica gel eluting with 5 to 15% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-(3-methyl-2-nitrophenyl)piperazine-1-carboxylate (50.0 mg, 16.81 %) as anbsp;orange oil." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C(=CC=C1)N2CCN(CC2)C(=O)OC(C)(C)C)[N+](=O)[O-]" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 16.81 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/29/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "281" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00469 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N" + } + amount { + moles { + value: 0.00396 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C=C1Br)F)C=O" + } + amount { + moles { + value: 0.0033 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000264 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" + } + amount { + moles { + value: 0.000132 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A solution of 4-bromo-2-fluorobenzaldehyde (0.670 g, 3.30 mmol) dissolved in toluene (10 mL) was treated with tert-butyl carbamate (0.464 g, 3.96 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.164 g, 0.26 mmol), Bis(dibenzylideneacetone)palladium (0.076 g, 0.13 mmol) and cesium carbonate (1.527 g, 4.69 mmol)nbsp;under nitrogen. The mixture was degassed under vacuum several times before heating at 100 C for 24 hours. Reaction incomplete so heated for further 10 hours. The reaction mixture was diluted with water (250 mL), and extracted with ethyl acetate (250 mL X 2).nbsp;The organic was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution 10% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 3-fluoro-4-formylphenylcarbamate (0.660 g, 84 %) as a yellow solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC1=CC(=C(C=C1)C=O)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 83.59 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/20/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "282" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0216 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.04 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N" + } + amount { + moles { + value: 0.0183 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C=C1Br)F)C=O" + } + amount { + moles { + value: 0.0152 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00122 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" + } + amount { + moles { + value: 0.000609 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A solution of 4-bromo-2-fluorobenzaldehyde (3.09 g, 15.22 mmol) dissolved in toluene (40 mL) was treated with tert-butyl carbamate (2.140 g, 18.27 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.758 g, 1.22 mmol), Bis(dibenzylideneacetone)palladium (0.350 g, 0.61 mmol) and cesium carbonate (7.04 g, 21.62 mmol)nbsp;under nitrogen. The mixture was degassed under vacuum several times before heating at 100 C for 30 hours. The reaction mixture was diluted with water (250 mL), and extracted with ethyl acetate (250 mL X 2).nbsp;The organic was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution 10% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 3-fluoro-4-formylphenylcarbamate (3.55 g, 97 %) as a yellow solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC1=CC(=C(C=C1)C=O)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 97.47 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/24/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "283" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "[O-]P(=O)([O-])[O-].[K+].[K+].[K+]" + } + amount { + moles { + value: 0.003 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NCCC1CCNCC1" + } + amount { + moles { + value: 0.0015 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)I" + } + amount { + moles { + value: 0.00218 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" + } + amount { + moles { + value: 0.00015 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C.[Pd]" + } + amount { + moles { + value: 0.00015 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a solution of tert-butyl 2-(piperidin-4-yl)ethylcarbamate (0.342 g, 1.5 mmol) in anhydrous DME were added iodobenzene (0.444 g, 2.18 mmol), bis(tri-t-butylphosphine)palladium(0) (0.077 g, 0.15 mmol) and potassium phosphate (0.245 mL, 3.00 mmol). The reaction was heated to 100C overnight. This reaction did not work." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NCCC1CCN(CC1)C2=CC=CC=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/08/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "284" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00679 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CN(CCN1)CC2=CC=CC=C2" + } + amount { + moles { + value: 0.0063 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(O1)C(=CC=C2)Br" + } + amount { + moles { + value: 0.00485 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.000485 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000242 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 95.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "The mixture ofnbsp;Tris(dibenzylideneacetone)dipalladium(0) (0.222 g, 0.24 mmol) and 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (0.231 g, 0.48 mmol) in dioxane (10 mL) (degassed with argon for 5 min) was heated at 95 C under argon for 5 min . This was transferred to a flask containing 7-bromo-N,N-dimethylbenzofuran-2-carboxamide (1.3 g, 4.85 mmol), 1-benzylpiperazine (1.111 g, 6.30 mmol) and Cesium carbonate (2.212 g, 6.79 mmol) in dioxane (10 mL) (degassed with argon for 5 min). The resulting mixture was heated at 95 C over night.nbsp;After cooling, the reaction mixture was filtered, the solid washed with DCM and concentrated. The product was purified by isco (DCM:MeOH; 0-3%). A small portion was also purified by prepLC giving EN02745-79-" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(O1)C(=CC=C2)N3CCN(CC3)CC4=CC=CC=C4" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 52.15 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/26/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "285" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000191 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0022 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NCCC1CCNCC1" + } + amount { + moles { + value: 0.0015 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)Br" + } + amount { + moles { + value: 0.000955 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000191 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 9.55e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 50.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "palladium(II) acetate (21.45 mg, 0.10 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (111 mg, 0.19 mmol) were placed in a round-bottomed vessel that was filled with nitrogen. Toluene (0.8 mL) was added and the mixture was heated to 50C for 30 min.sodium tert-butoxide (138 mg, 1.43 mmol) was added to a second vessel and inerted with nitrogen. tert-butyl 2-(piperidin-4-yl)ethylcarbamate (342 mg, 1.5 mmol) and bromobenzene (150mg, 0.96 mmol) and toluene (1.4 mL) were added. 1404 2009 13:57:24 +0200 The catalyst solution was added to the reagent mixture and the combined mixture was heated to reflux for several hours. The reaction did not work." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NCCC1CCN(CC1)C2=CC=CC=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/09/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "287" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000355 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CN(CCN1)CCC2=CC=CC=C2" + } + amount { + moles { + value: 0.000254 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC2=C(C(=C1)Br)OC=C2" + } + amount { + moles { + value: 0.000254 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 1.02e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 5.08e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A dried Radley tube was charged with rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (6.32 mg, 10.15 mol), Tris(dibenzylideneacetone)dipalladium(0) (4.65 mg, 5.08 mol) and Sodium tert-butoxide (34.1 mg, 0.36 mmol). Argon atmosphere was introduced andnbsp;toluene (3ml) was added followed by 7-bromobenzofuran (50mg, 0.25 mmol) and 1-phenethylpiperazine (48.3 mg, 0.25 mmol). The reaction mixture was heated at reflux over night.2010-03-25 The reaction mixture was filtered, concentrated and purified by flash chromatography (Isolute Si 10g, heptane: ethyl acetate; 4:1) to give 1-(benzofuran-7-yl)-4-phenethylpiperazine (48.3 mg, 62." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CN(CCN1CCC2=CC=CC=C2)C3=CC=CC4=C3OC=C4" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 62.12 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/24/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "288" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00097 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@@H]1CNC[C@@H](N1)C" + } + amount { + moles { + value: 0.00194 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)Br)[N+](=O)[O-]" + } + amount { + moles { + value: 0.000646 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 9.05e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 6.46e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a solution of 4-bromo-1-methoxy-2-nitrobenzene (150 mg, 0.65 mmol) in dioxane (4 mL) was added (2R,6S)-2,6-dimethylpiperazine (221 mg, 1.94 mmol) followed by cesium carbonate (316 mg, 0.97 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (56.4 mg, 0.09 mmol) and diacetoxypalladium (14.51 mg, 0.06 mmol). The resulting mixture was heated at 100 C under argon over night (black). LCMS Ok. The solids were filtered through celite and washed with ethyl acetate. The ethyl acetate was evaporated under reduced pressure and the crude product was purified by flash-chromatograpy eluated with dichloromethane Methanol + 0.2% Et3Nnbsp;1000 =gt;9010 over 20 min. The pure fractions was collected and concentrated to give (3R,5S)-1-(4-methoxy-3-nitrophenyl)-3,5-dimethylpiperazine (96 mg, 56.0 %) as red solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@@H]1CN(C[C@@H](N1)C)C2=CC(=C(C=C2)OC)[N+](=O)[O-]" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 55.97 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/05/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "290" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0097 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.04 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@@H]1CNC[C@@H](N1)C" + } + amount { + moles { + value: 0.0194 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)Br)[N+](=O)[O-]" + } + amount { + moles { + value: 0.00646 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000905 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000646 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a solution of 4-bromo-1-methoxy-2-nitrobenzene (1500 mg, 6.46 mmol) in dioxane (40 mL) was added (2R,6S)-2,6-dimethylpiperazine (2215 mg, 19.39 mmol) followed by cesium carbonate (3159 mg, 9.70 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (564 mg, 0.91 mmol) and diacetoxypalladium (145 mg, 0.65 mmol). The resulting mixture was heated at 100 C under argon over night (black). LCMS Ok. The solids were filtered through celite and washed with ethyl acetate. The ethyl acetate was evaporated under reduced pressure and the crude product was purified by flash-chromatograpy eluated with Dichloromethane 2 M NH3 in Methanolnbsp;1000 =gt;8020 over 20 min. The pure fractions was collected and concentrated to give (3R,5S)-1-(4-methoxy-3-nitrophenyl)-3,5-dimethylpiperazine (1540 mg, 90 %) as red solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@@H]1CN(C[C@@H](N1)C)C2=CC(=C(C=C2)OC)[N+](=O)[O-]" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 89.79 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/18/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "291" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00554 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.03 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)N)C" + } + amount { + moles { + value: 0.00471 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=C(C=CC=C1OC)NC2=CC(=NC=C2C(F)(F)F)Cl" + } + amount { + moles { + value: 0.00461 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000738 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000369 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "i2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-6-methoxy-N-methylbenzamide (1.66 g, 4.61 mmol)ii, ii1,3-dimethyl-1H-pyrazol-5-amine (0.523 g, 4.71 mmol)ii, iidiacetoxypalladium (0.083 g, 0.37 mmol)ii, ii(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.427 g, 0.74 mmol)ii and iicesium carbonate (1.804 g, 5.54 mmol)ii were mixed together in iidioxane (30 mL)ii. Reaction was degassed with argon and was stirred at ii90 Cii for 3 hours under argon.The mixture was filtered ,the filtrate was concentrated andnbsp;purified by flash chromatography on silica gel 15-40m eluting with ii0ii to ii4ii% methanol in CH2Cl2AcOEt (6040).The product obtained was not enough purenbsp;so the product was repurifiednbsp;by flash chromatography on silica gel 15-40m eluting with 0 to 4% methanol in CH2Cl2AcOEt (6040).The solvent was evaporated to dryness to afford i2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)omethyl)pyridin-4-ylamino)-6-methoxy-N-methylbenzamide (0.882 g, 44.0 %)i as anbsp;ibeigei isolidi.iiEN 02814-27-01i" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=C(C(=CC=C3)OC)C(=O)NC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 44.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/17/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "292" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00174 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" + } + amount { + moles { + value: 0.00058 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OCC1CN(CC2=C(O1)N=C(C=C2)Cl)C" + } + amount { + moles { + value: 0.00058 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 5.8e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 5.8e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "8-chloro-2-(isopropoxymethyl)-4-methyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.157 g, 0.58 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.118 g, 0.58 mmol), Palladium acetate (0.013 g, 0.06 mmol), 2-(Dicyclohexylphosphino)biphenyl (0.020 g, 0.06 mmol) and Cesium carbonate (0.567 g, 1.74 mmol) were placed in a microwave vial. The mixture was capped and flushed with argon.nbsp;1,2-dimethoxyethane (5 mL) was added and the mixture was run in a microwave for 60 minutes at 100C. Very little product. Added 0.1 eq ligand and palladium acetate, flushed with argon and run in the microwave at 100C for 60 min. Still have a lot of startingmaterial (oxazepine) left. Added 0.1 eq ligand and palladium acetate, flushed with argon and run in the microwave at 100C for 60 min. The reaction mixturenbsp;was filtrated through Celite and washed with dichloromethane. The filtrate was concentrated and the crude product was purified by preparative chromatography. The productcontaining fractions, concentrated and the residue was partitioned between sat. NaHCO3 (aq) and dichloromethane. The organic layer was separated by a Phase Separator and concentrated giving 2-(isopropoxymethyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-methyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (0.013 g, 5.28 %)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(CN(CC(O4)COC(C)C)C)C=C3)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 5.28 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/02/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "294" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00197 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CCO" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=N1)C2=C(C=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000655 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.000655 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 6.55e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 6.55e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (180 mg, 0,66 mmol), 3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (134 mg, 0,66 mmol), Palladium acetate (14,71 mg, 0,07 mmol), 2-(Dicyclohexylphosphino)biphenyl (22,96 mg, 0,07 mmol) and Cesium carbonate (640 mg, 1,97 mmol) were mixed in DME (3 mL) in a microwave vial. EtOH (0,3 mL) was added and the mixture was run for 1 hour at 100C in a microwave reactor. the reaction had to be run for an additional 2 hours with more catalyst and ligand added. the mixture was filtered and purified using flash chromatography 0-10% MeOH in DCM." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(CN(C[C@H](O4)C5=CC=CC=C5)C)C=C3)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 18.97 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "12/02/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "297" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00383 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CONC(=O)C1=CC=CC=C1N" + } + amount { + moles { + value: 0.00326 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C(=NN1C)C)NC2=NC=C(C(=C2)I)C(F)(F)F" + } + amount { + moles { + value: 0.00192 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000287 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000172 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-amino-N-methoxybenzamide (541 mg, 3.26 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (166 mg, 0.29 mmol), cesium carbonate (1249 mg, 3.83 mmol) and diacetoxypalladium (38.7 mg, 0.17 mmol) were added to a stirred solution of 4-iodo-5-(trifluoromethyl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-amine (759 mg, 1.92 mmol) dissolved in dioxane (20 mL) in a wave vial at RT.nbsp;Argon was let to bubble in the mixture for 5 minutes and the resulting slurry was then stirred at 90 C for 15 hours. Lcms showed complete reaction.The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane, filtered, silica gel was added and the mixture was concentrated. The crude product was purified by flash chromatography on silica gel eluting with 30 to 100% ethyl acetate in petroleum ether. The solvent was evaporated to dryness, the remainning gum was taken up in DCM and concentrated in the cold. The precipitate was collected by filtration, washed with diethyand dried to a constant weight to afford N-methoxy-2-(5-(trifluoromethyl)-2-(1,3,5-trimethyl-1H-pyrazol-4-ylamino)pyridin-4-ylamino)benzamide (742 mg, 89 %) (batch EN03692-99-01) as a off-white solid. NMR showed the presence of solvents (ethyl acetate and diethyl ether). The solid was then dried several days under vacuum at 55C to removed these solvents (--gt; batch EN03692-99-02 (723 mg, 1.664 mmol, 87 %)) : unsuccessfully!bAnalysis: - NMR (CDE) --gt; strenght = 95%, bbethyl acetatebb= 0.06 molemole and diethyl ether = 0.11 molemolebbnbsp;- analytical lcms (DDO) --gt; purity = 99%b" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C(=NN1C)C)NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 89.15 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/12/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "298" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0121 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.03 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CN(CCN1)CC2=CC=CC=C2" + } + amount { + moles { + value: 0.0102 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(O1)C=CC=C2Br" + } + amount { + moles { + value: 0.00929 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.000929 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000465 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 95.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2010 2009 10:10:14 +0200To ethyl 4-bromobenzofuran-2-carboxylate (2.50 g, 9.29 mmol) and 1-benzylpiperazine (1.776 mL, 10.22 mmol) in dry degassed dioxane (30 mL) were added Cesium carbonate (3.94 g, 12.08 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-triisopropylbiphenyl (0.443 g, 0.93 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (0.425 g, 0.46 mmol) under argon and the reaction heated at 95C on. All starting material consumed.nbsp;The crude solution was pooled with the corresponding solution in EN03307-46Water and DCM were added and the layers separated. The aq phase was extracted with DCM (3x). The combined org phases were washed with water, dried (MgSO4), filtered and evaporated. The crude was purified by flash chrom. (SiO2; HeptaneEtOAc 7030) to give 3.05 g (50%) of the product as a yellow solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(C=CC=C2O1)N3CCN(CC3)CC4=CC=CC=C4" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 90.08 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/20/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "300" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00446 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CN(CCN1)CC2=CC=CC=C2" + } + amount { + moles { + value: 0.00483 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(O1)C=CC=C2Br" + } + amount { + moles { + value: 0.00372 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C1=CC=CC=C1C2=CC=CC=C2)C(C)(C)C" + } + amount { + moles { + value: 0.000223 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 7.43e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "bPurpose:b Buchwald-Hartwig coupling using unpurified ethyl 4-bromobenzofuran-2-carboxylate. The analysis on crude 4-bromobenzofuran-2-carboxylate shows traces of non cyclized and non aromoatized by-products.2010-03-1016:38:11: To a 25 mL rounbottomed flask was added ethyl 4-bromobenzofuran-2-carboxylate (1 g; 3.72 mmol) and toluene (10 mLg-bulk-LR; 10 mL). The mixture was concentrated under reduced pressure to remove traces of water. The procedure was repeated once more. and finally toluene (10 mLg-bulk-LR; 10 mL). The system was inerted three times and stirred under nitrogen gas.17:03:56: To the homogenous mixture was added 1-benzylpiperazine (1.3 eq; 0.852 g; 0.84 mL; 4.83 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.02 eq; 68 mg; 0.07 mmol), 2-(DI-T-BUTYLPHOSPHINO)BIPHENYL (0.06 eq; 67 mg; 0.22 mmol) and CESIUM CARBONATE (1.2 eq; 1.453 g; 4.46 mmol). The system was inerted three times and stirred under nitrogen gas.17:07:37: The Tj was set to Tj=100 C. mixture was stirred under nitrogen gas over night.2010-03-1108:42:44: IPC1 (15 h) sample was gathered and diluted with methanol. The analysis (EN03690-35-001-A) showed only 16 % conversion.bResults and conclusion: bThe experiment was discarded due to poor conversion.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(C=CC=C2O1)N3CCN(CC3)CC4=CC=CC=C4" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/10/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "301" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00483 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CN(CCN1)CC2=CC=CC=C2" + } + amount { + moles { + value: 0.00334 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(O1)C=CC=C2Br" + } + amount { + moles { + value: 0.00372 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.000372 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000186 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 95.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "ethyl 4-bromobenzofuran-2-carboxylate (1 g, 3.72 mmol), 1-Benzylpiperazine (0.580 mL, 3.34 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.170 g, 0.19 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (0.177 g, 0.37 mmol) and CESIUM CARBONATE (1.574 g, 4.83 mmol) in dioxane (5 mL) were heated under argon to 95 C overnight.nbsp;The mixture was allowed to cool. The mixture was diluted with EtOAc and the mixture was filtered through a pad of Celite.nbsp;The filterate was collected and the solvent was removed by rotary evaporation.nbsp;The crude product was added to a silica gel column and was eluted withnbsp;0-50% EtOAc in heptane.nbsp;The collected fractions were combined and the solvent was removed to yield ethyl 4-(4-benzylpiperazin-1-yl)benzofuran-2-carboxylate (0.360 g, 26.6 %).MSnbsp;(m+1) = 365.6.HPLC Peak RT = 3.33 minutes is product.nbsp;Purity = 96%." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(C=CC=C2O1)N3CCN(CC3)CC4=CC=CC=C4" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 26.58 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/08/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "302" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[K+]" + } + amount { + moles { + value: 0.0052 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.007 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CN(CCN1)CC2=CC=CC=C2" + } + amount { + moles { + value: 0.00483 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(O1)C=CC=C2Br" + } + amount { + moles { + value: 0.00372 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000149 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 7.43e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 50.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "bPurpose:b Buchwald-Hartwig coupling using unpurified ethyl 4-bromobenzofuran-2-carboxylate. The analysis on crude 4-bromobenzofuran-2-carboxylate shows traces of non cyclized and non aromoatized by-products.2010-03-0215:25:22: To a 25 mL roundbottomed flask was added ethyl 4-bromobenzofuran-2-carboxylate (LR; 1 g; 3.72 mmol) and toluene (7 mLg-bulk-LR; 7 mL). The mixture was concentrated under reduced pressure. To the mixture was added toluene (7 mLg-bulk-LR; 7 mL) and the mixture was concentrated a second time under reduced pressure. To the mixture was added toluene (7 mLg-bulk-LR; 7 mL) followed by 1-benzylpiperazine (1.3 eq; 0.852 g; 0.84 mL), BINAP (0.04 eq; 93 mg) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.02 eq; 68 mg). The mixture was stirred for 5 minutes followed by addition of POTASSIUM TERT-BUTOXIDE (1.4 eq; 0.58 g). The mixture is stirred at Tm=50 C.15:45:57: IPC1 (15 min) sample was gathered. The sample was quenched with a mixture consisting of 700 metic acid buffer pH=2 and methanol. The sample was filtered and analyzed by means of HPLC-UV (EN03690-30-001-F) which indicated 44 % conversion17:09:21: IPC2 (100 min) sample was gathered. The sample was quenched with a mixture consisting of 700 mM acetic acid buffer pH=2 and methanol. The sample was filtered and analyzed by means of HPLC-UV (EN03690-30-001-H) which indicated 95 % conversion.17:20:00: The temperature was allowed to reach rt and the mixture was stirred over night. 2010-03-0309:51:29: IPC3 (18 h) sample was gathered. The sample was quenched with a mixture consisting of 700 mM acetic acid buffer pH=2 and methanol. The sample was filtered and analyzed by means of HPLC-UV (EN03690-30-001-J) which indicated +99 % conversion.10:10:32: The mixture was transfered to a mixture consisting of 700 mM acetate buffer pH=2 (12.5 mLg-bulk-LR; 12.5 mL) and isopropyl acetate (6.2 mLg-bulk-LR; 6.2 mL) to give pH=5.65. To the mixture was added 4 M aqueous sulfuric acid (1.77 mLg-bulk-LR; 1.77 mL) to give pH=2. The mixture was stirred for 15 minutes. The phases were separated and analyzed by means of HPLC-UVnbsp;12:32:57: To the water phase was added dichloromethane (10 mLg-bulk-LR; 10 mL). The mixture was stirred and 50 % aqueous sodium hydroxide (1 mL) was added to give pH=12. The phases were separated and analyzed by means of HPLC-UV. The organic phase was concentrated under reduced pressure to give yellow oil. The crude product was purified by means of column chromatography (40 g SiO2; 4 % MeOH, 1 NH3 in MeOH in DCM; Rf=0.2). Yellow solid was obtained (250 mg). 1H NMR showed not correct product. bResult:b Correct product was not isolated.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(C=CC=C2O1)N3CCN(CC3)CC4=CC=CC=C4" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/01/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "303" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0242 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.025 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CN(CCN1)CC2=CC=CC=C2" + } + amount { + moles { + value: 0.0186 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(O1)C=CC=C2Br" + } + amount { + moles { + value: 0.0186 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.00186 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000929 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 95.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "ethyl 4-bromobenzofuran-2-carboxylate (5 g, 18.58 mmol), 1-benzylpiperazine (3.22 mL, 18.58 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (0.886 g, 1.86 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.851 g, 0.93 mmol) and CESIUM CARBONATE (7.87 g, 24.16 mmol) were heated under argon to 95 C overnight.nbsp;The mixture was allowed to cool. The mixture was diluted with EtOAc and the mixture was filtered through a pad of Celite.nbsp;The filterate was collected and the solvent was removed by rotary evaporation.nbsp;The crude product was added to a silica gel column and was eluted withnbsp;0-50% EtOAc in heptane.nbsp;The collected fractions were combined and the solvent was removed to yield ethyl 4-(4-benzylpiperazin-1-yl)benzofuran-2-carboxylate (2.160 g, 31.9 %).MSnbsp;(m+1) = 365.6.HPLC Peak RT = 3.30 minutes is product.nbsp;Purity = 94%." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(C=CC=C2O1)N3CCN(CC3)CC4=CC=CC=C4" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 31.9 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/13/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "305" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0524 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCCC12OCCO2" + } + amount { + moles { + value: 0.0349 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=NC(=C1)Br" + } + amount { + moles { + value: 0.0349 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.0015 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.0015 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: nan + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "The same procrdure as EN03653-93-01. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CN(CCC12OCCO2)C3=CC=CC=N3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 66.56 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/09/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "306" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00268 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)S(=O)(=O)N)N" + } + amount { + moles { + value: 0.00134 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(N=C1Cl)Cl" + } + amount { + moles { + value: 0.00134 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000161 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 6.71e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2,4-dichloropyrimidine (200 mg, 1.34 mmol), 3-aminobenzenesulfonamide (231 mg, 1.34 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (93 mg, 0.16 mmol), cesium carbonate (875 mg, 2.68 mmol) and diacetoxypalladium (15.07 mg, 0.07 mmol) were suspended in dioxane (5 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT. The reaction mixture was diluted with EtOAc (150 mL) and washed with water (150 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 4% (10:1 MeOHNH3 (aq)) in DCM. NMR analysis showed a trace amount of product." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)S(=O)(=O)N)NC2=NC=CC(=N2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/23/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "307" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 4.35e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.000956 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC(=CN=C1)Br" + } + amount { + moles { + value: 0.000869 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C1=CC=CC=C1C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 4.35e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.17e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "ethyl 5-bromonicotinate (200 mg, 0.87 mmol), morpholine (0.083 mL, 0.96 mmol), sodium 2-methylpropan-2-olate (167 mg, 1.74 mmol), 2\'-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (17.11 mg, 0.04 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (19.90 mg, 0.02 mmol) were suspended in dioxane (5 mL) and sealed into a microwave tube. The reaction was heated to 100 C for 1 hour in the microwave reactor and cooled to RT. LCMS analysis appeared to indicate addition of 2 morpholine rings and the reaction was abandoned." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC(=CN=C1)N2CCOCC2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/01/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "308" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 4.35e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.000956 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC(=CN=C1)Br" + } + amount { + moles { + value: 0.000869 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C1=CC=CC=C1C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 4.35e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.17e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "ethyl 5-bromonicotinate (200 mg, 0.87 mmol), morpholine (0.083 mL, 0.96 mmol), sodium 2-methylpropan-2-olate (167 mg, 1.74 mmol) and 2\'-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (17.11 mg, 0.04 mmol) were suspended in dioxane (5 mL). The reaction flask was purged with nitrogen and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (19.90 mg, 0.02 mmol) was added. The reaction was stirred at 80 C for 90 minutes. LCMS analysis appeared to indicate addition of 2 morpholine rings and the reaction was abandoned." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC(=CN=C1)N2CCOCC2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/05/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "309" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0108 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.00678 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)C1=CC(=CN=C1)Br" + } + amount { + moles { + value: 0.00542 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000814 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000271 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "tert-butyl 5-bromonicotinate (1.4 g, 5.42 mmol), morpholine (0.591 ml, 6.78 mmol), cesium carbonate (3.53 g, 10.85 mmol) and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.507 g, 0.81 mmol) were dissolved in toluene (20 ml). The reaction flask was purged with nitrogen and diacetoxypalladium (0.061 g, 0.27 mmol) was added. The resulting suspension was stirred at 80 C for 5 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 5-morpholinonicotinate (0.381 g, 26.6 %) as a yellow oil which solidified on standing. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)C1=CC(=CN=C1)N2CCOCC2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 26.56 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/11/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "310" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0305 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.05 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C(=C1)N)Cl" + } + amount { + moles { + value: 0.0167 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC2=C(C=C1Br)NN=C2" + } + amount { + moles { + value: 0.0152 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00228 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00152 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium(II) acetate (0.342 g, 1.52 mmol) and rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (1.422 g, 2.28 mmol) were added to a stirred slurry of 2-chloroaniline (1.763 mL, 16.75 mmol), 6-bromo-1H-indazole (3 g, 15.23 mmol) and cesium carbonate (9.92 g, 30.45 mmol) in toluene (50 mL) at 23C under nitrogen. The resulting slurry was stirred at 80 C for 2 hours. The reaction was incomplete (both SM left) so the temperature was increased to 100C and the reaction mixture was stirred for a further 2 hours. Mainly 2 SM detected. problem of solubility of bromoindazole?The reaction was incomplete and further Palladium(II) acetate (30mg), rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (200mg) and cesium carbonate (1g) were added as well as dioxane and the slurry was stirred at 110 C for a further 3 hours. Only SMs detected.No further work on this sample.Perform coupling with reverse coupling partners using Boc 6-aminoindazole. Known to work as used" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C(=C1)NC2=CC3=C(C=C2)C=NN3)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/19/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "311" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000655 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000284 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CC(OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.000218 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 2.18e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.18e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (60.0 mg, 0.22 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (57.7 mg, 0.28 mmol), palladium(II) acetate (4.90 mg, 0.02 mmol), 2-(Dicyclohexylphosphino)biphenyl (7.65 mg, 0.02 mmol) and CS2CO3 (213 mg, 0.66 mmol) were weighed into a microwave vial. The vial was capped and flushed with argon. DME (4 mL) was added and the mixture was heated to 100C in a microwave apparatus for 1 h. The cooled reaction mixture was diluted with dichloromethane and methanol, filtered through a plug of Celite and the solvents were evaporated. The residue was purified by HPLC to give 36 mg (37 % Yield) of the title product." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(CN(CC(O4)C5=CC=CC=C5)C)C=C3)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 37.23 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/25/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "312" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "[Li+].C[Si](C)(C)[N-][Si](C)(C)C" + } + amount { + moles { + value: 0.0399 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.087 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCNCC1" + } + amount { + moles { + value: 0.0208 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1O)Br" + } + amount { + moles { + value: 0.0173 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)CN1CCN2CCN(P1N(CC2)CC(C)C)CC(C)C" + } + amount { + moles { + value: 0.000347 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000173 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (0.039 g, 0.17 mmol) was added in one portion to 4-bromophenol (3 g, 17.34 mmol) and 1-methylpiperazine (2.308 mL, 20.81 mmol) in toluene (87 mL) at 25C under nitrogen. To this was added toluene (87 mL) then a solution of 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (0.123 mL, 0.35 mmol) in Toluene (1 mL) and finally 1M LITHIUM BIS(TRIMETHYLSILYL)AMIDE (39.9 mL, 39.88 mmol) in THF was added dropwise over 1 minute.nbsp;The resulting mixture was stirred at 80 C for 18 hours.nbsp;The reaction was allowed to cool to room temperature, SiO2 (23g) was added and evaporated to dryness.nbsp;The crude product was purified by flash silica chromatography (120g), elution gradient 0 to 10% MeOH in EtOAc. Pure fractions were evaporated to dryness to afford 4-(4-methylpiperazin-1-yl)phenol (1.700 g, 51.0 %) as a beige solid. n" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CCN(CC1)C2=CC=C(C=C2)O" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 50.99 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/13/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "313" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.191 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.2 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CC1C(=O)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.0763 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1OC2=C(C(=CN=C2O1)Cl)N" + } + amount { + moles { + value: 0.0763 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00839 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.0061 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a stirred solution of N-(4-chloropyridin-2-yl)cyclopropanecarboxamide (15 g, 76.28 mmol) in dioxane (200 mL) was added 6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-amine (13.16 g, 76.28 mmol), cesium carbonate (62.1 g, 190.71 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4.86 g, 8.39 mmol) and diacetoxypalladium (1.370 g, 6.10 mmol).Mixture was degassed 3 times with N2 and heated at reflux (110C) for 4h: OK.Reaction was cooled down, diluted with 200mL of CH2Cl2 and filtered. The filtrate was concentrated and the residue purified on silica, eluting with 2% of MeOH in CH2Cl2.Solvent were evaporated, diluted with a little CH2Cl2 until crystallisation occurs and diethyl ether was added. Solid was filtered, washed with diethyl ether and dried to afford N-(4-(6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-ylamino)pyridin-2-yl)cyclopropanecarboxamide (15.00 g, 59.1 %) as a white powder.1H NMR OK." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CC1C(=O)NC2=NC=CC(=C2)NC3=C4C(=NC=C3Cl)OCO4" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 59.09 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/25/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "316" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[K+]" + } + amount { + moles { + value: 0.000221 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C=O" + } + amount { + volume { + value: 0.000198 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CN" + } + amount { + moles { + value: 0.000885 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CNC(=O)C2=C1C=C(C=C2)Br" + } + amount { + moles { + value: 0.000221 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 1.11e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.11e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 130.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "buRef:ub Synthesis, 2002, No. 11, p 1597, M. AltermanIn a 5 mL sealed MW* test tube was 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (50 mg, 0.22 mmol), phenylmethanamine (97 l, 0.88 mmol), BINAP (6.89 mg, 0.01 mmol) and palladium(II) acetate (2.483 mg, 0.01 mmol) in DMF (500 mL) combined to give a tan suspension.nbsp;potassium tert-butoxide (24.82 mg, 0.22 mmol) was then added last.nbsp;Placed test tube onto Smith MW* platform.nbsp;Heated reaction to 130C for 4 minutes.nbsp;Reaction know has a heavy black ppt present.nbsp;Took LCMS - there is some product (~15%) beginning to form.nbsp;Placed sealed test tube in heated (130C) oil bath overnight. Took LCMS - all SM is consumed with a moderate product peak in evidence.nbsp;Transferred reaction to separatory funnel.nbsp;Partitioned reaction with EtOAc (40 ml) and water (25 ml). Separated off aq layer.nbsp;Washed with sat NaCl.nbsp;The organic was dried MgSO4, filt and conc - pale yellow syrup, 02915-84-0.nbsp;Dissolv 100% MeOH, added 2 drops NH4OH to adjust pH of sample and filtered off insolubles.nbsp;The residue was purified via Agilent prep HPLC: Gradient run of 20-95% MeOHH2O with 10 mmol NH4CO3 buffer (pH 10) over 25 mins.nbsp;Flow rate 40 mlmin at wavelength 220 nM collection.nbsp;250 X 21.2 mm Gemini Axia pakC18 10 micron column.nbsp;Collected like fractions which were concentrated under pump vacuum.nbsp;Yield is low but see a mixture of products by NMR.nbsp;Spectra shows desired material plus dialkylation product.nbsp;Will reset and scale up reaction but lower amount of benzylamine and try the MW* only.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CNC(=O)C2=C1C=C(C=C2)NCC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/06/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "317" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C[O-].[Na+]" + } + amount { + moles { + value: 2.21e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.00219 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CN" + } + amount { + moles { + value: 0.000221 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CNC(=O)C2=C1C=C(C=C2)Br" + } + amount { + moles { + value: 0.000221 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(CCP(C2=CC=CC=C2)C3=CC=CC=C3)C4=CC=CC=C4" + } + amount { + moles { + value: 2.21e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.11e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a small MW* sealed test tube was 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (50 mg, 0.22 mmol), phenylmethanamine (24.16 l, 0.22 mmol), palladium(II) acetate (2.483 mg, 0.01 mmol), Ethylenebis(diphenylphosphine) (8.81 mg, 0.02 mmol) and sodium methoxide (13.14 mg, 0.24 mmol) in toluene (2188 l) combined to give a orange suspension.nbsp;Heated reaction to 100C overnight.nbsp;Took LCMS - No reaction, only see unreacted SM.nbsp;Discarded r" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CNC(=O)C2=C1C=C(C=C2)NCC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/06/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "318" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[K+]" + } + amount { + moles { + value: 0.000442 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C=O" + } + amount { + volume { + value: 0.000493 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CN" + } + amount { + moles { + value: 0.000885 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CNC(=O)C2=C1C=C(C=C2)Br" + } + amount { + moles { + value: 0.000442 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 2.21e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.21e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 130.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "bRepeat 02915-84 but use MW* only.nbsp;Reduce benzylamine from 4 to 2 eqs.bIn a 10 mL sealed MW* test tube was 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (100 mg, 0.44 mmol), phenylmethanamine (97 l, 0.88 mmol), BINAP (13.77 mg, 0.02 mmol) and palladium(II) acetate (4.97 mg, 0.02 mmol) in DMF (500 mL) combined to give a tan suspension.nbsp;potassium tert-butoxide (49.6 mg, 0.44 mmol) was then added last.nbsp;Placed test tube onto Smith MW* platform.nbsp;Heated reaction to 130C for 15 minutes.nbsp;Reaction know a cloudy pale amber.nbsp;Took LCMS - there is NO product present, ALL SM!!!nbsp;Placed sealed test tube in heated (130C) oil bath over weekend.nbsp;Took LCMS - all SM is consumed but NO desired product is seen!!!nbsp;Discarded r" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CNC(=O)C2=C1C=C(C=C2)NCC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/08/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "319" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[K+]" + } + amount { + moles { + value: 0.000221 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CN" + } + amount { + moles { + value: 0.000885 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CNC(=O)C2=C1C=C(C=C2)Br" + } + amount { + moles { + value: 0.000221 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 1.11e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.11e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 130.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "bRepeat 02915-84 but use NO solventbIn a 5 mL sealed MW* test tube was 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (50 mg, 0.22 mmol), phenylmethanamine (97 l, 0.88 mmol), BINAP (6.89 mg, 0.01 mmol) and palladium(II) acetate (2.483 mg, 0.01 mmol) combined to give a tan suspension.nbsp;potassium tert-butoxide (24.82 mg, 0.22 mmol) was then added last.nbsp;Placed test tube onto Smith MW* platform.nbsp;Heated reaction to 70C for 5 minutes.nbsp;NO reaction!!!nbsp;Added DMF (0.5 ml) and reheated reaction to 130C for 15 mins.nbsp;Took LCMS - no reaction, only unreacted SM!!nbsp;Discarded r" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CNC(=O)C2=C1C=C(C=C2)NCC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/12/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "320" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0017 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000566 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OCC1CN(CC2=C(O1)N=C(C=C2)Cl)C(=O)C" + } + amount { + moles { + value: 0.000566 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 5.66e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 5.66e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "1-(8-chloro-2-(isopropoxymethyl)-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)ethanone (0.169 g, 0.57 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.115 g, 0.57 mmol), Palladium acetate (0.013 g, 0.06 mmol), 2-(Dicyclohexylphosphino)biphenyl (0.020 g, 0.06 mmol) and Cesium carbonate (0.553 g, 1.70 mmol) were placed in a microwave vial. The mixture was capped and flushed with argon.nbsp;1,2-dimethoxyethane (5 mL) was added and the mixture was run in a microwave for 60 minutes at 100C. No product. Added 0.1 eq ligand and palladium acetate, flushed with argon and run in the microwave at 100C for 60 min. Reaction still not complete. Added 0.1 eq ligand and palladium aceate, flushed with argon and run in the microwave at 100C for 60 min. The reaction mixture was filtrated through Celite and washed with dichloromethane. The filtrate was concentrated and the crude product was purified by preparative chromatography. The productcontaining fractions were pooled, concentrated and the rertitioned between sat. NaHCO3 (aq) and dichloromethane. The organic layer was separated by a Phase Separator and concentrated giving 1-(2-(isopropoxymethyl)-8-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)ethanone (0.039 g, 14.66 %)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(CN(CC(O4)COC(C)C)C(=O)C)C=C3)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 14.66 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/02/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "323" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.18 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C(=C1)N)Cl" + } + amount { + moles { + value: 0.025 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C=C1Br)F)C#N" + } + amount { + moles { + value: 0.025 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00375 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.0025 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium(II) acetate (0.561 g, 2.50 mmol) and rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (2.335 g, 3.75 mmol) was added to a stirred slurry of 2-chloroaniline (2.63 mL, 25.00 mmol), 4-bromo-2-fluorobenzonitrile (5 g, 25.00 mmol) and cesium carbonate (16.29 g, 50.00 mmol) in toluene (180 mL) at 23Cunder nitrogen. The resulting slurry was stirred at 80 C for 2 hours. The reaction was incomplete (both SM left) so the temperature was increased to 100C and the reaction mixture was stirred for a further 2 hours. The reaction was incomplete and further Palladium(II) acetate (100mg), rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (400mg) and cesium carbonate (3g) were added and the slurry was stirred at 100 C for a further 3 hours. Only small amount of 2 SM left and more product being formed. So further Palladium(II) acetate (100mg), rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (400mg) and cesium carbonate (3g) were added and the slurry was stirred at 100 e 6 hours. traces of SM leftThe reaction mixture was filtered through PTFE,nbsp;diluted with DCM (100 mL), and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford productnbsp;as a pale yellow solid. LCMS showed 97% pure and 3% aniline.It was resuspended in DCM and the precipitate was collected by filtration, washed with DCM (10 mL) and dried under vacuum to afford 4-(2-chlorophenylamino)-2-fluorobenzonitrile (5.15 g, 84 %) as a white solid. EN03289-99-01 (2.75 g, 11.15 mmol, 44.6 %)Filtrate repurified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 4-(2-chlorophenylamino)-2-fluorobenzonitrile (5.15 g, 84 %) as a pale yellow solid. (pic 2) EN03289-99-02 (0.760 g, 3.08 mmol, 12.32 %)Pic 1 from column gave compound not 100% pure. Therefore it was triturated with isohexane to give a solid which was collected by filtration and dried under vacuum to give 4-(2-chlorophenylamino)-2-fluorobenzonitrile (5.15 g, 84 %) as a pale yellow solid. EN03289-99-03 (1.64 g, 6.65 mmol, 26.6 %)mixed fractions not kept as small amount.1H NMR (400 MHz, DMSO) d 6.63 - 6.77 (2H, m), 7.21 - 7.30 (1H, m), 7.39 (1H, m), 7.46 (1H, m), 7.54 - 7.69 (2H, m), 8.99 (1H, s).mz (ES-), (M-H)- = 245-247; HPLC tR =nbsp;2.62 min (acid and basic)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C(=C1)NC2=CC(=C(C=C2)C#N)F)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 83.52 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/09/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "324" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00233 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.007 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N1CCC2=CC(=C(C=C21)N)OC" + } + amount { + moles { + value: 0.00155 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN=C(N=C1C2=C3C=CC=CN3N=C2)Cl" + } + amount { + moles { + value: 0.00155 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000155 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000155 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of 3-(2-chloro-5-methylpyrimidin-4-yl)pyrazolo[1,5-a]pyridine (400 mg, 1.55 mmol), 1-(6-amino-5-methoxyindolin-1-yl)ethanone (341 mg, 1.55 mmol) and diacetoxypalladium (34.9 mg, 0.16 mmol) 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (97 mg, 0.16 mmol) cesium carbonate (759 mg, 2.33 mmol) were degassednbsp;with nitrogen then dioxane (7 mL)nbsp;was added to mixture and the solution was degassed under vacuum and placed under nitrogen. The resulting suspension was stirred at 90 C for 5hours.Control uplcms OKControl t.l.c : 100%EtOAc and 5%MeOHCH2Cl2After cooling, the mixture was filtered and the filtrate evaporated to dryness after addition of silica gelThe crude product was purified by flash chromatography on silica gel 45g Merck column solid injectioneluting with 0 to 10%MeOHEtOAc. The solvent was evaporated to dryness to afford 1-(5-methoxy-6-(5-methyl-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-ylamino)indolin-1-yl)ethanone (301 mg, 46.8 %) as anbsp;oranolid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN=C(N=C1C2=C3C=CC=CN3N=C2)NC4=C(C=C5CCN(C5=C4)C(=O)C)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 46.76 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/12/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "325" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000337 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)C2CN(CC3=C(O2)N=C(C=C3)Cl)CC#N)C" + } + amount { + moles { + value: 0.000337 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 3.37e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.37e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.068 g, 0.34 mmol),2-(8-chloro-2-(1,3-dimethyl-1H-pyrazol-5-yl)-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)acetonitrile (0.107 g, 0.34 mmol)nbsp;Palladium acetate (7.56 mg, 0.03 mmol) and Cesium carbonate (0.329 g, 1.01 mmol) were added in a microwave vial. The mixture was capped and flushed with argon.1,2-dimethoxyethane (5 mL) was added, the reaction mixture was flushed with argon and the mixture was run in a microwave for 60 minutes at 100C. Reaction complete. The reaction mixture was filtrated through Celite and washed with dichloromethane. The filtrate was concentrated and the crude product was purified by preparative chromatography. The productcontaining fractions were pooled, concentrated and the residue was partitioned between sat. NaHCO3 (aq) and dichloromethane. The organic layer was separated by a Phase Separator and concentrated giving 2-(2-(1,3-dimethyl-1H-pyrazol-5-yl)-8-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylo)-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)acetonitrile (0.027 g, 16.55 %). " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)C2CN(CC3=C(O2)N=C(C=C3)NC4=CC(=C(C=C4)N5C=C(N=C5)C)OC)CC#N)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 16.55 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/25/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "326" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00196 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0103 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CONC(=O)C1=C(C=CC(=C1)F)N" + } + amount { + moles { + value: 0.00168 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C(=CN=C1Cl)C(F)(F)F)I" + } + amount { + moles { + value: 0.00163 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000261 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000131 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-chloro-4-iodo-5-(trifluoromethyl)pyridine (0.502 g, 1.63 mmol), 2-amino-5-fluoro-N-methoxybenzamide (0.344 g, 1.68 mmol), diacetoxypalladium (0.029 g, 0.13 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.151 g, 0.26 mmol) and cesium carbonate (0.638 g, 1.96 mmol) were weighed out in a microwave vial and sealed. dioxane (10.31 ml) was added and argon was let to bubble through the reaction mixture then it was stirred at 90 C for 5 hours. The reaction mixture was allowed to cool to room temperature, silca gel was added and the mixture was concentrated to afford the crude, which was purified by flash chromatography on silica gel eluting with 20 to 50% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford 2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-5-fluoro-N-methoxybenzamide (0.240 g, 40.4 %) as an yellow oil which crystallised on standing." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CONC(=O)C1=C(C=CC(=C1)F)NC2=CC(=NC=C2C(F)(F)F)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 40.43 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/14/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "327" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 4.32e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CONC(=O)C1=C(C=C(C=C1)F)N" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" + } + amount { + moles { + value: 0.000288 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 4.32e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.59e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 95.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (24.98 mg, 0.04 mmol), diacetoxypalladium (5.82 mg, 0.03 mmol), 2-amino-4-fluoro-N-methoxybenzamide (90 mg, 0.49 mmol), N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (110 mg, 0.29 mmol) and cesium carbonate (188 mg, 0.58 mmol) were weighed out in a wave vial, sealed and dioxane (3 mL) was added. Argon was let to bubble in the mixture for 5 minutes. The reaction was stirred at 95 C for 6h. The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane, silica gel was added and the mixture was concentrated. The crude product was purified by flash chromatography on silica gel (25g) eluting with 0 to 5% methanol in ethyl acetateDCM (11). The solvent was evaporated to dryness. The residue was triturated in tBuOMe (a bit soluble and soluble in diethyl ether) and the resulting precipitate was collected by filtration and dried to a constant weight to afford 2-(2-(1,3-dimethyl-1H-pyrazol-o)-5-(trifluoromethyl)pyridin-4-ylamino)-4-fluoro-N-methoxybenzamide (50.0 mg, 39.6 %) as a white solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=C(C=CC(=C3)F)C(=O)NOC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 39.62 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/11/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "328" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00288 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" + } + amount { + moles { + value: 0.00096 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1[C@H](OC2=C(CN1CC#N)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.00096 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 9.6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 9.6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (195 mg, 0.96 mmol), (R)-2-(8-chloro-2-phenyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)acetonitrile (288 mg, 0.96 mmol)nbsp;Palladium acetate (21.55 mg, 0.10 mmol) and Cesium carbonate (938 mg, 2.88 mmol) were added in a microwave vial. The mixture was capped and flushed with argon. 1,2-dimethoxyethane (5 mL) was added, the reaction mixture was flushed with argon and the mixture was run in a microwave for 60 minutes at 100C. Only after two additional additions of catalyst and ligand with 3h extra runtime was the reaction complete. The reaction mixture was filtrated through Celite and washed with dichloromethane. The filtrate was concentrated and the crude product was purified by preparative chromatography 3 times yielding (R)-2-(8-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-2-phenyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)acetonitrile (35.0 mg, 7.81 %). " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(CN(C[C@H](O4)C5=CC=CC=C5)CC#N)C=C3)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 7.81 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/28/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "329" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000984 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=N1)C2=C(C=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000328 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1[C@H](OC2=C(CN1CCO)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.000328 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 3.28e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.28e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (67.0 mg, 0.33 mmol), (R)-2-(8-chloro-2-phenyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)ethanol (100 mg, 0.33 mmol), Palladium acetate (7.37 mg, 0.03 mmol), 2-(Dicyclohexylphosphino)biphenyl (11.50 mg, 0.03 mmol) and Cesium carbonate (321 mg, 0.98 mmol) were added to a microwave vial. 1,2-dimethoxyethane (2 mL) was added. The reaction mixture was flushed with argon and the mixture was run in a microwave for 60 minutes at 100C. No product was observed. Additional catalyst and ligand were added and the reaction was run 1h @ 100C. Still no reaction occurred. EtOH (0.500 mL) was added and another h @ 100C was executed. Full conversion into product was observed. The solids were filtered off and the solvent was concentrated. The crude product was purified twice on Si. 20-80% MeOH in DCM. Yield: (R)-2-(8-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-2-phenyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)ethanol (33.0 ." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(CN(C[C@H](O4)C5=CC=CC=C5)CCO)C=C3)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 21.28 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/28/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "330" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00148 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000492 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(N=C1)Cl" + } + amount { + moles { + value: 0.000492 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 4.92e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.92e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-Chloropyrimidine (0.056 g, 0.49 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.100 g, 0.49 mmol), Palladium acetate (0.011 g, 0.05 mmol), 2-(Dicyclohexylphosphino)biphenyl (0.017 g, 0.05 mmol) and Cesium carbonate (0.481 g, 1.48 mmol) were placed in a microwave vial. The mixture was capped and flushed with argon.nbsp;1,2-dimethoxyethane (5 mL) was added and the mixture was run in a microwave for 60 minutes at 100C. Very little product. Added 0.1 eq ligand and palladium acetate, flushed with argon and run in the microwave at 100C for 60 min. No change. Seems as if the 2-chloropyrimidine is not very soluble in DME. Added 1.5 mL DMF and the reaction was run again in the microwave for 60 minutes.nbsp;The reaction mixture was filtrated through Celite and washed with dichloromethane. The filtrate was concentrated and the crude product was purified by preparative chromatography. The productcontaining fractions were pooled, concentrated and the residue was partitioned between sat.ub3 (aq) and dichloromethane. The organic layer was separated by a Phase Separator and concentrated giving N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)pyrimidin-2-amine (0.026 g, 18.78 %)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC=CC=N3)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 18.78 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/28/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "332" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[K+]" + } + amount { + moles { + value: 0.00288 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.006 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC1=CC=C(C=C1)F" + } + amount { + moles { + value: 0.000766 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1CO)Cl" + } + amount { + moles { + value: 0.000697 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 6.97e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 3.48e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 105.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 50 mL round-bottomed flask (t=g) was (2-chloropyridin-4-yl)methanol (.1 g, 0.70 mmol), Pd2dba3 (0.032 g, 0.03 mmol), and biphenyl-2-yldicyclohexylphosphine (0.024 g, 0.07 mmol) in toluene (6 mL) to give a dark red solution. 4-fluoro-N-methylaniline (0.096 g, 0.77 mmol) and KOtBu (.323 g, 2.88 mmol) were added.Mixture was degassed by bubbling N2 for 20 minutes, then placed in oil bath at 105 C. Reaction went for 3 hours, at which point LCMS was taken. No product was observed. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(C1=CC=C(C=C1)F)C2=NC=CC(=C2)CO" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/15/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "333" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000599 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.016 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC1=CC=C(C=C1)F" + } + amount { + moles { + value: 0.0004 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=NC=C1Br)Br" + } + amount { + moles { + value: 0.000479 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 5.99e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 50 mL round-bottomed flask (t=g) was 4-fluoro-N-methylaniline (.05 g, 0.40 mmol), 3,5-dibromopyridine (0.114 g, 0.48 mmol), and Pd2(dba)3 (0.018 g, 0.02 mmol) in toluene (16 mL) ([VOLUME]) to give a purple suspension. biphenyl-2-yldicyclohexylphosphine (0.021 g, 0.06 mmol) and CS2CO3 (0.195 g, 0.60 mmol) were added. After LCMS indicated no reaction had taken place at room temp, the temperature was gradually rasied to up to 110 degrees. LCMS indicated that the reaction was not progressing.Reaction was discarded." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(C1=CC=C(C=C1)F)C2=CC(=CN=C2)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/25/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "336" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[K+]" + } + amount { + moles { + value: 0.0104 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.016 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC1=CC=C(C=C1)F" + } + amount { + moles { + value: 0.00799 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=NC=C1Br)Br" + } + amount { + moles { + value: 0.00959 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 0.0012 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.0004 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 50 mL round-bottomed flask (t=g) was 4-fluoro-N-methylaniline (1 g, 7.99 mmol), 3,5-dibromopyridine (2.272 g, 9.59 mmol), and Pd2(dba)3 (0.366 g, 0.40 mmol) in toluene (16 mL) ([VOLUME]) to give a purple suspension. biphenyl-2-yldicyclohexylphosphine (0.420 g, 1.20 mmol) and KOtBu (1.166 g, 10.39 mmol) were added. Reaction was allowed to stir for 1.5 hours at which point LCMS was taken which indicated that all the dibromopyridine had been consumed. Reaction was quenched by addition of excess ammonium chloride. Mixture was filtered though a plug of celite, extracted with ethyl acetate. The organic fractions were collected and washed with water, then dried over NaSO4, rotovapped down to an oil, redissolved in DCM then purified over a 120g column using 5 minutes of pure hexane, followed by a 0-50% EtOAc gradient (product comes off at around 35%). The relevant fractions were collected and rotovapped down yielding the product as an oil." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(C1=CC=C(C=C1)F)C2=CC(=CN=C2)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 12.46 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/24/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "338" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00048 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=C(N=C(C=N1)Cl)N" + } + amount { + moles { + value: 0.006 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CS(=O)(=O)C1=CC=C(C=C1)Br" + } + amount { + moles { + value: 0.006 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00048 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00024 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "i1-bromo-4-(methylsulfonyl)benzene (1410 mg, 6.00 mmol)ii then iicesium carbonate (2540 mg, 7.80 mmol)iinbsp;were successively added to a solution of ii6-chloropyrazin-2-amine (777 mg, 6.00 mmol)iinbsp;ii1,4-dioxane (20 ml)ii into a microwave reactor.ii The mixture was purged by bubbling nitrogen for 5 minutes, thenii ii(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (278 mg, 0.48 mmol)ii and iidiacetoxypalladium (53.9 mg, 0.24 mmol)ii were added ,nbsp;the mixture was degassed by vacuumnitrogen three times, then heatednbsp;tonbsp;ii75 Cii in an heating block( internal temperature )for 1 hr then at ii85 Ciinbsp;and finally at ii90 Cii for 30 minioling the mixture was diluted with ethylacetate , filtered , the solid washed with ethyl acetate, and the organic solution washed with water, pre-dried with brine and dried over MgSO4 , filtratednbsp;and concentrated in vacuo.The solid was taken up with ethylacetatenbsp;( 20 ml) stirred 15 min , and diluted with diethylether until some trouble occured; the solid was filterednbsp;and the procedure was repeated.The solid was dried under vacuum ( 1 mmHg1 hr 50C ) to afford 6-chloro-N-(4-(methylsulfonyl)phenyl)pyrazin-2-amine (1000 mg, 58.8%)ii. The filtrate was concentrated and the abovenbsp;purification procedure was repeated three times to afford a second batch ii6-chloro-N-(4-(methylsulfonyl)phenyl)pyrazin-2-amine (0.200 mg, 11.75 %) of the same purity . The 2nbsp;batches were combined to affordnbsp;ii6-chloro-N-(4-(methylsulfonyl)phenyl)pyrazin-2-amine (1200 mg, 70.5 %)ii as a beige solidi" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CS(=O)(=O)C1=CC=C(C=C1)NC2=CN=CC(=N2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 70.51 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/03/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "340" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00088 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.075 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=C(N=C(C=N1)Cl)N" + } + amount { + moles { + value: 0.02 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CS(=O)(=O)C1=CC=C(C=C1)Br" + } + amount { + moles { + value: 0.02 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00088 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00044 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "i1-bromo-4-(methylsulfonyl)benzene (4.70 g, 19.99 mmol)ii then iicesium carbonate (8.47 g, 25.99 mmol)iinbsp;were successively added to a solution of ii6-chloropyrazin-2-amine (2.59 g, 19.99 mmol)iinbsp;ii1,4-dioxane (75 ml)ii into a microwave reactor.ii The mixture was purged by bubbling nitrogen for 5 minutes, thenii ii(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.509 g, 0.88 mmol)ii and iidiacetoxypalladium (0.099 g, 0.44 mmol)ii were added , the mixture was degassed by vacuumnitrogen three times, then heatednbsp;tonbsp;ii80 Cii in an heating block fornbsp;2 hours then at ii90 Cii for 30 minnbsp;and a further 1 hour heatingnbsp;at ii85 Cii. iing the mixture was diluted with ethylacetate , filtered , the solid washed with ethyl acetate, the organic solution was washed with water,nbsp;pre-dried with brine and dried over MgSO4 , filtratednbsp;and concentrated in vacuo.The solid was taken up with ethylacetatenbsp;( 50 ml) stirred 15 min , and diluted with diethylether until some trouble occured; the solid was filterednbsp;and the procedure was repeated twice The solid was dried under vacuum ( 1 mmHg1 hr 50C ) to afford 6-chloro-N-(4-(methylsulfonyl)phenyl)pyrazin-2-amine (3. 15g, 55.5% , purity uv 98.6% ). The filtrate was concentrated and purified by flash chromatography on silica gel eluting with 0 to 3% methanol in dichloromethane. The solvent was evaporated to dryness to afford 6-chloro-N-(4-(methylsulfonyl)phenyl)pyrazin-2-amine (1.95 g,34.4% uv purity 94.6%) as a white solid.nbsp;Nevertheless the 2nbsp;batches were combined to affordnbsp;6-chloro-N-(4-(methylsulfonyl)phenyl)pyrazin-2-amine (5.10 g, 90 %)nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CS(=O)(=O)C1=CC=C(C=C1)NC2=CN=CC(=N2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 89.91 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/04/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "341" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[K+]" + } + amount { + moles { + value: 0.000468 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C=O" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.000936 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C(=CC=C1)C)C(=O)NC(C2=CC=C(C=C2)Br)C34CCC(N3C)CC4" + } + amount { + moles { + value: 0.000234 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 2.34e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.34e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 130.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a CEM microwave vial was N-((4-bromophenyl)(7-methyl-7-azabicyclo[2.2.1]heptan-1-yl)methyl)-2,6-dimethylbenzamide (100 mg, 0.23 mmol), morpholine (0.082 mL, 0.94 mmol), palladium(II) acetate (5.25 mg, 0.02 mmol), BINAP (14.57 mg, 0.02 mmol), and potassium tert-butoxide (52.5 mg, 0.47 mmol) solid and DMF (2 mL) was added. The vial was capped and placed into the microwave at 300 watts, 130 C for 4 minutes.nbsp;After reaction completion, the the mixture was concentrated and crude taken up in CH2Cl2 and washed with water and dried (Na2SO4).nbsp;The material was purified on anbsp;12 gram Isco silica cartridge and eluted with 0% to 5% MeOH 2M NH3CH2Cl2 to give a light yellowish solid 2,6-dimethyl-N-((7-methyl-7-azabicyclo[2.2.1]heptan-1-yl)(4-morpholinophenyl)methyl)benzamide (30.0 mg, 29.6 %)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C(=CC=C1)C)C(=O)NC(C2=CC=C(C=C2)N3CCOCC3)C45CCC(N4C)CC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 29.57 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/16/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "342" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00122 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" + } + amount { + moles { + value: 0.00122 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CC(OC2=C(C1)C=CC(=N2)Cl)C3CC3" + } + amount { + moles { + value: 0.00122 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 0.000122 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000122 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.249 g, 1.22 mmol), 8-chloro-2-cyclopropyl-4-methyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.292 g, 1.22 mmol), Palladium acetate (0.027 g, 0.12 mmol), 2-(Dicyclohexylphosphino)biphenyl (0.043 g, 0.12 mmol) and Cesium carbonate (0.399 g, 1.22 mmol) were added in a microwave vial. The mixture was capped and flushed with argon. 1,2-dimethoxyethane (4 mL) was added and the mixture was run in a microwave for 60 minutes at 100C. No product, only unreacted startingmaterial. Added 1 eq CsCO3, and 0.1 eq ligand and palladium acetate, flushed with argon and run in the microwave at 100C for 60 min. 9% product according to LCMS. Added 0.1 eq ligand and palladium acetate, flushed with argon and run in the microwave at 100C for 60 min. No change.nbsp;Added 0.1 eq ligand and palladium acetate, flushed with argon and run in the microwave at 100C for 60 min. No change. Decided to isolate the intermediate and eventual product. The was filtrated through celite and concentrated. The crude was purified by preparative chromatography. The little product-containing fractions were collected but HPLC showed that they were not pure. The solvent was evaporated and the crude was partitioned between dichloromethane and sat. NaHCO3 (aq). The organic layer was separated with a phase separator and concentrated. Have 3 mg which is not pure. Discarded. Fractions with the intermediate 8-chloro-2-cyclopropyl-4-methyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine was collected, concentrated and the residue was partitioned with dichloromethane and sat. NaHCO3 (aq). The organic layer was separated, dried (Na2SO4) and concentrated giving 0.036 g of 8-chloro-2-cyclopropyl-4-methyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(CN(CC(O4)C5CC5)C)C=C3)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/10/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "343" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000151 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000151 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CC(OC2=C(C1)C=CC(=N2)Cl)C3CC3" + } + amount { + moles { + value: 0.000151 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 1.51e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.51e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.031 g, 0.15 mmol), 8-chloro-2-cyclopropyl-4-methyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.036 g, 0.15 mmol), Palladium acetate (3.39 mg, 0.02 mmol), 2-(Dicyclohexylphosphino)biphenyl (5.29 mg, 0.02 mmol) and Cesium carbonate (0.049 g, 0.15 mmol) were added in a microwave vial. The mixture was capped and flushed with argon. 1,2-dimethoxyethane (2 mL) was added and the mixture was run in a microwave for 60 minutes at 100C. Extremely little product was formed according to LCMS and all oxazepinestartingmaterial was consumed. Did not isolate, discarded." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(CN(CC(O4)C5CC5)C)C=C3)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/12/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "344" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00093 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" + } + amount { + moles { + value: 0.00093 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CC(OC2=C(C1)C=CC(=N2)Cl)C3CC3" + } + amount { + moles { + value: 0.00093 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 9.3e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 9.3e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.189 g, 0.93 mmol), 8-chloro-2-cyclopropyl-4-methyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.222 g, 0.93 mmol), Palladium acetate (0.021 g, 0.09 mmol), 2-(Dicyclohexylphosphino)biphenyl (0.033 g, 0.09 mmol) and Cesium carbonate (0.303 g, 0.93 mmol) were added in a microwave vial. The mixture was capped and flushed with argon. 1,2-dimethoxyethane (2 mL) was added and the mixture was run in a microwave for 60 minutes at 100C. Extremely little product was formed according to LCMS. Added 0.1 eq of Palladium acetate and 2-(Dicyclohexylphosphino)biphenyl and 1 eq Cesium carbonate and let run for another 60 min at 100C in the microwave. According to LCMS ther is 13% startingmaterial oxazepine left. Added a small spatula of acetoxy(2\'-(di-tert-butylphosphino)biphenyl-2-yl)palladium and 0.3 mL ethanol and let run for 30 minutes at 100C. The reaction mixture was filtrated through celite and concentrated. The crude product was purified by siliomatography using a gradient of metanol (+ 10%7M ammonia) in dichloromethane. Unreacted starting material 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline came out together with the product. Obtained 0.203 mg of impure product (at 254 nm 18% pure, at 220 nm 28% pure, at 290 nm 60% pure). Combined this with EN03597-98-001 and EN03597-99-001 at EN03597-97-001." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(CN(CC(O4)C5CC5)C)C=C3)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/18/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "345" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00148 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=CC(=C1)N)C#N" + } + amount { + moles { + value: 0.000492 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1[C@H](OC2=C(CN1CCO)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.000492 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 4.92e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.92e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;4-amino-2-methoxybenzonitrile (72.9 mg, 0.49 mmol), (R)-2-(8-chloro-2-phenyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)ethanol (150 mg, 0.49 mmol),nbsp;Palladium acetate (11.05 mg, 0.05 mmol), 2-(Dicyclohexylphosphino)biphenyl (17.25 mg, 0.05 mmol)and Cesium carbonate (481 mg, 1.48 mmol) were added to a microwave vial. 1,2-dimethoxyethane (2 mL) and EtOH (0.500 mL) were added. The reaction mixture was flushed with argon and the mixture was run in a microwave for 60 minutes at 100C. The solvent was decanted and the solids were washed with 5ml DCM. The solvent was evaporated and the crude product was purified on Si, 0-6% MeOH in DCM, yielding (R)-4-(4-(2-hydroxyethyl)-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-ylamino)-2-methoxybenzonitrile (27.0 mg, 13.17 %)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=C(C=CC(=C1)NC2=NC3=C(CN(C[C@H](O3)C4=CC=CC=C4)CCO)C=C2)C#N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 13.17 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/10/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "347" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[K+].[K+]" + } + amount { + moles { + value: 0.00518 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" + } + amount { + moles { + value: 0.00345 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=NC(=NC=C2C1)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.00363 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000173 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000104 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Purpose:nbsp;to examine scale-up of microwave conditions established in a previous experiment.Charged a round-bottom flask with a mixture of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.702 g, 3.45 mmol), (R)-2-chloro-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine (1.0 g, 3.63 mmol), palladium (II) acetate (0.023 g, 0.10 mmol), rac-BINAP (0.108 g, 0.17 mmol), potassium carbonate (0.716 g, 5.18 mmol), and toluene (20 mL).nbsp;The atmosphere s inerted through nitrogen purge cycles, then heated at 120 C or 16 hours.HPLC-UV shows the reaction is not as clean as in the microwave, and conversion is very poor.nbsp;The contents were allowed to continue heating over the weekend, but although conversion improved, the mixture contained many impurities.nbsp;Not progressed.autotext key=quot;0C636C73quot; name=quot;[Samples]quot; index=quot;0quot; field=quot;Samplesquot; type=quot;fieldquot; length=quot;9quot;gt;ber-coloured foam." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC=C4CN(C[C@H](OC4=N3)C5=CC=CC=C5)C)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/16/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "348" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000218 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.001 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000181 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=NC(=NC=C2C1)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.000181 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" + } + amount { + moles { + value: 1.4e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 5.44e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(R)-2-chloro-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine (0.05 g, 0.18 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.037 g, 0.18 mmol) (0.65), PALLADIUM(II) ACETATE (1.221 mg, 5.44 mol), CESIUM CARBONATE (0.071 g, 0.22 mmol) and Tri-tert- butylphosphonium tetrafluoriborate (0.0043 g, 0.014 mmol, 6 mol%) in 1 ml of dioxane was degaset over argone and heated in MW 120C 30 min. 002 - 4.8% of conversionmixture was heated more in MW 140C 30 min.003 - 15% of conversionmixture was heated more in MW 160C 30 min.Experiment was not" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC=C4CN(C[C@H](OC4=N3)C5=CC=CC=C5)C)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/20/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "349" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CCC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0002 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.001 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000181 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=NC(=NC=C2C1)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.000181 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" + } + amount { + moles { + value: 1.4e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 5.44e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(R)-2-chloro-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine (0.05 g, 0.18 mmol), PALLADIUM(II) ACETATE (1.221 mg, 5.44 mol) (1.6), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.037 g, 0.18 mmol) (0.64), Tri-tert- butylphosphonium tetrafluoriborate (0.0043 g, 0.014 mmol, 6 mol%) and Na-t-amilate (0.022 g, 1.1 equ, 0.2 mmol)nbsp;in 1 ml of dioxane was degaset over argone and heated in MW 120C 30 min. No reaction.Experiment was not progres" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC=C4CN(C[C@H](OC4=N3)C5=CC=CC=C5)C)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/20/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "351" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00029 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.018 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" + } + amount { + moles { + value: 0.00131 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=NC(=NC=C2C1)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.00145 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00029 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000145 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 130.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(R)-2-chloro-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine (400 mg, 1.45 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (265 mg, 1.31 mmol), Cesium carbonate (709 mg, 2.18 mmol), Palladium(II) acetate (32.6 mg, 0.15 mmol) and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (168 mg, 0.29 mmol) were added to a microwave vial then dioxane (18 mL) was added. The reaction mixture was flushed with argon and then heated at 140C for 60 min in a MW. The reaction mixture was filtered through celite and concentrated. The crude product was purified by silica flash chromatography using a gradient of methanol (0 to 5%) in dichloromethane. Not pure enough. The product was purified further with preparative chromatography. The productcontainng product was collected and the methanol was evaporated off. The wather phase was extracted three times with dichloromethane, dried (Na2SO4) and concentrated giving (R)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-6-methnyl-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepin-2-amine (195 mg, 30.4 %) as a dry film.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC=C4CN(C[C@H](OC4=N3)C5=CC=CC=C5)C)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 30.38 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/27/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "352" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 1.47e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.001 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000105 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=NC(=NC=C2C1)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.000105 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 1.47e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 7.36e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "The aim is optimization.(R)-2-chloro-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine (29 mg, 0.11 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (21.38 mg, 0.11 mmol), Sodium tert-butoxide (15.16 mg, 0.16 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (9.17 mg, 0.01 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (6.74 mg, 7.36 mol) were added to a microwave vial then toluene (1 mL) was added. The reaction mixture was flushed with nitrogen and the mixture was heated to 120C for 45 min. Small amount of product was formed. Abando" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC=C4CN(C[C@H](OC4=N3)C5=CC=CC=C5)C)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/27/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "353" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00119 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000357 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=NC(=NC=C2C1)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.000297 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 2.97e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.97e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium(II) acetate (6.68 mg, 0.03 mmol), 2-(Dicyclohexylphosphino)biphenyl (10.42 mg, 0.03 mmol) and Cesium carbonate (0.388 g, 1.19 mmol) were put in a 5 mL microwave vial and sealed. The vial was flushed with argon. (R)-2-chloro-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine (0.082 g, 0.30 mmol) in DME (5 mL) was added to the vial. The reaction mixture was run in the microwave at 100C for 60 minutes. Forgot the aniline! Added 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.086 g, 0.36 mmol) and a small spatula of Palladium(II) acetate and 2-(Dicyclohexylphosphino)biphenyl and the reaction mixture was run in the microwave for 60 minutes for 100C. The reaction mixture was filtrated through celite, concentrated and purified first by preparative chromatography. The productcontaining fractions were pooled, concentrated and partitioned between sat. NaHCO3 (aq) and dichloromethane. The organic layer was washed with sat. NaHCO3 (aq), dried (Na2) and concentrated giving (R)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepin-2-amine (9.00 mg, 6.84 %)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC=C4CN(C[C@H](OC4=N3)C5=CC=CC=C5)C)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 6.84 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/18/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "355" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 2.18e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.001 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000109 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=NC(=NC=C2C1)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.000109 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 2.18e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.09e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 130.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "The aim is optimization.(R)-2-chloro-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine (30 mg, 0.11 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (22.11 mg, 0.11 mmol), Cesium carbonate (53.2 mg, 0.16 mmol), [Reactants] and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (12.59 mg, 0.02 mmol) were added to a microwave vial then dioxane (1 mL) was added. The reaction mixture was flushed with nitrogen and then heated at 130C for 45 min in a MW. Small amount of product, quite messy. Abandoned." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC=C4CN(C[C@H](OC4=N3)C5=CC=CC=C5)C)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/27/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "357" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000491 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1[C@H](OC2=NC(=NC=C2CN1CCF)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.000409 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 4.09e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.09e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.118 g, 0.49 mmol), Palladium(II) acetate (9.19 mg, 0.04 mmol), 2-(Dicyclohexylphosphino)biphenyl (0.014 g, 0.04 mmol) and Cesium carbonate (0.00 mol) were put in a 5 mL microwave vial and sealed and purged with argon.nbsp;(R)-2-chloro-6-(2-fluoroethyl)-8-phenyl-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine (0.126 g, 0.41 mmol) in DME (5 mL) was added. The reaction mixture was run in the microwave at 100C for 60 minutes. Reaction still not complete. Additional palladium(II)acetate and 2-(dicyclohexylphosphino)biphenyl (small spatula) andnbsp;the reaction was run again in the microwave for 60 minutes. The reaction mixture was filtrated through celite, concentrated and purifiednbsp;by preparative chromatography. The productcontaining fractions were pooled, concentrated and partitioned between sat. NaHCO3 (aq) and dichloromethane. The organic layer was washed with brine, dried (NaSO4) and concentrated giving (R)-6-(2-fluorN-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-8-phenyl-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepin-2-amine (0.029 g, 14.93 %) as the product. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC=C4CN(C[C@H](OC4=N3)C5=CC=CC=C5)CCF)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 14.93 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/18/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "358" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0019 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC=CN1C2=CC=C(C=C2)N" + } + amount { + moles { + value: 0.000696 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)C2CN(CC3=C(O2)N=C(C=C3)Cl)CC#N)C" + } + amount { + moles { + value: 0.000633 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 6.33e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 6.33e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;4-(2-methyl-1H-imidazol-1-yl)aniline (0.121 g, 0.70 mmol), Palladium acetate (0.014 g, 0.06 mmol) and Cesium carbonate (0.618 g, 1.90 mmol) were added in a microwave vial. The mixture was capped and flushed with argon. 2-(8-chloro-2-(1,3-dimethyl-1H-pyrazol-5-yl)-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)acetonitrile (0.201 g, 0.63 mmol) innbsp;1,2-dimethoxyethane (5 mL) was added, the reaction mixture was flushed with argon and the mixture was run in a microwave for 60 minutes at 100C. No product, only unreacted startingmaterial. Added 1 eq CsCO3, and 0.1 eq ligand and palladium acetate, flushed with argon and run in the microwave at 100C for 60 min. Reaction complete. The reaction mixture was filtrated through Celite and washed with dichloromethane. The filtrate was concentrated and the crude product was purified by preparative chromatography. The productcontaining fractions were pooled, concentrated and the residue was partitioned between sat. NaHCO3 (aq) anromethane. The organic layer was separated by a Phase Separator and concentrated giving 2-(2-(1,3-dimethyl-1H-pyrazol-5-yl)-8-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)acetonitrile (0.041 g, 14.26 %)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)C2CN(CC3=C(O2)N=C(C=C3)NC4=CC=C(C=C4)N5C=CN=C5C)CC#N)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 14.26 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/24/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "359" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00118 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.0025 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C=C1N)Cl)N2C=NC=N2" + } + amount { + moles { + value: 0.000394 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1[C@H](OC2=C(CN1CCO)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.000394 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 3.94e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.94e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;3-chloro-4-(1H-1,2,4-triazol-1-yl)aniline (77 mg, 0.39 mmol), (R)-2-(8-chloro-2-phenyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)ethanol (120 mg, 0.39 mmol),nbsp;Palladium acetate (8.84 mg, 0.04 mmol), 2-(Dicyclohexylphosphino)biphenyl (13.80 mg, 0.04 mmol)and Cesium carbonate (385 mg, 1.18 mmol) were added to a microwave vial. 1,2-dimethoxyethane (2 mL) and EtOH (0.500 mL) were added. The reaction mixture was flushed with argon and the mixture was run in a microwave for 60 minutes at 100C. The solvent was decanted and the solids were washed with DCM, 5ml. The solvent was then evaporated and the crude product was purified on prepHPLC yielding (R)-2-(8-(3-chloro-4-(1H-1,2,4-triazol-1-yl)phenylamino)-2-phenyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)ethanol (16.00 mg, 8.78 %)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1[C@H](OC2=C(CN1CCO)C=CC(=N2)NC3=CC(=C(C=C3)N4C=NC=N4)Cl)C5=CC=CC=C5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 8.78 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/04/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "360" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00232 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(N=C1N)Cl" + } + amount { + moles { + value: 0.00193 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=CC=C1I" + } + amount { + moles { + value: 0.00193 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 0.00019 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00015 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (0.035 g, 0.15 mmol) was added to a mixture of 2-chloropyrimidin-4-amine (0.250 g, 1.93 mmol), 4-iodopyridine (0.396 g, 1.93 mmol), cesium carbonate (0.755 g, 2.32 mmol) and (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (0.105 g, 0.19 mmol) in 1,4-dioxane (10 mL) and the reaction mixture stirred for 18 hours at 80 C under nitrogen. EtOAc (50ml) was added to the reaction mixture and then the organics washed with water (3 x 50ml), brine (50ml) and then dried over MgSO4. The organics were then evaporated in vacuo to give the crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 2-chloro-N-(pyridin-4-yl)pyrimidin-4-amine (0.181 g, 45.3 %) as an orange solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CN=CC=C1NC2=NC(=NC=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 45.34 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/29/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "361" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0105 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.005 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1O)Br" + } + amount { + moles { + value: 0.005 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.0005 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.00025 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "4-Bromophenol (865 mg, 5 mmol), Tris(dibenzylideneacetone)dipalladium(0) (229 mg, 0.25 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (238 mg, 0.50 mmol), Morpholine (0.437 mL, 5.00 mmol) and sodium tert-butoxide (1009 mg, 10.50 mmol) were stirred in toluene (5 mL) overnight at 100 C.nbsp;The mixture was allowed to cool to ambient temperature.nbsp;Ethylacetate was added and the mixture was washed with aqueous NaHCO3 (satd.) and water.nbsp;The organic phase was separated, dried over MgSO4, filtered and the solvent removed by rotary evaporation.nbsp;The crude product was added to a silica gel column and was eluted with 0-2 % MeOH in DCM.nbsp;The collected fraction were combined and the solvent was removed by rotary evaporation.1H NMR in CDCl3 is consistent with desired productMSnbsp;(m+1) = 180.HPLC Peak RT = 2.55 minutes is product.nbsp;Purity = 96%." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1COCCN1C2=CC=C(C=C2)O" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 31.25 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/04/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "362" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0213 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.0102 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC2=C(C(=C1)Br)OC=C2" + } + amount { + moles { + value: 0.0102 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.00102 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000508 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "7-bromobenzofuran (2 g, 10.15 mmol), tert-Butyl 1-piperazinecarboxylate (1.891 g, 10.15 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.465 g, 0.51 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (0.484 g, 1.02 mmol) and sodium t-butoxide (1.856 mL, 21.32 mmol) were heated to 100 C in toluene (10 mL) for 3h.nbsp;The mixture was allowed to cool to ambient temperature.nbsp;Ethylacetate was added and the mixture was filtered through Celite.nbsp;The filtrate was concentrated and redissolved in ethylacetate.nbsp;The organic mixture was washed with satd. aqueous Na2CO3 and brine.nbsp;The organic phase was separated, dried over Na2CO3, filtered and the solvent removed by rotary evaporation.nbsp;The crude product was redissolved in diethylether and loaded onto a silica gel column and eluted with 0-50% EtOAc in heptanes.nbsp;The collected fractions were combined and the solvent removed by rotary evaporation to yield tert-butyl enzofuran-7-yl)piperazine-1-carboxylate (2.58 g, 84 %).MSnbsp;(m+1) = 303.HPLC Peak RT = 5.97 minutes is product.nbsp;Purity = 94%." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC=CC3=C2OC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 84.06 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/21/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "363" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00533 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00254 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC2=C(C(=C1)Br)OC=C2" + } + amount { + moles { + value: 0.00254 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.000254 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000127 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "7-bromobenzofuran (500 mg, 2.54 mmol), tert-Butyl 1-piperazinecarboxylate (473 mg, 2.54 mmol), Tris(dibenzylideneacetone)dipalladium(0) (116 mg, 0.13 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (121 mg, 0.25 mmol) and sodium t-butoxide (0.464 mL, 5.33 mmol) were heated in toluene (2 mL) to 100 C for 2h.nbsp;The mixture was allowed to cool.nbsp;Ethylacetate was added and the mixture was filtered through Celite.nbsp;The filtrate was concentrated and redissolved in ethylacetate.nbsp;The organic mixture was washed with satd. aqueous Na2CO3 and brine.nbsp;The organic phase was separated, dried over Na2CO3, filtered and the solvent removed by rotary evaporation.nbsp;The crude product was added to a silica gel column and was eluted with 0-2% MeOH in DCM and to a second silica gel column eluted with 0-100% EtOAc in heptane.nbsp;The collected fractions were combined to yield tert-butyl 4-(benzofuran-7-yl)piperazine-1-carboxylate (560 73.0 %).1H NMR in CD3OD is consistent with desired productMSnbsp;(m+1) = 303.1.HPLC Peak RT = 5.99 minutes is product.nbsp;Purity = 98%." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC=CC3=C2OC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 72.98 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/25/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "364" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00118 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.0025 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CC2=NN=C(N2C1)C3=CC=C(C=C3)N" + } + amount { + moles { + value: 0.000394 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1[C@H](OC2=C(CN1CCO)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.000394 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 3.94e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.94e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;4-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)aniline (79 mg, 0.39 mmol), (R)-2-(8-chloro-2-phenyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)ethanol (120 mg, 0.39 mmol)nbsp;Palladium acetate (8.84 mg, 0.04 mmol), 2-(Dicyclohexylphosphino)biphenyl (13.80 mg, 0.04 mmol)and Cesium carbonate (385 mg, 1.18 mmol) were added to a microwave vial. 1,2-dimethoxyethane (2 mL) and EtOH (0.500 mL) were added. The reaction mixture was flushed with argon and the mixture was run in a microwave for 60 minutes at 100C. The crude product was taken up in DCM and the solids were thoroughly washed with DCM. The solvents were evaporated and the crude product was purified on Si. 0-20% MeOH in DCM with 2% triethylamine. Yield: (R)-2-(8-(4-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)phenylamino)-2-phenyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)ethanol (39.0 mg, 21.14 %)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CC2=NN=C(N2C1)C3=CC=C(C=C3)NC4=NC5=C(CN(C[C@H](O5)C6=CC=CC=C6)CCO)C=C4" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 21.14 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/02/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "365" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00755 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.018 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.0036 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=C(C=C(C=C1)I)O" + } + amount { + moles { + value: 0.0036 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00036 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.00018 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "tert-butyl piperazine-1-carboxylate (0.670 g, 3.60 mmol) and methyl 2-hydroxy-4-iodobenzoate (1 g, 3.60 mmol), BINAP (0.224 g, 0.36 mmol), cesium carbonate (2.461 g, 7.55 mmol) were put inDME (18 mL),nbsp;tris(dibenzylideneacetone)dipalladium(0) (0.165 g, 0.18 mmol) was added last.nbsp;Reaction wsa purged by nitrogen, and heated at90 C overnight.nbsp;No desired product was found. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC(=C(C=C2)C(=O)OC)O" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/17/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "366" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0382 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0764 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CONC(=O)C1=C(C=CC(=C1)F)N" + } + amount { + moles { + value: 0.0287 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" + } + amount { + moles { + value: 0.0191 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00191 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000955 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (7.3 g, 19.10 mmol), 2-amino-5-fluoro-N-methoxybenzamide (5.28 g, 28.66 mmol), diacetoxypalladium (0.214 g, 0.96 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.105 g, 1.91 mmol) and cesium carbonate (12.45 g, 38.21 mmol) were suspended in 1,4-dioxane (76 ml). The reaction was degased, purged with nitrogen and heated to 90C (internal temperature) overnighti. iReaction was concentrated to dryness. Residue was diluted with EtOAc (200 mL) and water (200 mL). Aqueous was extracted with EtOAc (100 mL) then with EtOAcMeOH 91 (100 mL) =gt; iaqueous still contained some expected product.i Aqueous was saturated with NaCl and extracted with EtOAcMeOH 91 (100 mL). Combined organic layers were dried over MgSO4 and concentrated to dryness. The crude product (12g) was dissolved in CH2Cl2 (80 mL) for liquid injection but product started to precipitate. Solid was filtered and washed twice with CH2Cl2 to aff2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-5-fluoro-N-methoxybenzamide (7.1 g) as an off-white solid. The filtrate was purified by flash chromatography on silica gel eluting with 10 to 100% ethyl acetate in dichloromethane (ielution of impuritiesi) then with 5%, 10% and 15% MeOH in ethyl acetate (iproduct elutes on TLC plate with 100% EtOAc but n MeOH to elute from the column probably due to poor solubility in EtOAci). The solvent was evaporated to dryness. Residual oil was triturated in CH2Cl2. Resulting solid was filtered nad dried to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (0.9 g) as an off-white solid.Both batches (8g) were combined and recrystallised from EtOH (70 mL) to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (3.6 g) as a white crystalline solid =gt;i less hot EtOH (lt;60 mL ?) could have been used to solubilise all.iFiltrate was concentrated to ~half the volume and then stirred at room temperature for 4 hours. The resulting solid was filtered to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (3.2 g) as a white solid.Both batches of solid (6.8 g) were combined and slurried in EtOAc (65 mL) at room temperature for 24 hours. The resulting solid was filtered and dried at 50C under high vacuum overnight to afford 2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-5-fluoro-N-methoxybenzamide (4.52g, 54%, EN03787-13-01) as a white solid.Filtrate was concentrated to ~20 mL and then stirred at room temperature 24 hours. The resulting solid was filtered and dried under high vacuum at 50C overnight to afford 2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-5-fluoro-N-methoxybenzamide (1.12g, 13.4%, EN03787-13-02) as a white so" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=C(C=C(C=C3)F)C(=O)NOC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 67.7 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/14/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "367" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000592 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CONC(=O)C1=C(C=CC(=C1)F)N" + } + amount { + moles { + value: 0.000326 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" + } + amount { + moles { + value: 0.000296 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 2.96e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.48e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 95.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (113 mg, 0.30 mmol), 2-amino-5-fluoro-N-methoxybenzamide (60 mg, 0.33 mmol) and Cesium carbonate (193 mg, 0.59 mmol) in degassed dioxane (4 mL) under nitrogen at room temperature were degassed (nitrogen) for a further 5 minutes before adding Palladium(II) acetate (3.32 mg, 0.01 mmol) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (17.14 mg, 0.03 mmol) the reaction mixture then being allowed to stir at 95 C for 6 hours and cooled to RT.nbsp;LCMS analysis showed a new peak for product (9%) but both SM\'s still remained (pyridine 71%, benzamide 13 %).nbsp;Another 1.1 eq of benzamide (60 mg in 2ml dioxane) was added and thenbsp;RMnbsp;was then heated at 95 C overnight. Lcms after this time showed no further progression with the reaction.nbsp;Therefore a further portion of palladium acetate (0.05 eq. 3.32 mg)nbsp;and the xanthene ligand (0.1 eq. 17.14 mg) were added and the RM stirred on at 95C.nbsp;An this time showed a majority peak for product and no pyridine SM remaining.nbsp;The RM was concentrated and dry loaded onto silica.nbsp;It was then purified on a 12g isco column using initially 0-100 % ethyl acetate in DCM followed by 0-10 % methanol in ethyl acetate to givenbsp;2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-5-fluoro-N-methoxybenzamide (60.0 mg, 46.2 %) which was not very pureTrituration with diethyl ether did not produce a purer product." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=C(C=C(C=C3)F)C(=O)NOC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 46.21 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/10/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "369" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000942 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.04 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CONC(=O)C1=C(C=CC(=C1)F)N" + } + amount { + moles { + value: 0.0141 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" + } + amount { + moles { + value: 0.00942 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000942 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000471 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-amino-5-fluoro-N-methoxybenzamide (2.60 g, 14.13 mmol), N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (3.6 g, 9.42 mmol) (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.545 g, 0.94 mmol) diacetoxypalladium (0.106 g, 0.47 mmol) and cesium carbonate (6.14 g, 18.84 mmol) were suspended in dioxane (40 mL). The reaction was degased, purged with argon (3 times) and heated to 100 C overnight.The reaction mixture was allowed to cool to room temperature under stirring, diluted with ethyl acetate and the insolubles were removed by filtration, washed with EtOAc and the filtrate was concentrated.The crude product was purified by flash chromatography on silica gel eluting with 0 to 15% methanol in ethyl acetateDCM (11). Fractions containing the most part of pure product were evaporated. This residue was re-purified by trituration with DCM (with 5% MeOH), to give after filtration EN03299-42-01 (3.5 g, 7.98 mmol, 85 %) which contains trace of AcOEt and 3l DCM.The resulting solid was recrystallised from ethanol (35 ml) and the resulting crystalline solid was collected by filtration, washed with ethanol and dried to a constant weight in a vacuum oven to afford EN03299-42-02 (2.7 g, 5.54 mmol, 58.8 %)nbsp;as anbsp;white crystalline solid.TSB 46.938" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=C(C=C(C=C3)F)C(=O)NOC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 58.84 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/23/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "370" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000916 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.04 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=C(C=C(C=C1)F)N" + } + amount { + moles { + value: 0.0137 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)I)C(F)(F)F)C" + } + amount { + moles { + value: 0.00916 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000916 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000458 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-amino-4-fluoro-N-methylbenzamide (2.310 g, 13.74 mmol), N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (3.5 g, 9.16 mmol) (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.530 g, 0.92 mmol) diacetoxypalladium (0.103 g, 0.46 mmol) and cesium carbonate (5.97 g, 18.32 mmol) were suspended in dioxane (40 mL). The reaction was degased, purged with argon (3 times) and heated to 100 C for 5 hours.The reaction mixture was allowed to cool to room temperature under stirring, diluted with ethyl acetate and the insolubles were removed by filtration, washed with EtOAc and the filtrate was concentrated.The crude product was purified by flash chromatography on silica gel eluting with 0 to 10% methanol in ethyl acetateDCM (11). Fractions containing pure product were evaporated to give a foam. This residue was triturated with DCM and filtered to afford EN03299-43-01 (1.4 g, 3.31 mmol, 36.2 %) as an off-white product.combined with APE-03299-487g of aniline was recovered" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=C(C=CC(=C3)F)C(=O)NC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 36.19 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/24/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "373" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000262 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.000436 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC=CC(=C1C(=O)NOC)N" + } + amount { + moles { + value: 0.000222 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)I)C(F)(F)F)C" + } + amount { + moles { + value: 0.000131 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 1.31e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 6.54e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (50 mg, 0.13 mmol), 2-amino-N,6-dimethoxybenzamide (43.6 mg, 0.22 mmol), diacetoxypalladium (1.469 mg, 6.54 mol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (8.15 mg, 0.01 mmol) and cesium carbonate (85 mg, 0.26 mmol) were suspended in 1,4-dioxane (436 l) and sealed into a microwave tube. The reaction was degased, purged with nitrogen and heated to 90 C overnight =gt; islow reaction, a few expected product formed, no des-iodo observed, both SM leftibiNOT ISOLATED" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=C(C(=CC=C3)OC)C(=O)NOC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/12/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "374" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[K+].[K+]" + } + amount { + moles { + value: 0.000262 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.000436 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC=CC(=C1C(=O)NOC)N" + } + amount { + moles { + value: 0.000222 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)I)C(F)(F)F)C" + } + amount { + moles { + value: 0.000131 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 1.31e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 6.54e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (50 mg, 0.13 mmol), 2-amino-N,6-dimethoxybenzamide (43.6 mg, 0.22 mmol), diacetoxypalladium (1.469 mg, 6.54 mol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (7.57 mg, 0.01 mmol) and potassium carbonate (36.2 mg, 0.26 mmol) were suspended in 1,4-dioxane (423 l) and sealed into a microwave tube. The reaction was degased, purged with nitrogen and heated to 90 C overnight =gt; inot complete but seemed to be clean, no des-iodo by-product formed, both SM leftiSame reaction was performed in toluene (423 l) =gt; ireaction complete, LCMS profile similar to the conception document referenceibiNOT ISOL" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=C(C(=CC=C3)OC)C(=O)NOC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/12/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "376" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00597 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.199 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC=CC(=C1C(=O)NOC)N" + } + amount { + moles { + value: 0.101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)I)C(F)(F)F)C" + } + amount { + moles { + value: 0.0597 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00597 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00298 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (22.8 g, 59.67 mmol), 2-amino-N,6-dimethoxybenzamide (19.90 g, 101.43 mmol), diacetoxypalladium (0.670 g, 2.98 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (3.45 g, 5.97 mmol) and cesium carbonate (23.33 g, 71.60 mmol) were suspended in 1,4-dioxane (199 ml). The reaction was degased, purged with nitrogen and heated to 90 C =gt; ireaction turned to dark brown and solidified after ~15 minutes.i1,4-dioxane (50 mL) was added and reaction was stirred at 90C (internal temperature) overnight =gt; istirring became easier and mixture turned to beigeyellow then to dark greengrey during the night. iReaction was concentrated to dryness. Residue was diluted with CH2Cl2 (300 mL) and water (300 mL). Aqueous was extracted with CH2Cl2 (100 mL) then with CH2Cl2MeOH 91 (100 mL) =gt; iaqueous still contained expected product.i Aqueous was saturated with NaCl and extracted with CH2Cl2MeOH 91 (100 bined organic layers were dried over MgSO4 and concentrated to dryness. The crude product (38.5g) was dissolved in CH2Cl2 (100 mL) for liquid injection but some product started to precipitate. Solid was filtered and washed twice with CH2Cl2 to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (5.2 g) as a white solid. The filtrate was purified by flash chromatography on silica gel eluting with 0 to 7% methanol in ethyl acetate. The solvent was evaporated to dryness to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (20.6 g) as a beige solid.Both batches of product (25.8 g) were combined and triturated in tBuOMe (50 mL) CH2Cl2 (20 mL). The resulting solid was filtered, washed with tBuOMe (50 mL) to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (23 g) as a white solid.It was suspended in H2O (350 mL) and stirred at room temperature overnight =gt; imixture solidified.i It was filtered and dried over P2O5 under high vacuum for 6 hours.The resulting solid was suspended in acetonitrile (460 mL) and stirred at room temperature over the weekend. It was filtered, washed with cold acetonitrile and dried under high vacuum at 50C overnight to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (8.4 g, 31.3%, EN03787-12-01) as a white solid =gt; iproduct is quite soluble in acetonitrile, volume of solvent was too important (ref from PARD : 50mg in 1mL)iFiltrate was concentrated to ~100 mL (= until preciptation occured on the rotavapor) and then stirred at room temperature for 4 hours. The resulting solid was filtered and dried under high vacuum at 50C overnight to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (9.3 g, 34.6%, EN03787-12-02) as a white solid.Filtratecentrated to dryness to afford another batch of impure product (2.8g) which was slurried in CH3CN (28 mL) at room temperature overnight. The resulting solid was filtered and dried under high vacuum at 50C to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (1.54 g, 5.73%, EN03787-12-03) as a white solid =gt; ithis batch is less pure than the 2 othersi" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=C(C(=CC=C3)OC)C(=O)NOC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 71.59 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/13/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "377" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00183 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.008 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC=CC(=C1C(=O)NOC)N" + } + amount { + moles { + value: 0.00138 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)I)C(F)(F)F)C" + } + amount { + moles { + value: 0.000917 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 9.17e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.59e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (351 mg, 0.92 mmol), 2-amino-N,6-dimethoxybenzamide (270 mg, 1.38 mmol) and Cesium carbonate (598 mg, 1.83 mmol) in degassed dioxane (8 mL) under nitrogen at room temperature were allowed to stir, degassing (nitrogen) for a further 5 minutes before adding Palladium(II) acetate (10.30 mg, 0.05 mmol) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (53.1 mg, 0.09 mmol).nbsp;The reaction mixture was then stirred at 90 C for 4 hours and cooled to RT.nbsp;LCMS analysis showed a new peak for product but both SM\'s still remained.nbsp;The RMnbsp;was then heated at 100 C for a further 4 hours, after this time LCMS analysis showed none of the pyridine SM remaining and a bigger peak for product.nbsp;The RM was concentrated and then dissolved in methanol and dry loaded onto silica.nbsp;The crude was purified on a 12g Si column eluting with 0-10 % methanol in DCM.nbsp;Fractions 3-8 and 18-28 contained product and wered.nbsp;LCMS analysisTLC showed that the product was still not pure.Diethyl ether trituration gave 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (235 mg, 56.9 %) as a pure product." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=C(C(=CC=C3)OC)C(=O)NOC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 56.87 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/30/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "378" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0307 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.111 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)N)C" + } + amount { + moles { + value: 0.0307 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=C(C=C(C=C1)F)NC2=CC(=NC=C2C(F)(F)F)Cl" + } + amount { + moles { + value: 0.0256 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.0041 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00205 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-4-fluoro-N-methylbenzamide (8.9 g, 25.60 mmol), 1,3-dimethyl-1H-pyrazol-5-amine (3.41 g, 30.72 mmol), diacetoxypalladium (0.460 g, 2.05 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.370 g, 4.10 mmol) and cesium carbonate (10.01 g, 30.72 mmol) were suspended in 1,4-dioxane (111 ml). The reaction was degased, purged with nitrogen and heated to 90C (internal temperature) for 4 hoursi. iReaction was concentrated to dryness. Residue was diluted with CH2Cl2MeOH 91 (200 mL) and water (200 mL). Aqueous was extracted with CH2Cl2MeOH 91 (100 mL). Combined organic layers were dried over MgSO4 and concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 0 to 5% methanol in ethyl acetate. The solvent was evaporated to dryness to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-4-fluoro-N-methylbenzamide (7.6 g) as a yellow foam =gt; i1H NMR shothat it contained EtOAc and a vey small amount of an impurityi. This residue was triturated in CH2Cl2 (10 mL) =gt; icomplete solubilisation followed by precipitation. iThe resulting solid was filtered and washed with tBuOMe (10 mL) to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-4-fluoro-N-methylbenzamide (6.3 g) as a pale yellow solid =gt; i1H NMR showed that EtOAc and impurity has been removediThis solid was suspended in tBuOMe (20 mL) and stirred at 50C (heating block temperature) for 1 hour. Mixture was allowed to cool for 5 minutes then filtered, washed once with tBuOMe (10 mL) and dried overnight under high vacuum at 50C to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-4-fluoro-N-methylbenzamide (6.00 g, 55.5 %) as a white so" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=C(C=CC(=C3)F)C(=O)NC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 55.5 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/21/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "379" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0069 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.025 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)N)C" + } + amount { + moles { + value: 0.0069 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=C(C=C(C=C1)F)NC2=CC(=NC=C2C(F)(F)F)Cl" + } + amount { + moles { + value: 0.00575 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00092 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00046 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-4-fluoro-N-methylbenzamide (2 g, 5.75 mmol), 1,3-dimethyl-1H-pyrazol-5-amine (0.767 g, 6.90 mmol) diacetoxypalladium (0.103 g, 0.46 mmol) (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.533 g, 0.92 mmol) and cesium carbonate (2.249 g, 6.90 mmol) were suspended in dioxane (25 ml). The reaction was degased, purged with argon (3 times) and heated to at 90 C for 4 hours.The reaction mixture was allowed to cool to room temperature, diluted with DCM (some drop of MeOH) and filtered. Silica gel was added and solvents were evaporated to afford the crude, which was purified by flash chromatography on silica gel eluting with 0 to 10% methanol in ethyl acetateDCM (11) . The solvent was evaporated to dryness to give a residue which was triturated with DCM, filtered and dried to afford EN03299-48-01 (1.5 g, 3.55 mmol, 61.7 %) as a off-white solid.This sample EN03299-48-01 (1.5 g, 3.55 mmol, 61.7 %) and uEN03299-43-01u werebined and triturated with hot tBuOMe, filtered and dried to afford EN03299-48-02 (2.1 g, 4.90 mmol, 85 %) as a white solid.Trituration filtrates were evaporated and the residue was taken with DCM, filtered and dried to afford EN03299-48-03 (0.5 g, 1.184 mmol, 20.58 %) as a white solidTSB 46.916" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=C(C=CC(=C3)F)C(=O)NC)C(F)(F)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 61.74 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/01/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "380" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00212 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CS(=O)(=O)C1=CC=C(C=C1)N" + } + amount { + moles { + value: 0.00193 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(N=C(C=N1)Cl)Cl" + } + amount { + moles { + value: 0.00193 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000193 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000193 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2,6-dichloropyrazine (287 mg, 1.93 mmol), 4-(methylsulfonyl)aniline (330 mg, 1.93 mmol), diacetoxypalladium (43.3 mg, 0.19 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (120 mg, 0.19 mmol) and cesium carbonate (690 mg, 2.12 mmol) in 1,4-dioxane (2 mL) were degazed andnbsp;stirred at 90 C for 16 hours under nitrogen.The reaction mixture was evaporated to dryness and was purified by preparative HPLC using a Waters SunFire reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 6-chloro-N-(4-(methylsulfonyl)phenyl)pyrazin-2-amine (120 mg, 21.95 %)nbsp;as anbsp;yellow solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CS(=O)(=O)C1=CC=C(C=C1)NC2=CN=CC(=N2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 21.95 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/30/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "381" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "[Li+].C[Si](C)(C)[N-][Si](C)(C)C" + } + amount { + moles { + value: 0.123 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCCC1C#N" + } + amount { + moles { + value: 0.0642 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC(=CC=C1)Br" + } + amount { + moles { + value: 0.0535 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)CN1CCN2CCN(P1N(CC2)CC(C)C)CC(C)C" + } + amount { + moles { + value: 0.00214 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.0107 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Reaction carried out by Rolf Walker uEN03350-58u, work up and purification on this page.piperidine-4-carbonitrile (7.07 g, 64.16 mmol); 1-bromo-3-methoxybenzene (6.77 mL, 53.47 mmol) and diacetoxypalladium (2.401 g, 10.69 mmol) were thoroughly placed under an inert atmoshere. To this was added 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (0.732 g, 2.14 mmol); LITHIUM BIS(TRIMETHYLSILYL)AMIDE (123 mL, 122.97 mmol) and toluene (20 mL). The resultant mixture was stirred overnight at 100 C (suspect that it did not need overnight. The reaction mixture was poured onto DCM (200 mL), the mixture was filtered through celite and evaporated to afford a black residue. This was suspended in EtOAc (200 mL) and water (20 mL) and filtered through a pad of silica, washing through with EtOAc (300 mL) and water (20 mL). The filtrate was evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Pure tions were evaporated to dryness to afford 1-(3-methoxyphenyl)piperidine-4-carbonitrile (3.29 g, 28.5 %) as a yellow oil which solidified on standing." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=CC=CC(=C1)N2CCC(CC2)C#N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 28.45 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/03/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "382" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "[Li+].C[Si](C)(C)[N-][Si](C)(C)C" + } + amount { + moles { + value: 0.00615 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCCC1C#N" + } + amount { + moles { + value: 0.00321 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC(=CC=C1)Br" + } + amount { + moles { + value: 0.00267 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)CN1CCN2CCN(P1N(CC2)CC(C)C)CC(C)C" + } + amount { + moles { + value: 0.000107 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000535 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "piperidine-4-carbonitrile (0.353 g, 3.21 mmol); 1-bromo-3-methoxybenzene (0.339 mL, 2.67 mmol) and diacetoxypalladium (0.120 g, 0.53 mmol) were thoroughly placed under an inert atmoshere. To this was added 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (0.037 g, 0.11 mmol); LITHIUM BIS(TRIMETHYLSILYL)AMIDE (6.15 mL, 6.15 mmol) and toluene (10 mL). The resultant mixture was stirred overnight at 100 C (suspect that it did not need overnight.Equal vol of DCM was added and the reaction mixture filtered. Removal of the solvent under reduced pressure gave a dark brown gum.The crude product was purified by flash Silica chromatography {CombiFlash Companion - Presearch Ltd}, column size = 12 g , flow rate = 30 ml min, elution gradient 0 to 30% EtOAc in isohexane over 10 minutes {excluding lead in amp; wash etc.}. Pure fractions were evaporated to dryness to afford 1-(3-methoxyphenyl)piperidine-4-carbonitrile (0.315 g, 54.5 %) as a tan brown solid. nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=CC=CC(=C1)N2CCC(CC2)C#N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 54.48 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/21/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "385" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "[Li+].C[Si](C)(C)[N-][Si](C)(C)C" + } + amount { + moles { + value: 0.00615 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCCC1C(=O)N" + } + amount { + moles { + value: 0.00321 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC(=CC=C1)Br" + } + amount { + moles { + value: 0.00267 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)CN1CCN2CCN(P1N(CC2)CC(C)C)CC(C)C" + } + amount { + moles { + value: 0.000107 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000535 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "piperidine-4-carboxamide (0.411 g, 3.21 mmol); 1-bromo-3-methoxybenzene (0.339 mL, 2.67 mmol) and diacetoxypalladium (0.120 g, 0.53 mmol) were thoroughly placed under an inert atmoshere. To this was added 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (0.037 g, 0.11 mmol); LITHIUM BIS(TRIMETHYLSILYL)AMIDE (6.15 mL, 6.15 mmol) and toluene (10 mL). The resultant mixture was stirred at 100 C overnight.No sign of reaction by LCMS overnight.Abandonednbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=CC=CC(=C1)N2CCC(CC2)C(=O)N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/21/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "387" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000463 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.008 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN" + } + amount { + moles { + value: 0.0193 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC2=C(C=C1[N+](=O)[O-])SC(=N2)Br" + } + amount { + moles { + value: 0.00386 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000463 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000193 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;methanamine (0.793 mL, 19.30 mmol), 2-bromo-6-nitrobenzo[d]thiazole (1 g, 3.86 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.268 g, 0.46 mmol), cesium carbonate (1.886 g, 5.79 mmol) and diacetoxypalladium (0.043 g, 0.19 mmol) were suspended in 1,4-dioxane (8 mL) and sealed into a microwave tube. The reaction was heated to 150C for 30 minutes in the microwave reactor and cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness to afford a crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% DCM in EtOAc. Pure fractions were evaporated to dryness to afford N-methyl-6-nitrobenzo[d]thiazol-2-amine (0.050 g, 6.19 %) as a yellow solid. nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CNC1=NC2=C(S1)C=C(C=C2)[N+](=O)[O-]" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 6.19 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/23/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "388" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 4.54e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)[N+](=O)[O-])N" + } + amount { + moles { + value: 0.000379 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C2C(=C1)C(=CN2)C3=NC(=NC=C3Cl)Cl" + } + amount { + moles { + value: 0.000379 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 4.54e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.27e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a stirred solution of 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (100 mg, 0.38 mmol) in dioxane (10 mL) was added 2-methoxy-5-nitroaniline (63.7 mg, 0.38 mmol), cesium carbonate (247 mg, 0.76 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (26.3 mg, 0.05 mmol). The resulting suspension was purged with nitrogen for 5 minutes. diacetoxypalladium (5.10 mg, 0.02 mmol) was added and the mixture was purged with nitrogen for a further 5 minutes, and then heated at 80 C overnight. UPLC shows di-Cl SM almost completely consumed but no evidence of desired product.Reaction stopped" + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)[N+](=O)[O-])NC2=NC=C(C(=N2)C3=CNC4=CC=CC=C43)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/04/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "390" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 3.56e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.006 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000509 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC(=NC2=C1CN(CC(O2)CC(F)(F)F)C)Cl" + } + amount { + moles { + value: 0.000509 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 3.56e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 3.56e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (104 mg, 0.51 mmol), 8-chloro-4,6-dimethyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (150 mg, 0.51 mmol), Sodium tert-butoxide (73.4 mg, 0.76 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (22.19 mg, 0.04 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (32.6 mg, 0.04 mmol) were added to a radley tube followed by toluene (6 mL). The reaction mixture was flushed with argon and the mixture was heated to 100C and stirred overnight. The solids were filtered off and washed with DCM. The crude product was purified on prepHPLC yielding N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4,6-dimethyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (23.00 mg, 9.77 %)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CC(=NC2=C1CN(CC(O2)CC(F)(F)F)C)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 9.77 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/23/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "391" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00253 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCNCC1" + } + amount { + moles { + value: 0.00169 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=NC=C1Br)Br" + } + amount { + moles { + value: 0.00169 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000253 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000169 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 140.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Trial # 3:3,5-dibromopyridine (1000 mg, 4.22 mmol), 1-methylpiperazine (423 mg, 4.22 mmol), Pd2(dba)3 (387 mg, 0.42 mmol), XANTPHOS (366 mg, 0.63 mmol), SODIUM TERT-BUTOXIDE (609 mg, 6.33 mmol), PhCH3 (10 mL) as added to a 10 mL microwave vial. This was degassed and refilled with N2 and then heated at 140 C in microwave for 1h.LCMS showed reaction done with the peak at Rf0.52 showed a fragment mass of 256.Evaporated solvent. Residue purified by Gilson (CH3CNH2O 0-30%+TFA buffer )to get the desired product 1-(5-bromopyridin-3-yl)-4-methylpiperazine (107 mg, 9.90 %).Trial # 13,5-dibromopyridine (1000 mg, 4.22 mmol), 1-methylpiperazine (423 mg, 4.22 mmol), Pd2(dba)3 (387 mg, 0.42 mmol), XANTPHOS (366 mg, 0.63 mmol), [Reactants], PhCH3 (5 mL) as added to a 10 mL microwave vial. This was degassed and refilled with N2 and then heated at 140 C in microwave for 1h.LCMS showed reaction done with no desired peak formed.Trial # 2:3,5-dibromo (400 mg, 1.69 mmol), 1-methylpiperazine (169 mg, 1.69 mmol), Pd2(dba)3 (155 mg, 0.17 mmol), XANTPHOS (117 mg, 0.20 mmol), SODIUM TERT-BUTOXIDE (243 mg, 2.53 mmol), PhCH3 (5 mL) as added to a 10 mL microwave vial. This was degassed and refilled with N2 and then heated at 140 C in microwave for 1h.LCMS showed reaction done with the peak at Rf0.46 showed a fragment mass of 256.Evaporated solvent. Residue purified by Gilson (CH3CNH2O 0-30%+TFA buffer )to get the desired product 1-(5-bromopyridin-3-yl)-4-methylpiperazine (92 mg, 21.27 %)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CCN(CC1)C2=CC(=CN=C2)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 21.27 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/26/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "392" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CCN(CC)CC" + } + amount { + moles { + value: 0.00805 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C=O" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00268 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CSC(=C1)Cl" + } + amount { + moles { + value: 0.00268 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3" + } + amount { + moles { + value: 5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.[Pd]" + } + amount { + moles { + value: 5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 95.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a mixture of 2-chlorothiophene (0.248 mL, 2.68 mmol), tert-butyl piperazine-1-carboxylate (500 mg, 2.68 mmol), and TEA (1.123 mL, 8.05 mmol) in DMF (4 mL) was added Pd(Ph3P)4 (57.8 mg, .05 mmol). The reaction was allowed to heat at 95 C for overnight. LCMS and TLC showed the starting material peak as well as the triphenyl phosphene ionized M+1 peak. The tryphenyl phosphene showed up at the same retention time as 2-chlorothiophene. No new peak was observed following the reaction so no purification techniques were run.MSnbsp;(m+1) = not seen" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC=CS2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/19/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "394" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000677 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.001 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C(=C1)CN)C(F)(F)F" + } + amount { + moles { + value: 0.000677 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=NC=C1C(=O)N)Cl" + } + amount { + moles { + value: 0.000339 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 3.39e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.39e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a stirred solution of 6-chloronicotinamide (0.053 g, 0.34 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.021 g, 0.03 mmol), sodium 2-methylpropan-2-olate (0.065 g, 0.68 mmol) and diacetoxypalladium (7.60 mg, 0.03 mmol) in DME (1 mL) was added (2-(trifluoromethyl)phenyl)methanamine (0.095 mL, 0.68 mmol). The reaction mixture was jected to microwave irradiation for 4h at 120 C. Only traces of product was observed. The crude product was dissolved in DMSO (2 mL) and purified using Fractionlynx I, (Xbridge Prep C18 5m OBD 19x150 mm column), with 5 to 95% acetonitrile in 0.2% ammonia at pH 10.6-(2-(trifluoromethyl)benzylamino)nicotinamide: 1.45 mg (1.5 %)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C(=C1)CNC2=NC=C(C=C2)C(=O)N)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 1.45 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/21/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "395" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 3.39e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.001 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)C(F)(F)F)CN" + } + amount { + moles { + value: 0.000339 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=NC=C1C(=O)N)Cl" + } + amount { + moles { + value: 0.000339 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.39e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.39e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a stirred solution of 6-chloronicotinamide (0.053 g, 0.34 mmol), sodium 2-methylpropan-2-olate (0.065 g, 0.68 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.020 g, 0.03 mmol) and diacetoxypalladium (7.60 mg, 0.03 mmol) in DME (1 mL) was added (3-(trifluoromethyl)phenyl)methanamine (0.049 mL, 0.34 mmol). The reaction was run in microwave at 120 C for 4h. only traces of product observed. Reaction wasted." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)C(F)(F)F)CNC2=NC=C(C=C2)C(=O)N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/22/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "396" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000677 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.001 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1CN)C(F)(F)F" + } + amount { + moles { + value: 0.000677 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=NC=C1C(=O)N)Cl" + } + amount { + moles { + value: 0.000339 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 3.39e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.39e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a stirred solution of 6-chloronicotinamide (0.053 g, 0.34 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.021 g, 0.03 mmol), sodium 2-methylpropan-2-olate (0.065 g, 0.68 mmol) and diacetoxypalladium (7.60 mg, 0.03 mmol) in DME (1 mL) was added (4-(trifluoromethyl)phenyl)methanamine (0.097 mL, 0.68 mmol). The reaction was run in microwave at 100 C for 4h. The compound was purified by preparative HPLC on a Kromasil C8 column (10 m 250x20 ID mm) using a gradient of 51-55% acetonitrile in H2OACNFA 9550.2 buffer, over 25 minutes with a flow of 19 mLmin. The compounds were detected by UV at 270nm.6-(4-(trifluoromethyl)benzylamino)nicotinamide (7.40 mg, 7.40 %) was obtai" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1CNC2=NC=C(C=C2)C(=O)N)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 7.4 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/18/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "398" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00236 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.1 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" + } + amount { + moles { + value: 0.0283 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)Br)C#N" + } + amount { + moles { + value: 0.0236 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.00236 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00236 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "PdOAc2 (0.529 g, 2.36 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (1.124 g, 2.36 mmol) were added in one portion tonbsp;a degassed solution of 5-bromo-2-methoxybenzonitrile (5 g, 23.58 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (5.36 g, 28.30 mmol) and cesium carbonate (11.52 g, 35.37 mmol) in toluene (100 mL) at 20Cnbsp;under nitrogen. The resulting suspension was stirred at 120 C for 50 hours. The reaction mixture was diluted with EtOAc (150 mL)nbsp;and water (150 mL) and the biphasic mixture was filtered through celite. The organic layer was separated and washed sequentially with water (150 mL) and saturated brine (150 mL). The organic layer was evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-5-(2-(tert-butyldimethylsilyloxy)propylamino)-2-methoxybenzonitrile (3.60 g, 47.6 %) as a pale yellow o" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@H](CNC1=CC(=C(C=C1)OC)C#N)O[Si](C)(C)C(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 47.64 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/25/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "399" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0318 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.1 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" + } + amount { + moles { + value: 0.0255 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)Br)C#N" + } + amount { + moles { + value: 0.0212 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.00212 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00212 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Reaction carried out by Phill Walker in RSLPdOAc2 (0.476 g, 2.12 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (1.012 g, 2.12 mmol) were added in one portion to a degassed solution of 5-bromo-2-methoxybenzonitrile (4.50 g, 21.22 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (4.82 g, 25.47 mmol) and cesium carbonate (10.37 g, 31.83 mmol) in toluene (100 mL) at 20C in a microwave vial. The microwave vial was sealed and the reaction was heated to 120 C for 12 hours in the microwave reactor and cooled to RT.nbsp;The reaction mixture was diluted with EtOAc (100 mL) and water (100 mL). The biphasic mixture was filtered through celite. The organic layer was separated and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was filtered and dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was evaporated and was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohere fractions were evaporated to dryness to afford (R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)-3-fluoroaniline (0.851 g, 61.4 %) as a orange oil. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@H](CNC1=CC(=C(C=C1)OC)C#N)O[Si](C)(C)C(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 20.58 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/29/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "401" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 9.43e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" + } + amount { + moles { + value: 0.00113 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)Br)C#N" + } + amount { + moles { + value: 0.000943 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 9.43e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 9.43e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Trial reaction for Phil WalkerPdOAc2 (0.021 g, 0.09 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.045 g, 0.09 mmol) were added in one portion to a degassed solution of 5-bromo-2-methoxybenzonitrile (0.200 g, 0.94 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (0.214 g, 1.13 mmol) and cesium carbonate (0.461 g, 1.41 mmol) in toluene (10 mL) at 20C in a microwave vial. The reaction mixture was diluted with EtOAc (20 mL) and water (20 mL). The biphasic mixture was filtered through celite. The organic layer was separated and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was filtered and dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was evaporated and was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-5-(2-(tert-butyldimethylsilyloxy)propylamino)-2-methoxybenzonitrile (0.188 g, 62.2 %) as a ge oil. repated on a lager scale in RSL - See EN04063-90" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@H](CNC1=CC(=C(C=C1)OC)C#N)O[Si](C)(C)C(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 62.19 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/28/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "403" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00691 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N" + } + amount { + moles { + value: 0.00645 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=NC=C(C=N1)Br" + } + amount { + moles { + value: 0.00461 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000461 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00023 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "The methyl 5-bromopyrimidine-2-carboxylate (1 g, 4.61 mmol), tert-butyl carbamate (0.756 g, 6.45 mmol), diacetoxypalladium (0.052 g, 0.23 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.267 g, 0.46 mmol), cesium carbonate (2.252 g, 6.91 mmol) and dioxane (15 mL) were placed and sealed into a microwave tube. The reaction was degased, purged with argon and heated to 90 C (oil bath) over a period of 7 hours . The mixture was poured in water, extracted with ethyl acetate (x2). The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel 15-40m eluting with 5 to 50% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford methyl 5-(tert-butoxycarbonylamino)pyrimidine-2-carboxylate (0.710 g, 60.8 %) as a white so" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC1=CN=C(N=C1)C(=O)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 60.84 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/02/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "404" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0276 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.05 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N" + } + amount { + moles { + value: 0.0258 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=NC=C(C=N1)Br" + } + amount { + moles { + value: 0.0184 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00184 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000922 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "The methyl 5-bromopyrimidine-2-carboxylate (4 g, 18.43 mmol), tert-butyl carbamate (3.02 g, 25.80 mmol), diacetoxypalladium (0.207 g, 0.92 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.066 g, 1.84 mmol), cesium carbonate (9.01 g, 27.65 mmol) and dioxane (50 mL) were placed and sealed into a microwave tube. The reaction was degased, purged with argon and heated to 90 C (oil bath) over a period of 7 hours . The mixture was poured in water, extracted with ethyl acetate (x2). The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel 15-40m eluting with 5 to 50% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford methyl 5-(tert-butoxycarbonylamino)pyrimidine-2-carboxylate (3.00 g, 64.3 %) as a beige so" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC1=CN=C(N=C1)C(=O)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 64.27 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/09/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "406" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00105 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.0007 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CSC(=N1)C2CN(CC3=C(O2)N=C(C=C3)Cl)C" + } + amount { + moles { + value: 0.0007 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 7e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 7e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To 8-chloro-4-methyl-2-(4-methylthiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (207 mg, 0.70 mmol) in DME (3 mL) were 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (143 mg, 0.70 mmol), cesium carbonate (342 mg, 1.05 mmol), 2-(Dicyclohexylphosphino)biphenyl (24.53 mg, 0.07 mmol) and Palladium acetate (15.71 mg, 0.07 mmol) added. The reaction was heated to 110C for 60 min under N2 atmosphere. The solids were filtered off and washed with DCM, the solvents were evaporated and the crude product was purified by silica flash chromatography using DCM : [DCM:MeOH:NH3 = 90:10:1] = 100:0 to 35:65 as gradient. The title compound was obtained as yellow foam. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CSC(=N1)C2CN(CC3=C(O2)N=C(C=C3)NC4=NC(=C(C=C4)C5=CN(N=C5)C)OC)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 56.41 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/12/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "407" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.002 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(OC(=N1)N)C" + } + amount { + moles { + value: 0.001 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.001 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 140.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: Repeat of experiment EN04881-63 in an attempt to improve isolated yield using different normal phase eluent system (isolation was problematic for EN04881-63).Pd2(dba)3 (22.89 mg, 0.025 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (43.4 mg, 0.075 mmol), 2,4-dichloropyridine (148 mg, 1.00 mmol), cesium carbonate (652 mg, 2.00 mmol) and 4,5-dimethyloxazol-2-amine (112 mg, 1.00 mmol) were added to an oven dried microwave vial, the vial was capped and placed under an inert atmosphere, dioxane (4 mL) was added and the resulting mixture was heated to 140 C for 1 h by microwave irradiation under a nitrogen atmosphere.The crude product was purified by flash silica chromatography, elution gradient 0 to 3% methanolic ammmonia (7 M) in DCM. Pure fractions were evaporated to dryness to afford P1 as a brown solid. The product was further purified by crystallisation from hot DCMMeOH to afford N-(4-chloropyridin-2-yl)-4,5-dimethyloxazol-2-amine (34.0 mg, 15.20 %) as a besolid. Conclusion: A relatively low yield of the desired product was isolated here, it may be possible to increase the above yield at higher temperature or by using excess amine as electron rich oxazoles are prone to decomposition. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(OC(=N1)NC2=NC=CC(=C2)Cl)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 15.2 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/06/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "408" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.002 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(OC(=N1)N)C" + } + amount { + moles { + value: 0.001 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.001 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 140.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: To find out which strates are efficient coupling partners, is there a robust link between how electron poor the strate is and yield i.e. more electron poor aminooxazoles produce greater yields.Pd2(dba)3 (22.89 mg, 0.025 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (43.4 mg, 0.075 mmol), 2,4-dichloropyridine (148 mg, 1.00 mmol), cesium carbonate (652 mg, 2.00 mmol) and 4,5-dimethyloxazol-2-amine (112 mg, 1.00 mmol) were added to an oven dried microwave vial, the vial was capped and placed under an inert atmosphere, dioxane (4 mL) was added and the resulting mixture was heated to 140 C for 1 h by microwave irradiation under a nitrogen atmosphere.The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in heptane. Pure fractions were evaporated to dryness to afford N-(4-chloropyridin-2-yl)-4,5-dimethyloxazol-2-amine (34.0 mg, 15.20 %) as a pale yellow solid. Conclusion: The dimethyl stituted 2-aminooxazole (relaty electron rich) produces more coupled product than the unstituted 2-aminooxazole. Of the 2-aminooxazoles tested thus far the 4- and 5-ester stituted aminooxazoles are the most efficient coupling partners.Note: A run at T= 160 C may be beneficial, an increase in yield was seen for the ester stituted 2-aminooxazole under these more forcing conditions." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(OC(=N1)NC2=NC=CC(=C2)Cl)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 15.2 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/07/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "409" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000704 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=CN=C(C=C2)N" + } + amount { + moles { + value: 0.00047 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.00047 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 4.7e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.7e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (129 mg, 0.47 mmol), 5-(4-methyl-1H-imidazol-1-yl)pyridin-2-amine (82 mg, 0.47 mmol), PALLADIUM(II) ACETATE (10.54 mg, 0.05 mmol), 2-(DICYCLOHEXYLPHOSPHINO)BIPHENYL (16.46 mg, 0.05 mmol) and Cs2CO3 (229 mg, 0.70 mmol) were weighed into a microwave vial which was capped and flushed with argon. DME (5 mL) was added and the mixture was heated to 100C in a microwave apparatus for 2 h. The mixture was filtered and purified by column chromatography on Silica using gradient elution with increasing concentration of methanol, from 0 to 6 %, in dichloromethane to give(R)-4-methyl-N-(5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (69.5 mg, 35.9 %)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=CN=C(C=C2)NC3=NC4=C(CN(C[C@H](O4)C5=CC=CC=C5)C)C=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 35.89 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/08/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "410" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000763 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=CN=C(C=C2)N" + } + amount { + moles { + value: 0.000509 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC(=NC2=C1CN(CC(O2)CC(F)(F)F)C)Cl" + } + amount { + moles { + value: 0.000509 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 5.09e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 5.09e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To 8-chloro-4,6-dimethyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (300 mg, 0.51 mmol) in DME (4 mL) were 5-(4-methyl-1H-imidazol-1-yl)pyridin-2-amine (89 mg, 0.51 mmol), cesium carbonate (249 mg, 0.76 mmol), 2-(Dicyclohexylphosphino)biphenyl (17.84 mg, 0.05 mmol) and Palladium acetate (11.43 mg, 0.05 mmol) added. The reaction was heated to 110C for 3*90min. The solids were filtered of and washed with DCM and IPA and discarded. The solvents were evaporated and the crude product was purified using first flash chromatography, 0-7% MeOH in DCM and the prepHPLC yielding 4,6-dimethyl-N-(5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (34.0 mg, 15.45 %)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CC(=NC2=C1CN(CC(O2)CC(F)(F)F)C)NC3=NC=C(C=C3)N4C=C(N=C4)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 15.45 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/08/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "411" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0365 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.035 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.028 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(O1)C=CC=C2Cl" + } + amount { + moles { + value: 0.028 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.0028 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.0014 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 95.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "tert-butyl piperazine-1-carboxylate (5.22 g, 28.04 mmol), ethyl 4-chlorobenzofuran-2-carboxylate (6.3 g, 28.04 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (1.337 g, 2.80 mmol), Tris(dibenzylideneacetone)dipalladium(0) (1.284 g, 1.40 mmol) and CESIUM CARBONATE (11.88 g, 36.46 mmol) were heated under argon to 95 C 14:51:42 overnight, LC showed no s.m. EN03969-25-001. The mixture was allowed to cool to rt, diluted with EtOAc (35 mL) and filtered through a pad of Celite, washed with EtOAc (total of 100 mL). The filterate was collected and the solvent was removed by rotary evaporation.nbsp;The crude product was treated with diisopropylether under stirring at rt for 4 days, the mixture was filterered and washed with diisopropylether. The diisopropyletherphase was concentrated to give 3.6 g. The solid was treated with MeOH under stirring at rt for 4 h, filtrated, washed with MeOH, still not clear solution. The solid was vacuumdried at 40 C over night to give 7.6 g. The MeOH-mas filterered through a process K200 filter, the formed solution was concentrated to give 1.4 g.No pure product in any of the solids, were combined (12.6 g) and dissolved in CH2Cl2 and put on silica (200 g) using 1. CH2Cl2 (500 mL), 2. EtOAc (400 mL) as eluent. Fr. 5-6 were combined and concentrated to give EN03969-25-002 (10.6 g, 28.3 mmol, 101 %).To the brownish solid was added ether (40 mL) and the slurry was stirred at 35 C for 5-10 min. The now grey solid was filtered off, rinsed with 4x20 mL ether and dried under vacuum at 30 C o.n, yieldingnbsp;EN03969-25-003 (6.7 g, 17.89 mmol, 63.8 %).44 mg of EN03969-25-003 was sent to bStefan Elofsson bat Analytical Services and OA Support teamb bfor purity-assay (95 %), see report.EN03969-25-003 was delivered to CM Sdertlje in can: b3" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(C=CC=C2O1)N3CCN(CC3)C(=O)OC(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 63.8 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/29/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "412" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00142 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCCN1" + } + amount { + moles { + value: 0.00189 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C=C1Cl)Br)C#N" + } + amount { + moles { + value: 0.000947 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 9.47e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 4.74e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Tris(dibenzylideneacetone)dipalladium (0) (43.4 mg, 0.05 mmol) and rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (59.0 mg, 0.09 mmol) were added to a mixture of 2-bromo-4-chlorobenzonitrile (205 mg, 0.95 mmol), Cesium carbonate (463 mg, 1.42 mmol) and Piperazine (163 mg, 1.89 mmol) in dioxane (3 mL). Reaction vessel was placed in an oil bath set to 90 C 2.45pm.LCMS on shows large product peak (222).Cooled, filtered through a silica plug, washing with EtOAc until filtrate is clear. Crude NMR is very messy, target deprioritized. Discarded." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CN(CCN1)C2=C(C=CC(=C2)Cl)C#N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/14/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "413" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00187 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCCN1" + } + amount { + moles { + value: 0.0025 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C=C1F)Br)C#N" + } + amount { + moles { + value: 0.00125 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000125 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 6.25e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Tris(dibenzylideneacetone)dipalladium (0) (57.2 mg, 0.06 mmol) and rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (78 mg, 0.12 mmol) were added to a mixture of 2-bromo-4-fluorobenzonitrile (250 mg, 1.25 mmol), Cesium carbonate (611 mg, 1.87 mmol) and Piperazine (215 mg, 2.50 mmol) in dioxane (3 mL). Reaction vessel was placed in an oil bath at 90 C 4pm.LCMS on shows several peaks. Larger peak corresponding to displacement of F by piperazine (MW266) than for desired product (205).Discarded" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CN(CCN1)C2=C(C=CC(=C2)F)C#N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/15/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "414" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)[O-].[Na+]" + } + amount { + moles { + value: 3.05e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=COC(=N1)N" + } + amount { + moles { + value: 0.00112 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Br" + } + amount { + moles { + value: 0.00102 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.05e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.27e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 170.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: Improve yield of the desired product starting from the bromoaryl compound.To a flask containing 2-bromo-4-chloropyridine (196 mg, 1.02 mmol), sodium phenolate (177 mg, 1.52 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (11.63 mg, 0.01 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (17.64 mg, 0.03 mmol) (Xantphos), was added degassed dioxane (4 mL) and the mixture allowed to stir under nitrogen atmosphere for 5 min. To this solution was added oxazol-2-amine (94 mg, 1.12 mmol) and the reaction mixture was heated to 170 Cnbsp;for 2 h under microwave irradiation.Methanol was added to the crude reaction mixture together with silica (2 g), the solvent was removed under reduced pressure and the remaining residue was placed in dry load tube prior to chromatography. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to afford N-(4-chloropyridin-2-yl)oxazol-2-ami1.000 mg, 0.503 %) as a beige solid. Conclusion: Trace amount of the desired product isolated." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)NC2=NC=CO2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.5 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/11/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "415" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.002 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=COC(=N1)N" + } + amount { + moles { + value: 0.001 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Br" + } + amount { + moles { + value: 0.001 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 140.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: To find out if the 2-bromopyridine is a more efficient coupling partner than the chloro analogue.Pd2(dba)3 (22.89 mg, 0.025 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (43.4 mg, 0.075 mmol), 2-bromo-4-chloropyridine (192 mg, 1.00 mmol), cesium carbonate (652 mg, 2.00 mmol) and oxazol-2-amine (84 mg, 1.00 mmol) were added to an oven dried microwave vial, the vial was capped and placed under an inert atmosphere, dioxane (4 mL) was added and the resulting mixture was heated at 140 C for 1 h by microwave irradiation under a nitrogen atmosphere.The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in heptane. Pure fractions were evaporated to dryness to afford N-(4-chloropyridin-2-yl)oxazol-2-amine (15.00 mg, 7.67 %) as a white solid. Conclusion: A slightly improved yield of the desired product was formed with respect to the 2,4-dichloropyridine strate, however the difference could not be taken to be significant. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)NC2=NC=CO2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 7.67 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/05/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "416" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00203 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)[N+](=O)[O-])N" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000122 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000101 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;3-Nitroaniline (140 mg, 1.01 mmol), 2,4-dichloropyridine (150 mg, 1.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (70.4 mg, 0.12 mmol) and cesium carbonate (660 mg, 2.03 mmol) were stirred in dioxane (5 mL).nbsp;The mixture was purged with nitrogen for 10 minutes.nbsp;Palladium(II) acetate (22.76 mg, 0.10 mmol) was added and the mixture heated at 100 C for 1.5h.nbsp;The mixture was cooled, filtered and concentrated.nbsp;The crude product was purified by flash silica chromatography, eluting with 1% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-chloro-N-(3-nitrophenyl)pyridin-2-amine (121 mg, 47.8 %) as a yellow solid. nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)[N+](=O)[O-])NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 47.82 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/06/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "418" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00025 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N" + } + amount { + moles { + value: 0.000208 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CCN(CC1)C2=C(C=C(C(=C2)OC)N)Br" + } + amount { + moles { + value: 0.000167 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.33e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.67e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a suspension of 5-bromo-2-methoxy-4-(4-methylpiperazin-1-yl)aniline (50 mg, 0.17 mmol) in dioxane (4 mL) was added tert-butyl carbamate (24.39 mg, 0.21 mmol), cesium carbonate (81 mg, 0.25 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (19.27 mg, 0.03 mmol). The resulting suspension was degassed and Palladium(II) acetate (3.74 mg, 0.02 mmol) was added. The mixture was degassed and stirred at 120 C for 2 hours in the CEM microwave, then allowed to cool to ambient temperature. The reaction was incomplete so further cesium carbonate (81 mg, 0.25 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (19.27 mg, 0.03 mmol) and diacetoxyzinc (30.6 mg, 0.17 mmol) were added and the mixture was degassed. Further Palladium(II) acetate (3.74 mg, 0.02 mmol) was added, and the mixture was degassed and stirred at 130 C for 1 hour in the CEM microwave, then allowed to cool to amibient temperature. TLC (10% MeOH in DCM + 1% cNH3 (aq)) suggests bromo SM has been consumed but no evidence of desiret having been formed. UPLC shows only oxidised xantphos.Reaction stopped" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC1=C(C=C(C(=C1)N)OC)N2CCN(CC2)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/17/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "419" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000177 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCC(CC1)OC2=CC=CC(=C2)N" + } + amount { + moles { + value: 0.000177 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)NC(=O)C2=CC3=C(C=C2)OCCO3)NC(=O)C4=CN=C(C=C4)Cl" + } + amount { + moles { + value: 0.000118 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.08e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 3.54e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of 6-chloro-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)nicotinamide (50 mg, 0.12 mmol),3-(1-methylpiperidin-4-yloxy)aniline (36.5 mg, 0.18 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4.10 mg, 7.08 mol),TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (3.24 mg, 3.54 mol),sodium 2-methylpropan-2-olate (17.01 mg, 0.18 mmol) in toluene (2 mL)IPA (0.500 mL)was degassed with nitrogen and heated at reflux for 18 hours.The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with water (100 mL), The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% MeOH7MNH3 in EtOAc. lcms still showed 30% unreacted aniline. Fractions evaporated.The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (cont3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-(3-(1-methylpiperidin-4-yloxy)phenylamino)nicotinamide (23.00 mg, 32.8 %) as a cream solid. nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)NC(=O)C2=CC3=C(C=C2)OCCO3)NC(=O)C4=CN=C(C=C4)NC5=CC(=CC=C5)OC6CCN(CC6)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 32.84 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/13/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "420" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000177 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN(C)CC1=CC(=CC=C1)N" + } + amount { + moles { + value: 0.000177 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)NC(=O)C2=CC3=C(C=C2)OCCO3)NC(=O)C4=CN=C(C=C4)Cl" + } + amount { + moles { + value: 0.000118 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.08e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 3.54e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of 6-chloro-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)nicotinamide (50 mg, 0.12 mmol),3-((dimethylamino)methyl)aniline (26.6 mg, 0.18 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4.10 mg, 7.08 mol),TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (3.24 mg, 3.54 mol),sodium 2-methylpropan-2-olate (17.01 mg, 0.18 mmol) in toluene (2 mL)IPA (0.500 mL)was degassed with nitrogen and heated at reflux for 18 hours.The reaction mixture was filtered and filtered solid washed with ethyl acetate. The organic filtrate was washed with water (50ml), and organic layer dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-me6-(3-((dimethylamino)methyl)phenylamino)nicotinamide (24.60 mg, 38.8 %) as a cream solid. nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)NC(=O)C2=CC3=C(C=C2)OCCO3)NC(=O)C4=CN=C(C=C4)NC5=CC=CC(=C5)CN(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 38.79 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/21/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "421" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000248 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C1CCN(C1)C2=CC=CC(=C2)N" + } + amount { + moles { + value: 0.000248 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)NC(=O)C2=CC3=C(C=C2)OCCO3)NC(=O)C4=CN=C(C=C4)Cl" + } + amount { + moles { + value: 0.000165 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 9.91e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 4.95e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of 6-chloro-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)nicotinamide (70 mg, 0.17 mmol),[Reactants],(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (5.73 mg, 9.91 mol),TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (4.54 mg, 4.95 mol),sodium 2-methylpropan-2-olate (23.81 mg, 0.25 mmol) in toluene (4 mL)IPA (1.000 mL)was degassed with nitrogen and heated at reflux for 18 hours.The reaction mixture was filtered and filtered solid washed with ethyl acetate. The organic filtrate was washed with water (50ml), and organic layer dried over Na2SO4, filtered and evaporated.The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-(3-(3-(dimethylamino)pyrrolidylamino)nicotinamide (10.00 mg, 10.22 %) as a cream solid. nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)NC(=O)C2=CC3=C(C=C2)OCCO3)NC(=O)C4=CN=C(C=C4)NC5=CC(=CC=C5)N6CCC(C6)N(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 10.22 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/22/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "422" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.002 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=COC(=N1)N" + } + amount { + moles { + value: 0.001 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.001 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 140.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: To find out which strates are efficient coupling partners, is there a robust link between how electron poor the strate is and yield i.e. more electron poor aminooxazoles produce greater yields.Pd2(dba)3 (22.89 mg, 0.025 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (43.4 mg, 0.075 mmol), 2,4-dichloropyridine (148 mg, 1.00 mmol), cesium carbonate (652 mg, 2.00 mmol) and 4-methyloxazol-2-amine (98 mg, 1.00 mmol) were added to an oven dried microwave vial, the vial was capped and placed under an inert atmosphere, dioxane (4 mL) was added and the resulting mixture was heated to 140 C for 1 h by microwave irradiation under a nitrogen atmosphere.Dichloromethane (10 mL) was added to the crude reaction mixture and the mixture was adsorbed onto silica gel. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in heptane. Pure fractions were evaporated to dryness to afford N-(4-chloropyridin-2-yl)-4-methyloxazol-2-amine (59.0 mg.1 %) as a cream solid. Note: a further 34 mg of impure product came off the column early and so the yield for this reaction is probably closer to 35% had the purification been efficient.Conclusion: Somewhat surprisingly the methyl stituted amino-oxazole gave significant amounts of coupled product. It appears that certain moderately elctron rich strates may also undergo relatively efficient coupling." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=COC(=N1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 28.14 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/24/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "423" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00371 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0075 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CO[C@@H]1CCNC1" + } + amount { + moles { + value: 0.00247 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=NC=C1Br)Br" + } + amount { + moles { + value: 0.00272 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000124 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 4.94e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of 3,5-dibromopyridine (0.644 g, 2.72 mmol), (R)-3-methoxypyrrolidine (0.25 g, 2.47 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (0.045 g, 0.05 mmol), sodium 2-methylpropan-2-olate (0.356 g, 3.71 mmol) and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.077 g, 0.12 mmol) in degassed toluene (7.5 ml) was sealed into a microwave tube and stirred for 16 hours at 90 C. The reaction was completed.After cooling, an aqueous solution of Na2CO3 was added. Extraction with DCM (twice). The organic layers were dried over MgSO4 and evaporated iin vacuoi to give the crude product as an orange oil. PBO-04062-54-01 It was purified by chromatography (Merck cartridge SVF D26 - SI60 15-40 m - 30 g) on silica gel eluting with EtOAc 0 to 25% in petroleum ether. Pure collected fractions were evaporated to afford (R)-3-bromo-5-(3-methoxypyrrolidin-1-yl)pyridine (0.325 g, 51.1 %) as a yellow oil. PBO-04062-5" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CO[C@@H]1CCN(C1)C2=CC(=CN=C2)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 51.14 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/05/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "424" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00534 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.15 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" + } + amount { + moles { + value: 0.0667 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" + } + amount { + moles { + value: 0.0534 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.00534 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00534 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "PdOAc2 (1.198 g, 5.34 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (2.54 g, 5.34 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (15.00 g, 53.36 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (12.63 g, 66.70 mmol) and cesium carbonate (26.1 g, 80.04 mmol) in toluene (150 mL) at 120C under nitrogen. The resulting suspension was stirred at 120 C for 16 hours. The reaction was incomplete so the reaction mixture was stirred for a further 24 hours at 120C. The reaction mixture was cooled and diluted with EtOAc (150 mL) and water (150 mL). The biphasic mixture was filtered through celite. The organic layer was separated and washed sequentially with water (150 mL) and saturated brine (150 mL). The organic layer was filtered and dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was evaporated and was purified by flash silica chromatography*, elution gradient 0 to 20% EtOAc in isohexre fractions were evaporated to dryness to affordnbsp;(R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)-3-fluoroaniline (11.7 g, 30.0 mmol, 56.3 %) as a orange oil. Fractions that contained small amounts of impurities were also combined and were evaporated to dryness to affordnbsp;(R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)-3-fluoroaniline (2.5 g, 6.42 mmol, 12.03 %) as a dark orange oil." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@H](CNC1=CC(=C(C=C1)OCC2=CC=CC=C2)F)O[Si](C)(C)C(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 68.31 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/04/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "425" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000356 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" + } + amount { + moles { + value: 0.00356 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" + } + amount { + moles { + value: 0.00356 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.000356 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000356 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "PdOAc2 (0.080 g, 0.36 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.170 g, 0.36 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (1 g, 3.56 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (0.674 g, 3.56 mmol) and cesium carbonate (1.739 g, 5.34 mmol) in toluene (20 mL) at 120C under nitrogen. The resulting suspension was stirred at 120 C for 16 hours. The reaction mixture was diluted with EtOAc (20 mL) and water (20 mL). The biphasic mixture was filtered through celite. The organic layer was separated and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was filtered and dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was evaporated and was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)-3-fluoro(0.851 g, 61.4 %) as a orange oil. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@H](CNC1=CC(=C(C=C1)OCC2=CC=CC=C2)F)O[Si](C)(C)C(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 61.41 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/13/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "427" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000356 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" + } + amount { + moles { + value: 0.00427 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" + } + amount { + moles { + value: 0.00356 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.000356 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000356 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "PdOAc2 (0.080 g, 0.36 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.170 g, 0.36 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (1 g, 3.56 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (0.808 g, 4.27 mmol) and cesium carbonate (1.739 g, 5.34 mmol) in anhydrous dioxane (20 mL) at 20C in a microwave vial. The microwave vial was sealed and the reaction was heated to 120 C for 10 hours in the microwave reactor and cooled to RT. LCMS indicates mainly starting material bbNo further action was ta" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@H](CNC1=CC(=C(C=C1)OCC2=CC=CC=C2)F)O[Si](C)(C)C(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/17/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "428" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00356 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.15 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" + } + amount { + moles { + value: 0.0427 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" + } + amount { + moles { + value: 0.0356 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.00356 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00356 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "PdOAc2 (0.799 g, 3.56 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (1.696 g, 3.56 mmol) were added in one portion tonbsp;a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (10.00 g, 35.57 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (8.08 g, 42.69 mmol) and cesium carbonate (17.39 g, 53.36 mmol) in toluene (150 mL) at 20Cnbsp;under nitrogen. The resulting suspension was stirred at 120 C for 35 hours. The reaction mixture was diluted with EtOAc (150 mL)nbsp;and water (150 mL) and the biphasic mixture was filtered through celite. The organic layer was separated and washed sequentially with water (150 mL) and saturated brine (150 mL). The organic layer was evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)-3-fluoroaniline (9.38 g, 67.7 %) as a orange b" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@H](CNC1=CC(=C(C=C1)OCC2=CC=CC=C2)F)O[Si](C)(C)C(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 67.69 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/20/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "429" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00534 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.2 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" + } + amount { + moles { + value: 0.0667 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" + } + amount { + moles { + value: 0.0534 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.00534 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00534 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "PdOAc2 (1.198 g, 5.34 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (2.54 g, 5.34 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (15.00 g, 53.36 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (12.63 g, 66.70 mmol) and cesium carbonate (26.1 g, 80.04 mmol) in toluene (200 mL) at 120C under nitrogen. The resulting suspension was stirred at 120 C for 16 hours under nitrogen. The reaction was incomplete so the reaction mixture was stirred for a further 24 hours at 120C. The reaction mixture was cooled and diluted with EtOAc (150 mL) and water (150 mL). The biphasic mixture was filtered through celite. The organic layer was separated and washed sequentially with water (150 mL) and saturated brine (150 mL). The organic layer was filtered and dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography*, elution gradient 0 to 20% EtOAc in isohexane.ons were evaporated to dryness to affordnbsp;(R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)-3-fluoroanilinenbsp;(12.2 g, 31.3 mmol, 58.7 %) as a orange oil. Fractions that contained small amounts of impurities were also combined and were evaporated to dryness to affordnbsp;(R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)-3-fluoroaniline (2.05 g, 5.26 mmol, 9.86 %) as a dark orange oil." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@H](CNC1=CC(=C(C=C1)OCC2=CC=CC=C2)F)O[Si](C)(C)C(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 68.55 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/04/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "430" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000178 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" + } + amount { + moles { + value: 0.00178 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" + } + amount { + moles { + value: 0.00178 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.000178 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000178 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "PdOAc2 (0.040 g, 0.18 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.085 g, 0.18 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (0.500 g, 1.78 mmol), [Reactants] and cesium carbonate (0.869 g, 2.67 mmol) in toluene (15 mL) at 20C in a microwave vial. The microwave vial was sealed and the reaction was heated to 120 C for 12 hours in the microwave reactor and cooled to RT. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was filtered and dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was taken up in DCM (20 mL) and an isoluble white solid EN04063-43-1 (401 mg)nbsp;was filtered off (not product). The filtrate was evaporated and was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-4-(benzyloxy)-N-(2-(tedimethylsilyloxy)propyl)-3-fluoroaniline (0.482 g, 69.6 %) as a yellow oil. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@H](CNC1=CC(=C(C=C1)OCC2=CC=CC=C2)F)O[Si](C)(C)C(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 69.56 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/11/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "431" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00356 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.15 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" + } + amount { + moles { + value: 0.0427 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" + } + amount { + moles { + value: 0.0356 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.00356 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00356 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "PdOAc2 (0.799 g, 3.56 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (1.696 g, 3.56 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (10.00 g, 35.57 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (8.08 g, 42.69 mmol) and cesium carbonate (17.39 g, 53.36 mmol) in toluene (150 mL) at 120C under nitrogen. The resulting suspension was stirred at 120 C for 16 hours. The reaction was incomplete so the reaction mixture was stirred for a further 24 hours at 120C. The reaction mixture was diluted with EtOAc (150 mL) and water (150 mL). The biphasic mixture was filtered through celite. The organic layer was separated and washed sequentially with water (150 mL) and saturated brine (150 mL). The organic layer was filtered and dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was evaporated and was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fe evaporated to dryness to afford (R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)-3-fluoroaniline (8.98 g, 64.8 %) as a orange oil. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@H](CNC1=CC(=C(C=C1)OCC2=CC=CC=C2)F)O[Si](C)(C)C(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 64.8 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/18/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "432" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00178 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.12 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" + } + amount { + moles { + value: 0.0178 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" + } + amount { + moles { + value: 0.0178 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.00178 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00178 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "PdOAc2 (0.399 g, 1.78 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.848 g, 1.78 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (5.00 g, 17.79 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (3.37 g, 17.79 mmol) and cesium carbonate (8.69 g, 26.68 mmol) in toluene (120 mL) at 20C in a microwave vial. The microwave vial was sealed and the reaction was heated to 120 C for 10 hours in the microwave reactor and cooled to RT.b bnbsp;Split into 5 x 20 ml mw vials such as in each was:PdOAc2 (0.080 g, 0.36 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.170 g, 0.36 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (1.000 g, 3.56 mmol), Reactant 2 (1.143 g, 3.56 mmol) and cesium carbonate (1.739 g, 5.34 mmol) in toluene (20 mL) at 20C in a microwave vial. The microwave vial was sealed and the reaction was heated to 120 furs in the microwave reactor and cooled to RT.b bThe reaction was incomplete so the reaction was heated to 120 C for 10 hours in the microwave reactor and cooled to RT.b bThe reaction mixtures were combined and diluted with EtOAc (100 mL), and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was filtered and dried over Na2SO4. The filtrate was washed sequentially with water (100 mL), and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)-3-fluoroaniline (5.10 g, 73.6 %) as a orange oil. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@H](CNC1=CC(=C(C=C1)OCC2=CC=CC=C2)F)O[Si](C)(C)C(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 73.6 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/14/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "433" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00356 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.1 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" + } + amount { + moles { + value: 0.0356 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" + } + amount { + moles { + value: 0.0356 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.00356 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00356 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "PdOAc2 (0.799 g, 3.56 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (1.696 g, 3.56 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (10.00 g, 35.57 mmol), 1-(benzyloxy)-4-bromo-2-fluorobenzene (10.00 g, 35.57 mmol) and cesium carbonate (17.39 g, 53.36 mmol) in toluene (100 mL) at 20C in a microwave vial. The microwave vial was sealed and the reaction was heated to 120 C for 10 hours in the microwave reactor and cooled to RT. nbsp;uSplit into 10 x 20 ml mw vials such as in each was:uPdOAc2 (0.080 g, 0.36 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.170 g, 0.36 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (1.000 g, 3.56 mmol), 2-(tert-butyldimethylsilyloxy)ethanamine (0.832 g, 3.56 mmol) and cesium carbonate (1.739 g, 5.34 mmol) in toluene (20 mL) at 20C in a microwave vial. The microwave vial was sealed and the reacted to 120 C for 10 hours in the microwave reactor and cooled to RT. The reaction mixtures were combined and diluted with EtOAc (150 mL) and water (150 mL). The biphasic mixture was filtered through celite. The organic layer was separated and washed sequentially with water (150 mL) and saturated brine (150 mL). The crude product was evaporated and was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)-3-fluoroaniline (10.10 g, 72.9 %) as a orange oil. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@H](CNC1=CC(=C(C=C1)OCC2=CC=CC=C2)F)O[Si](C)(C)C(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 72.88 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/12/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "434" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000551 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" + } + amount { + moles { + value: 0.00551 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" + } + amount { + moles { + value: 0.00551 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.000551 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000551 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "PdOAc2 (0.124 g, 0.55 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.263 g, 0.55 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (1.550 g, 5.51 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (1.044 g, 5.51 mmol) and cesium carbonate (2.69 g, 8.27 mmol) in toluene (20 mL) at 20C in a microwave vial. The microwave vial was sealed and the reaction was heated to 120 C for 10 hours in the microwave reactor and cooled to RT.b bThe reaction was incomplete so the reaction was heated to 120 C for 2 hours in the microwave reactor and cooled to RT. The reaction was incomplete and further PdOAc2 (0.124 g, 0.55 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.263 g, 0.55 mmol) was added and the suspension was stirred at 120 C for a further 6 hours in the microwave reactor and cooled to RT. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (50 mL) and (50 mL). The organic layer was filtered and dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was taken up in DCM (20 mL) and an isoluble white solid EN04063-48-1 (1.45 g, 3.72 mmol, 67.5 %)nbsp;was filtered off (not product). The filtrate was evaporated and was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)-3-fluoroaniline (1.450 g, 67.5 %) as a yellow oil.b bReaction is slow if done on 1.5g scale in a 20 ml reaction vial. Next time do 1g reaction per 20 ml vial. See EN04063-50" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@H](CNC1=CC(=C(C=C1)OCC2=CC=CC=C2)F)O[Si](C)(C)C(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 67.5 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/13/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "435" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0019 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.075 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" + } + amount { + moles { + value: 0.0228 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)COC2=CC=C(C=C2)Br" + } + amount { + moles { + value: 0.019 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.0019 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.0019 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;Palladium(II) acetate (0.427 g, 1.90 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.906 g, 1.90 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromobenzene (5 g, 19.00 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (4.32 g, 22.80 mmol) and Cesium carbonate (2.281 mL, 28.50 mmol) in toluene (75 mL) at 20C under nitrogen. The resulting suspension was stirred at 120C for 72 hours. The reaction mixture was diluted with EtOAc (150mL) and water (150mL) and the biphasic mixture was filtered through celite. The organic layer was seperated and washed sequentially with water (150mL) and saturated brine (150mL). The organic layer was evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)aniline (4.60 g, 65.1 %) as an orange " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@H](CNC1=CC=C(C=C1)OCC2=CC=CC=C2)O[Si](C)(C)C(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 65.15 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/03/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "437" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00342 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.2 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" + } + amount { + moles { + value: 0.041 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)COC2=CC=C(C=C2)Br" + } + amount { + moles { + value: 0.0342 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.00342 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00342 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Reaction carried out by Phill Walker in RSL EN04482-07-01 as follows:PdOAc2 (0.768 g, 3.42 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (1.631 g, 3.42 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromobenzene (9.00 g, 34.20 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (7.77 g, 41.04 mmol) and cesium carbonate (16.72 g, 51.31 mmol) in toluene (200 mL) at 20C in a 300 ml Milestone microwave reactor. The microwave reactor was sealed and the reaction was heated to 120 C for 10 hours in and cooled to RT. LCMS indicated some product but mainly sm so another aliquot of catalyst was added and put back on for 10 hours at 130C. LCMS-2 indicated complete reaction. Handed back to chemist for work-up.WorkupThe reaction mixture was diluted with EtOAc (100 mL) and was filtered. The solid (inorganics and catalyst) was washed with ethylacete (50 mL). The filtrates were combined and washed with water (1 x 150 mL) and brimL). The crude product was evaporated and was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)aniline (2.400 g, 18.88 %) as a orange oil. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@H](CNC1=CC=C(C=C1)OCC2=CC=CC=C2)O[Si](C)(C)C(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 18.88 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/28/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "438" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.002 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=C(N=C(O1)N)C(F)(F)F" + } + amount { + moles { + value: 0.001 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.001 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 140.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Repeat of EN04881-41 to get pure sample of product in potentially higher isolated yield.cesium carbonate (652 mg, 2.00 mmol), Pd2(dba)3 (22.89 mg, 0.025 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (43.4 mg, 0.075 mmol), 4-(trifluoromethyl)oxazol-2-amine (152 mg, 1.00 mmol) and 2,4-dichloropyridine (148 mg, 1.00 mmol) were added to an oven dried microwave vial, the vial was capped and placed under an inert atmosphere, dioxane (4 mL) was added and the resulting mixture was heated at 140 C for 1 h by microwave irradiation under a nitrogen atmosphere.Dichloromethane (10 mL) was added to the reaction mixture and the crude reaction mixture was adsorbed onto silica gel. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in heptane. Pure fractions were evaporated to dryness to afford N-(4-chloropyridin-2-yl)-4-(trifluoromethyl)oxazol-2-amine (46.0 mg, 17.45 %) as a pale yellow solid. Regioisomeric assignment confirmed by NOESY expent (see sample P1 analytical data for details)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)NC2=NC(=CO2)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 17.45 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/18/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "439" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNC(=O)CN1" + } + amount { + moles { + value: 0.000499 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1F)Br" + } + amount { + moles { + value: 0.000499 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 4.99e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.99e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (11.21 mg, 0.05 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (28.9 mg, 0.05 mmol) were dissolved in toluene (0.5 mL) under nitrogen. Stirred at 50C for 30min.sodium 2-methylpropan-2-olate (96 mg, 1.00 mmol) and piperazin-2-one (50 mg, 0.50 mmol) were added to a second microwave vial and inerted with nitrogen. 1-bromo-4-fluorobenzene (0.055 mL, 0.50 mmol) and toluene (0.500 mL) were added.The catalyst solution wad added to the reaction mixture and the resulting solution was stirred at 100C for 1h in the microwave. No reaction. Then 150C for 1h, still no reaction. The reaction was discarded." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CN(CC(=O)N1)C2=CC=C(C=C2)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/29/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "440" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNC(=O)CN1" + } + amount { + moles { + value: 0.000499 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1F)Br" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 4.99e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.99e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (11.21 mg, 0.05 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (28.9 mg, 0.05 mmol) were dissolved in toluene (0.5 mL) under nitrogen. Stirred at 50C for 30min.sodium 2-methylpropan-2-olate (96 mg, 1.00 mmol) and piperazin-2-one (50 mg, 0.50 mmol) were added to a second microwave vial and inerted with nitrogen. 1-bromo-4-fluorobenzene (0.110 mL, 1.00 mmol) and toluene (0.500 mL) were added.The catalyst solution wad added to the reaction mixture and the resulting solution was stirred at 100C for 1h in the microwave. No reaction. Heated to 150C for 1h, still no reaction, the reaction was discarded." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CN(CC(=O)N1)C2=CC=C(C=C2)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/30/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "441" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00113 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CN(CCN1)CC2=CC=CC=C2" + } + amount { + moles { + value: 0.000567 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1F)Br" + } + amount { + moles { + value: 0.000851 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 5.67e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 5.67e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 50.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (12.74 mg, 0.06 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (32.8 mg, 0.06 mmol) were suspended in toluene (0.5 mL) under N2. Heated to 50C for 30 min (microwave).sodium 2-methylpropan-2-olate (109 mg, 1.13 mmol) was suspended in toluene (0.500 mL) under N2. 1-benzylpiperazine (0.099 mL, 0.57 mmol) and 1-bromo-4-fluorobenzene (0.093 mL, 0.85 mmol) were added, followed by the catalyst solution.Heated to 100C for 2h in the microwave (high abs), then rt over night.The product was purified on silica (0-25% EtOAcheptane) Yield: 1-benzyl-4-(4-fluorophenyl)piperazine (115 mg, 75.0 %)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CN(CCN1CC2=CC=CC=C2)C3=CC=C(C=C3)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 74.98 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/06/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "442" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000734 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.00049 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.00049 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" + } + amount { + moles { + value: 4.9e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.45e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Charged a standard microwave vial with a mixture of 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (100 mg, 0.49 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (135 mg, 0.49 mmol), cesium carbonate (239 mg, 0.73 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.42 mg, 0.02 mmol), Tri-tert-butylphosphonium tetrafluoroborate (14.21 mg, 0.05 mmol), and 1,2-dimethoxyethane.nbsp;The atmosphere was inerted through vacuum-nitrogen cycles and the contents were heated at 120 C for a period of 30 min.LCMS indicates reaction progression is less than 10%.nbsp;Reaction aborted.nbsp;Not progressed." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=CC=CC=C5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/05/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "446" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[K+].[K+]" + } + amount { + moles { + value: 0.000912 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC=CC=C1" + } + amount { + volume { + value: 0.0018 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)N" + } + amount { + moles { + value: 0.00122 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.000608 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000134 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 6.69e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: Repeat of optimised conditions found in process research and devellopment screen for an isolated yield.An activated catalyst solution was prepared by adding TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (61.3 mg, 0.07 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (77 mg, 0.13 mmol) to an oven-dried microwave vial. The vial was then capped and purged with nitrogen and anisole (1 mL) was added. The solution was stirred at 50C for 40 mins, then 90C for 15 mins (activated catalyst solution, Soln. 1).To another oven-dried microwave vial was added potassium carbonate (126 mg, 0.91 mmol), ethyl 2-aminooxazole-5-carboxylate (190 mg, 1.22 mmol) and 2,4-dichloropyridine (90 mg, 0.61 mmol) and the vial was capped and purged with nitrogen. anisole (1.35 mL) and the activated catalyst solution (0.45 mL Soln. 1 from above) were added (this corresponds to a catalyst loading of 10% Pd) and the vessel was heated to 90 C for 16 h.LCMS of the crude reactioowed the presence of a significant amount of amine starting material (Rt=0.95 min) as well as some 2,4-dichloropyridine starting material (Rt=1.75 min) together with a small amount of the desired product (Rt= 2.08). The mass corresponding to the double addition product was not observed.Conclusion: Reaction produced a small amount of the desired product but mainly starting material remained." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/06/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "447" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[K+].[K+]" + } + amount { + moles { + value: 0.000912 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC=CC=C1" + } + amount { + volume { + value: 0.00205 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)N" + } + amount { + moles { + value: 0.00122 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.000608 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000134 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 6.69e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: Repeat of optimised conditions found in process research and devellopment screen for an isolated yield.An activated catalyst solution was prepared by adding TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (61.3 mg, 0.07 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (77 mg, 0.13 mmol) to an oven-dried microwave vial. The vial was then capped, purged with nitrogen and anisole (1 mL) (degassed) was added. The solution was stirred at 50C for 40 mins, then 90C for 15 mins (activated catalyst solution, Soln. 1).To another oven-dried microwave vial was added potassium carbonate (126 mg, 0.91 mmol), ethyl 2-aminooxazole-5-carboxylate (190 mg, 1.22 mmol) and 2,4-dichloropyridine (90 mg, 0.61 mmol) and the vial was capped and purged with nitrogen. anisole (1.6 mL) and the activated catalyst solution (0.45 mL of Soln. 1 from above) were added (this corresponds to a catalyst loading of 10% Pd). The vessel was then heated to 120C for 16 h. LCMS and TLC of the on mixture showed none of the desired product to be present. Some of the amine starting material appears to be present and none of the 2,4-dichloropyridine remains. The mass for the double addition product (addition at the 2- and 4-positions) is present, but co-elutes with the reaction solvent anisole and is not quantifiable asnbsp;a result.nbsp;Conclusion: This is a somewhat surprising result, based on the fact that the previous reaction (EN05378-17) results in the formation of significant coupled product. These reaction conditions are apparently not suitable for the coupling of the ester stituted 2-aminooxazole. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/07/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "448" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00699 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.018 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)N" + } + amount { + moles { + value: 0.0035 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.0035 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000262 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 8.74e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 160.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: Peparation of the above coupled product on a larger scale for hydrolysis-protodecarboxylation study.To an oven-dried microwave vial was added ethyl 2-aminooxazole-5-carboxylate (546 mg, 3.50 mmol), 2,4-dichloropyridine (0.378 mL, 3.50 mmol), cesium carbonate (2279 mg, 6.99 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (80 mg, 0.09 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (152 mg, 0.26 mmol) and the vial was capped and purged with nitrogen. dioxane (18 mL) (degassed) was added and the reaction mixture was heated to 160 C for 1 h under microwave irradiation. LCMS of the crude reaction mixture shows the required product to be the major product together with an isomer of the same mass (Rt= 1.91), the ratio of the desired product to this isomeric product being circa 5:1. LCMS also shows that a small amount of the 2-aminooxazole ester starting material remains (Rt= 0.99 min) and so the reaction with this particular strate may benefit from slightly er reaction times, maybe 90 mins. A small amount of the coupled and decarboxylated product was also present (Rt= 1.68 min). Saturated ammonium chloride (15 mL) was added to the crude reaction mixture and the mixture was transfrred to a separating funnel. Ethyl acetate (80 mL) was then added and the organic layer was separated (keeping the interfacial material with the organic layer). The aqueous layer was washed with ethyl acetate (2 x 80 mL portions). (Note: During this extraction, a solid, presumably the required product was seen to crash out in the organic layer. If this reaction is to be repeated a work-up free approach is recommended where the crude reaction mixture is dry-loaded directly onto silica for chromatographic purification). The solvent was removed from the combined organics under reduced pressure. The crude product was loaded onto a pre-wetted silica column using the minimum DCM and methanol. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% DCM (5% methanolic ammonia) in DCM. Pure fractions were evaporated to dryness to afford 744 mg of impure product. The crude residue was triturated with Et2O to give a solid which was collected by filtration and dried under vacuum to give ethyl 2-(4-chloropyridin-2-ylamino)oxazole-5-carboxylate (415 mg, 44.3 %) as a beige solid. nbsp;Conclusion: The desired product was isolated in moderate yield and high purity (95% based on strength NMR). The moderate yield may be improved under a longer reaction time, it is also probable that purification difficulties were also detrimental to the yield of this reaction." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 44.34 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/11/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "450" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00699 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.018 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)N" + } + amount { + moles { + value: 0.0035 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.0035 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000262 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 8.74e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 160.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: To make the coupled product on a larger scale for hydrolysisdecarboxylationPd2(dba)3 (80 mg, 0.09 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (152 mg, 0.26 mmol), 2,4-dichloropyridine (0.378 mL, 3.50 mmol), cesium carbonate (2279 mg, 6.99 mmol) and ethyl 2-aminooxazole-5-carboxylate (546 mg, 3.50 mmol) were added to an oven dried microwave vial and the vial was capped and placed under an inert atmosphere, dioxane (18 mL) was added and the resulting mixture was heated to 160 C for 1 h by microwave irradiation under a nitrogen atmosphere.The crude product was purified by flash silica chromatography, elution gradient 0 to 3% MeOH (7 N ammonia) in DCM. Pure fractions were evaporated to dryness to afford ethyl 2-(4-chloropyridin-2-ylamino)oxazole-5-carboxylate (892 mg, 95 %) as a brown solid. Analysis of the product after chromatography showed that it was ~ 75% pure by proton NMR and LCMS, therefore the actual yield of the desired product is closer to 70%.Note: the reaction was carried out twice on the above scale." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 95.3 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/16/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "451" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 5e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)N" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 140.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: Poisoning experiment to find out if 2-aminooxazole or the coupled product from reaction of 2-aminooxazole and 2,4-dichloropyridine are \'poisoning\' the catalyst.Reaction (a): Control reaction under identical conditions to EN04881-40 (should produce similar yield)Reaction (b): As for control but spiked with 2 eq. of 2-aminooxazole with respect to catalyst, before dioxane was added (will produce decreased yield if 2-aminooxazole is a poison)Reaction (c): As for control but spiked with 1 eq. of N-(4-chloropyridin-2-yl)oxazol-2-amine, before dioxane was added (will produce decreased yield if N-(4-chloropyridin-2-yl)oxazol-2-aminenbsp;is a poison)Pd2(dba)3 (22.89 mg, 0.025 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (43.4 mg, 0.075 mmol), 2,4-dichloropyridine (148 mg, 1.00 mmol), cesium carbonate (651 mg, 2.00 mmol),ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol) and 4,4\'-di-tert-butylbiphenyl (26.6 mg, 0.10 mmol) were added to an oven dried microwave vial, the vial was capped and placed under an inert atmosphere. Dioxane (4 mL) was added and the resulting mixture was heated to 140 C for 1 h by microwave irradiation under a nitrogen atmosphere.nbsp;An isolated yield was obtained for reaction (a). Dichloromethane (10 mL) was added to the crude reaction mixture and the mixture was adsorbed onto silica. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in heptane. Pure fractions were evaporated to dryness to afford ethyl 2-(4-chloropyridin-2-ylamino)oxazole-5-carboxylate (111 mg, 41.5 %) as a white solid. Taking into account that the crude LCMS for reaction (A) corresponds to a ~ 42% isolated yield, the amount of product can be calculated for reactions (B) and (C) using the ratio between the t-Butyl biphenyl and the required product in the LCMS. The amount of required product produced in reaction (B) was 41% and for reaction (C) 45% product was produced.Conclusion: Thove compounds do not poison the catalyst.Note: Significant amounts of what is assumed to be the regioisomeric 4-aminated product were also formed in these reactions. Major regioisomer formed in ~ 4:1 ratio." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 41.51 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/21/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "453" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.002 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)N" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 140.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: To find out if the regioisomeric ester is also a reaction strate in this C-N bond forming reactionPd2(dba)3 (22.89 mg, 0.025 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (43.4 mg, 0.075 mmol), 2,4-dichloropyridine (148 mg, 1.00 mmol), cesium carbonate (651 mg, 2.00 mmol),ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol) were added to an oven dried microwave vial, the vial was capped and placed under an inert atmosphere, dioxane (4 mL) was added and the resulting mixture was heated at 140 C for 1 h by microwave irradiation under a nitrogen atmosphere.The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in heptane. Pure fractions were evaporated to dryness to afford ethyl 2-(4-chloropyridin-2-ylamino)oxazole-5-carboxylate (135 mg, 50.5 %) as a white solid. nbsp;Conclusion: The desired product was isolated in gt; 50% isolated yield. The electron withdrawing ester group again has a positive effect on reaction. More work needs to be carried out to probe the origin of this effect. NOESY confirmed expected regioisomer was formed (see sample details)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 50.48 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/07/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "454" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 9.99e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)N" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C(C)(C)C)C(C)(C)C)C(C)C" + } + amount { + moles { + value: 9.99e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 160.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: Series of experiments to optimise yield of the above coupled product.Pd2(dba)3 (22.89 mg, 0.025 mmol), di-tert-butyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (42.4 mg, 0.10 mmol), 2,4-dichloropyridine (148 mg, 1.00 mmol), cesium carbonate (651 mg, 2.00 mmol),ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol) and 4,4\'-di-tert-butylbiphenyl (60 mg, 0.23 mmol) were added to an oven dried microwave vial, the vial was capped and placed under an inert atmosphere, dioxane (4 mL) was added and the resulting mixture was heated at 160 C for 1 h by microwave irradiation under a nitrogen atmosphere.Crude LCMS shows a complete switch in regioselectivity, with the other isomer becoming the major product in 26% yield based on internal standard (note: this is a rough estimate as the U.V absorbance may be significantly different for this regioisomer). The regioisomeric ratio is 2.8:1 and although the product was not formed in synthetically useful yields, it is an interesting result.Conclusion: Switch in regioselectivty with the change in ligand may be worth pursuing." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/11/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "455" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 9.99e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)N" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=C(C=CC(=C2P(C(C)(C)C)C(C)(C)C)OC)OC)C(C)C" + } + amount { + moles { + value: 9.99e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 160.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: Series of experiments to optimise yield of the above coupled product.Pd2(dba)3 (22.89 mg, 0.025 mmol), di-tert-butyl(2\',4\',6\'-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (48.4 mg, 0.10 mmol), 2,4-dichloropyridine (148 mg, 1.00 mmol), cesium carbonate (651 mg, 2.00 mmol),ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol) and 4,4\'-di-tert-butylbiphenyl (60 mg, 0.23 mmol) were added to an oven dried microwave vial, the vial was capped and placed under an inert atmosphere, dioxane (4 mL) was added and the resulting mixture was heated at 160 C for 1 h by microwave irradiation under a nitrogen atmosphere.Crude LCMS shows a switch in regioselectivity, with the other isomer becoming the major product in 25% yield based on internal standard (note: this is a rough estimate as the U.V absorbance may be significantly different to the other regioisomer). The regioisomeric ratio is 1.7:1 and although the product was not formed in synthetically useful yields, it is an interestinsult.Conclusion: Switch in regioselectivty with the change in ligand may be worth pursuing, although greater selectivity was seen for this prduct in the preceeding reaction." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/11/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "456" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 9.99e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)N" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=C(C=CC(=C2P(C3=CC(=CC(=C3)C(F)(F)F)C(F)(F)F)C4=CC(=CC(=C4)C(F)(F)F)C(F)(F)F)OC)OC)C(C)C" + } + amount { + moles { + value: 9.99e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 160.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: Series of experiments to optimise yield of the above coupled product.Pd2(dba)3 (22.89 mg, 0.025 mmol), bis(3,5-bis(trifluoromethyl)phenyl)(2\',4\',6\'-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (80 mg, 0.10 mmol), 2,4-dichloropyridine (148 mg, 1.00 mmol), cesium carbonate (651 mg, 2.00 mmol),ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol) and 4,4\'-di-tert-butylbiphenyl (60 mg, 0.23 mmol) were added to an oven dried microwave vial, the vial was capped and placed under an inert atmosphere, dioxane (4 mL) was added and the resulting mixture was heated at 160 C for 1 h by microwave irradiation under a nitrogen atmosphere.Crude LCMS shows a switch in regioselectivity again with respect to the bidentate ligand Xantphos, with the other isomer becoming the major product in 28% yield based on internal standard (note: this is a rough estimate as the U.V absorbance may be significantly different to the other regioisomer). None of the other regioisomer observed.Concln: Switch in regioselectivty with the change in ligand may be worth pursuing, this reaction is uapparentlyu completely selective for the 4-regioisomer. Note: Necessary to isolate product to confirm." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/11/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "457" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00799 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.016 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)N" + } + amount { + moles { + value: 0.004 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.004 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.0003 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 9.99e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 160.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: Isolate a larger quantity of product for hydrolysisdecarboxylation studyPd2(dba)3 (91 mg, 0.10 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (173 mg, 0.30 mmol), 2,4-dichloropyridine (591 mg, 4.00 mmol), cesium carbonate (2604 mg, 7.99 mmol) and ethyl 2-aminooxazole-5-carboxylate (624 mg, 4.00 mmol)nbsp;were added to an oven dried microwave vial. The vial was capped and placed under an inert atmosphere, dioxane (16 mL) was added and the resulting mixture was heated at 160 C for 1 h by microwave irradiation under a nitrogen atmosphere.This reaction was run in four portions, i.e. four identical microwave reactions were carried out on 14 of the above scale. The reactions were then combined and purified as a single sample.Purification by chromatography on silica using heptane:ethyl acetate as eluent, on alumina with heptane:ethyl acetate and via reverse phase on C18 silica failed. The crude product was purified by flash silica chromatography, elution gradiento 3% Methanolic ammonia (7 M) in DCM. Pure fractions were evaporated to dryness to afford ethyl 2-(4-chloropyridin-2-ylamino)oxazole-5-carboxylate (534 mg, 49.9 %) as a pale yellow solid. Althought the LCMS looks good for the fractions combined for this sample, the proton NMR shows significant impurities to be present. Conclusion: Sufficient material isolated for hydrolysisdecarboxylation study." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 49.92 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/12/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "459" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.002 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)N" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=C(C=CC(=C2P(C3=CC(=CC(=C3)C(F)(F)F)C(F)(F)F)C4=CC(=CC(=C4)C(F)(F)F)C(F)(F)F)OC)OC)C(C)C" + } + amount { + moles { + value: 9.99e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 160.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: Attempt to synthesise the 4-stituted product using jackiephos as ligand.To an oven-dried microwave vial was added ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol), 2,4-dichloropyridine (0.108 mL, 1.00 mmol), cesium carbonate (651 mg, 2.00 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.87 mg, 0.02 mmol) and bis(3,5-bis(trifluoromethyl)phenyl)(2\',4\',6\'-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (80 mg, 0.10 mmol) and the vial was capped and purged with nitrogen. dioxane (4 mL) (degassed) was added and the reaction mixture was heated to 160 C for 1 h under microwave irradiation. The reaction mixture was heated to 160Cnbsp;for a further 3 h due to incomplete conversion. DCM (10 mL) was added to the crude reaction mixture together with silica (2 g). The solvent was then removed from the reaction mixture under reduced pressure. The resulting residue was then added tom a dry-load tube prior to chromatography.The crude product was purifiesh silica chromatography, elution gradient 0 to 2.5% methanolic ammonia (7 M) in DCM. The desired product (4-stitution) was isolated as a mixture with the 2-stituted product. The ratio of the 2-isomer to the 4-isomer is 2.4:1 for the mxture with no other fractions containing either isomer. Conclusion: The apparent higher selectivity for the 4-isomer is due to the overlap of the 2,4-dichloropyridine starting material with this isomer. Therefore this reaction actually forms the 2-isomer selectively and is not a very active catalyst for this transformation. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/19/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "460" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.002 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)N" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.49e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: Comparison of the reactivity of 2-aminooxazole and ester stituted 2-aminooxazole under identical reaction conditions. To an oven-dried round bottomed flask was added ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol), cesium carbonate (651 mg, 2.00 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.87 mg, 0.02 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (43.4 mg, 0.07 mmol) and 2,4-dichloropyridine (0.108 mL, 1.00 mmol). A reflux condenser was fitted and the vessel was purged with nitrogen.nbsp;dioxane (2 mL)DMSO (2 mL) (degassed) was added and the reaction mixture was heated to 100 C for 16 h. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness to afford the crude product.The crude product was purified by flash silica chromatography, elution gradient 1 to 3% methanolic ammonia (7 M) in DCM. Puractions were evaporated to dryness to afford ethyl 2-(4-chloropyridin-2-ylamino)oxazole-5-carboxylate (128 mg, 47.9 %) as a pale yellow solid. Conclusion: The desired product was formed in moderate yield. Normal-phase column DCM:methanolic ammonia" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 47.86 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/08/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "463" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[K+].[K+]" + } + amount { + moles { + value: 0.000912 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC=CC=C1" + } + amount { + volume { + value: 0.0018 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=COC(=N1)N" + } + amount { + moles { + value: 0.00122 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.000608 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000134 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 6.69e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: Repeat of optimised conditions found in process research and devellopment screen for an isolated yield.An activated catalyst solution was prepared by adding TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (61.3 mg, 0.07 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (77 mg, 0.13 mmol) to an oven-dried microwave vial. The vial was then capped and purged with nitrogen and anisole (1 mL) (degassed) was added. The solution was stirred at 50C for 40 mins, then 90C for 15 mins (activated catalyst solution; Soln. 1).To another oven-dried microwave vial was added potassium carbonate (126 mg, 0.91 mmol), oxazol-2-amine (102 mg, 1.22 mmol) and 2,4-dichloropyridine (90 mg, 0.61 mmol) and the vial was capped and purged with nitrogen. anisole (1.35 mL) and the activated catalyst solution (0.45 mL of Soln. 1 from above) were then added (this corresponds to a catalyst loading of 10% Pd). The vessel was then heated to 120 C for 16 h. LCMS of the crude reaction mixed that the desired product was present (Rt= 1.70) along with a trace amount of the double addition product i.e. amine addition at the 2- and 4-position (Rt= 1.22 min). The reaction mixture was quenched with saturated ammonium chloride (8 mL) and transferred to a separating funnel. Ethyl acetate (15 mL) was then added and the organic layer was separated (keeping the interfacial material with the organic layer). The aqueous layer was washed with ethyl acetate (2 x 15 mL portions). The combined organics were then dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. DCM (1 mL) was then added to the resulting residue (which still contained anisole (4 mL)) and this solution was loaded directly onto a silica column (40 g).The crude product was purified by flash silica chromatography, elution gradient 0 to 30% DCM (5% methanolic ammonia) in DCM, then 100% DCM (5% methanolic ammonia). Pure fractions were evaporated to dryness to afford N-(4-chloropyridin-2-yl)oxazol-2-amine (59.0 mg, 49.6 %) as an off-white solid. Note: This product was only 52% pure based on NMR strength.Conclusion: The desired product was isolated but in relatively low yield and low purity." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)NC2=NC=CO2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 49.6 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/07/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "465" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000101 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=COC(=N1)N" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=C(C=CC(=C2P(C3=CC(=CC(=C3)C(F)(F)F)C(F)(F)F)C4=CC(=CC(=C4)C(F)(F)F)C(F)(F)F)OC)OC)C(C)C" + } + amount { + moles { + value: 0.000101 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.53e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 140.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: Reactions using ligands not previously tested under these conditions2,4-dichloropyridine (0.109 mL, 1.01 mmol), oxazol-2-amine (85 mg, 1.01 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (23.20 mg, 0.03 mmol), bis(3,5-bis(trifluoromethyl)phenyl)(2\',4\',6\'-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (81 mg, 0.10 mmol) and cesium carbonate (660 mg, 2.03 mmol) were added to an oven-dried microwave vail and the vial was purged with nitrogen. Degassed dioxane (4mL) was then added andnbsp;the reaction mixture was heated to 140 Cnbsp;for 1 h under microwave irradiation. Conclusion: None of the desired product was observed in the LCMS of the crude reaction mixture, not progressed." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)NC2=NC=CO2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/10/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "466" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00203 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=COC(=N1)N" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 140.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: To isolate some of the required product to provide an analytical sample for a large catalyst screen.2,4-dichloropyridine (0.109 mL, 1.01 mmol), oxazol-2-amine (85 mg, 1.01 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.89 mg, 0.02 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (44.0 mg, 0.08 mmol) (Xantphos) and cesium carbonate (660 mg, 2.03 mmol) were added to a microwave vail and the vial was purged with nitrogen. Degassed dioxane (4 mL) was then added andnbsp;the reaction mixture was heated to 140 Cnbsp;for 1 h under microwave irradiation. LCMS of crude reaction mixture showed some of the required product was formed, however the LCMS using acidic modifier was somewhat misleading as a side-product co-elutes with the required product thus giving the impression that a greater amount of product was formed than is the case. LCMS under acidic modifier is more informative.The crude product was purified by flash silica chromatography, elution grnt 0 to 20% heptane in EtOAc. Pure fractions were evaporated to dryness to afford N-(4-chloropyridin-2-yl)oxazol-2-amine (4.00 mg, 2.018 %) as a pale yellow residue. Conclusion: 4 mg of impure product was isolated." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)NC2=NC=CO2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 2.02 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/09/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "468" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "[H-].[Na+]" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=COC(=N1)N" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 140.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: If deprotonation is rate-determining in this coupling quantitative deprotonation prior to jection to coupling conditions should prove beneficial.To an oven dried microwave vial was added oxazol-2-amine (85 mg, 1.01 mmol) together with sodium hydride (40.5 mg, 1.01 mmol), the vial was capped and purged with nitrogen and dioxane (1 mL) was added. The mixture was then stirred at rt for 1 h (initially effervescence was observed but sided within 20 min of stirring).To the above vial was added 2,4-dichloropyridine (0.109 mL, 1.01 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.89 mg, 0.02 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (44.0 mg, 0.08 mmol) (Xantphos) as a solution innbsp;dioxane (2 mL) andnbsp;the reaction mixture was heated to 140 Cnbsp;for 1 h under microwave irradiation. Dichloromethane (10 mL) was added to the crude reaction mixture and the mixture was absorbed onto silica. The crude product was purified by flash silicromatography, elution gradient 0 to 20% EtOAc in heptane. Pure fractions were evaporated to dryness to afford N-(4-chloropyridin-2-yl)oxazol-2-amine (6.00 mg, 3.03 %) as a pale yellow dry film. Conclusion: The formal deprotonation appears to have had no benificial effect on this coupling." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)NC2=NC=CO2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 3.03 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/28/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "469" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "[O-]P(=O)([O-])[O-].[K+].[K+].[K+]" + } + amount { + moles { + value: 0.00203 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=COC(=N1)N" + } + amount { + moles { + value: 0.00122 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000608 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000203 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 160.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: Will increased catalyst loading lead to increased isolated yield of the desired product?2,4-dichloropyridine (0.109 mL, 1.01 mmol), oxazol-2-amine (102 mg, 1.22 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (186 mg, 0.20 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (352 mg, 0.61 mmol) (Xantphos) and potassium phosphate (430 mg, 2.03 mmol) were added to a microwave vail and the vial was purged with nitrogen. Degassed dioxane (4mL) was then added andnbsp;the reaction mixture was heated to 160 Cnbsp;for 6 h under microwave irradiation. Dichloromethane (10 mL) was added to the crude reaction mixture and the mixture was adsorbed onto silica gel. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in heptane. Unfortunately and somewhat surprisingly, none of the desired product was isolated, although only a trace of required product was observed in the LCMS of the crude reaction mixture. Conclusion: It appethat under this higher catalyst loading the reaction is less efficent, potentially a concentration effect?" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)NC2=NC=CO2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/28/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "474" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00142 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=COC(=N1)N" + } + amount { + moles { + value: 0.00122 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 1.52e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.01e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a vial containing oxazol-2-amine (102 mg, 1.22 mmol), , TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (9.28 mg, 10.14 mol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (9.47 mg, 0.02 mmol) and sodium 2-methylpropan-2-olate (136 mg, 1.42 mmol), was added degassed toluene (4 mL) and 2,4-dichloropyridine (0.109 ml, 1.01 mmol) and the reaction mixture was heated to 100 degrees C for 20 h. None of the desired product was observed by LCMS or in crude proton NMR.bIt is of note that although the 2,4-dichloropyridine is present in the crude proton NMR, the oxazole-2-amine is notb. It is possible that under the strongly basic reaction conditions that this starting material decomposed. Product not isolated." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)NC2=NC=CO2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/07/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "475" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)[O-].[Na+]" + } + amount { + moles { + value: 3.04e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=COC(=N1)N" + } + amount { + moles { + value: 0.00111 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.04e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.27e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 130.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a microwave vial containing 2,4-dichloropyridine (0.109 mL, 1.01 mmol), sodium phenolate (177 mg, 1.52 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (11.60 mg, 0.01 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (17.59 mg, 0.03 mmol) (Xantphos), was added degassed dioxane (4 mL) and the mixture allowed to stir under nitrogen atmosphere for 5 min. To this solution was added oxazol-2-amine (94 mg, 1.11 mmol) and the reaction mixture was heated to 130 Cnbsp;for 30 min under microwave irradiation. bApparently no 2-aminooxazole remains by proton NMR of crude reaction mixture upon removal of dioxane, however it\'s presence was observed by LCMS of the crude reaction mixture (see attached). It is possible that the presence of impuritiessolvent etc. have shifted the resonances slightly for this starting material in bb1bbH NMR. bThe crude product was purified by reverse-phase flash chromatography on C-18 modified silica, elution gradient 0 t0% MeCN in water. Pure fractions were evaporated to dryness to afford N-(4-chloropyridin-2-yl)oxazol-2-amine (6.00 mg, 3.03 %) as a pale yellow dry film. 3 % of the required product was isolated and this sample was impure. Microwave heating has no positive effect under these reaction conditions.Upon mission of a crude sample of the reaction mixture to PCQ both starting materials were observed.Conclusion: 3% of impure material isolated, look for alternative conditions." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)NC2=NC=CO2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 3.03 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/04/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "476" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00236 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0048 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=COC(=N1)N" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 5.07e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium(II) acetate (11.38 mg, 0.05 mmol) was added in a single portion to a degassed solution of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (44.0 mg, 0.08 mmol), oxazol-2-amine (85 mg, 1.01 mmol), cesium carbonate (768 mg, 2.36 mmol),2,4-dichloropyridine (0.109 mL, 1.01 mmol), dioxane (4 mL) and DMSO (0.8 mL) and the resulting mixture was heated at 100 C for 16 hours under a nitrogen atmosphere.Note: the reaction mixture was degassed by first combing the reagents (with the exception of Pd((OAc)2), sealing the vessel and carrying out three pump-purge cycles (vac-nitrogen). Dioxane was then added to this mixture via syringe, followed by the Pd(OAc)2 in a single portion and the vessel was heated for the required time as above. Solvent boiled dry from reaction overnight. Only DMSO remained. bCrude proton NMR shows mainly dichlorpyridine starting material and the 2-aminooxazole starting material was absentb. Crude LCMS indicates that a product of the required mas present. The crude product was purified by flash chromatography on C-18 modified silica, elution gradient 0 to 100% MeCN in water with basic modifier (1% ammonium hydroxide). Pure fractions were evaporated to dryness to afford N-(4-chloropyridin-2-yl)oxazol-2-amine (22.00 mg, 11.10 %) as a pale yellow residue. The product isolated, although impure, looks like the required product based on LCMS. The 1H NMR of the purified material is in D6-DMSO here and so not directly comparable with previous spectra in CDCl3. Conclusion: This may be worth pursuing (i.e. adding DMSO to aid solubility) based on the slightly increased yield.bRevision: Required product not isolated, spectral analysis of isolated sample does not match those of authentic samples of the coupled productb. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)NC2=NC=CO2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 11.1 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/09/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "478" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00203 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=COC(=N1)N" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000122 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000101 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;oxazol-2-amine (85 mg, 1.01 mmol), 2,4-dichloropyridine (0.151 mL, 1.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (70.4 mg, 0.12 mmol) and cesium carbonate (660 mg, 2.03 mmol) were stirred in DMA (5 mL).nbsp;The mixture was purged with nitrogen for 10 minutes.nbsp;Palladium(II) acetate (22.76 mg, 0.10 mmol) was added and the mixture heated at 100 C for 70h.nbsp;The mixture was cooled, filtered and concentrated.nbsp;The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-(4-chloropyridin-2-yl)oxazol-2-amine (3.90 mg, 1.967 " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)NC2=NC=CO2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 1.97 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/06/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "479" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)[O-].[Na+]" + } + amount { + moles { + value: 3.04e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=COC(=N1)N" + } + amount { + moles { + value: 0.00111 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.04e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.27e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a flask containing 2,4-dichloropyridine (0.109 mL, 1.01 mmol), sodium phenolate (177 mg, 1.52 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (11.60 mg, 0.01 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (17.59 mg, 0.03 mmol) (Xantphos), was added degassed dioxane (4 mL) and the mixture allowed to stir under nitrogen atmosphere for 5 min. To this solution was added oxazol-2-amine (94 mg, 1.11 mmol) and the reaction mixture was heated to 80 Cnbsp;for three hours.A 1H NMR was measured of the crude reaction after the solvent had been removed. bThis indicated the presence of significant amounts of 2,4-dichloropyridine as well as 2-amino oxazoleb. LCMS of the crude reaction mixture at t= 90 min and at t= 3 h showed the desired product was present. The crude reaction mixture was dry loaded without workup and purified by automated flash chromatography. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)NC2=NC=CO2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 2.52 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "12/10/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "481" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0105 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.039 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCC(CC1)CN" + } + amount { + moles { + value: 0.00526 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)OC(F)(F)F)C2=CN=C3N2N=C(C=C3)Cl" + } + amount { + moles { + value: 0.00351 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C1=CC=CC=C1C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 0.00105 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000351 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 300 ml round bottom lfask was charged with a magnetic stir bar, toluene (39 ml), 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (1.1 g, 3.51 mmol), Pd2(dba)3 (0.321 g, 0.35 mmol), 2-(DIMETHYLAMINO)-2\'-(DICYCLOHEXYLPHOSPHINO)BIPHENYL (0.414 g, 1.05 mmol), SODIUM TERT-BUTOXIDE (1.011 g, 10.52 mmol), and (1-methylpiperidin-4-yl)methanamine (0.674 g, 5.26 mmol). The mixture was degassed with N2, the vessel fitted with a reflux condenser, and then placed in an oil bath heated to 110 C for 16hrs. The mixture was cooled to r.t, filtered throught a bed of celite, washed with methanol, the filtrate was concentrated, the residue was pre-absorbed onto silca gel (~10g) and purified with ISCO (eluent methanolDCM (13) to afford the title compound N-((1-methylpiperidin-4-yl)methyl)-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-amine (0.510 g, 35.9 %).(Note: the ligand I used was old)(note: tried direct displacement under microwave radiation at 180C in 4MHCl or KOethoxyethanol; both condition didn\'t result in the desired product)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CCC(CC1)CNC2=NN3C(=NC=C3C4=CC(=CC=C4)OC(F)(F)F)C=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 35.87 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/24/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "482" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0835 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.2 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCC(CC1)CN" + } + amount { + moles { + value: 0.0355 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)OC(F)(F)F)C2=CN=C3N2N=C(C=C3)Cl" + } + amount { + moles { + value: 0.0209 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C1=CC=CC=C1C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 0.00626 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.00209 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 500 ml round bottom lfask was charged with a magnetic stir bar, toluene (200 ml), 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (6.55 g, 20.88 mmol), Pd2dba3 (1.912 g, 2.09 mmol),nbsp;fresh bottle of 2\'-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (2.465 g, 6.26 mmol),nbsp;SODIUM TERT-BUTOXIDE (8.03 g, 83.53 mmol) and (1-methylpiperidin-4-yl)methanamine (4.55 g, 35.50 mmol). The mixture was degassed with N2, the vessel fitted with a reflux condenser, and then placed in an oil bath heated to 120 C for 16hrs. The mixture was filtered throught a bed of celite, washed with methanolDCM (31), the filtrate was concentrated, the residue was taken into a mixture of water and DCMIsopropanol (51), separated, the water layer was extrated twice with DCMisopropanol (51), the combined organics were dried (MgSO4), concentrated, the residue was pre-absorbed onto silca gel (~80g) and purified with ISCO (eluent methanolDCM (13) to afford the title compound as which was taken into he, the solid was collected by filtration, washed with hexane, dried in vacum at 60C to yield a light yellow solid as N-((1-methylpiperidin-4-yl)methyl)-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-amine (5.51 g, 62.9 %).405mgs of the free base product was dissolved into 2ml of methanol, treated with 1M H2SO4 in methanol (1ml conc. H2SO4 + 17ml of methanol). The solution was stirred for 2min, solid crushed out, the suspension was continually stirred at r.t for overnight before being diluted with ethyl ether, the solid was collected by filtration, dried to yield a white solid as desired product-bi-sulfuric acid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CCC(CC1)CNC2=NN3C(=NC=C3C4=CC(=CC=C4)OC(F)(F)F)C=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 62.89 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/28/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "483" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 1.99e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC2=C(C=C1)C=C(C=C2)C(=O)N" + } + amount { + moles { + value: 0.000199 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)[N+](=O)[O-])Br" + } + amount { + moles { + value: 0.000199 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 1.99e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 9.94e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (9.10 mg, 9.94 mol) was added to 2-bromo-1-methyl-4-nitrobenzene (42.9 mg, 0.20 mmol), 2-methylquinoline-6-carboxamide (37.0 mg, 0.20 mmol), cesium carbonate (194 mg, 0.60 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (11.50 mg, 0.02 mmol) in dioxane (2 mL) at 20C under nitrogen. The resulting solution was stirred at 100 C for 6 hours. Reaction seen to be progressing but very sluggish (5% conversion). Reaction abandoned." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)[N+](=O)[O-])NC(=O)C2=CC3=C(C=C2)N=C(C=C3)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/13/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "484" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00257 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CN1CCCC1=O" + } + amount { + volume { + value: 0.006 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)NC1=C(C=CC(=C1)N)N2CC[C@H](C2)NC(=O)OC(C)(C)C" + } + amount { + moles { + value: 0.00128 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.00128 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C(C)(C)C)C(C)(C)C)C(C)C" + } + amount { + moles { + value: 0.000128 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 6.42e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 105.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (300 mg, 1.28 mmol), (R)-tert-butyl 1-(2-acetamido-4-aminophenyl)pyrrolidin-3-ylcarbamate (429 mg, 1.28 mmol), CESIUM CARBONATE (837 mg, 2.57 mmol) and di-tert-butyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (54.5 mg, 0.13 mmol) were added into NMP (6 mL) in a 50mL round bottle.nbsp;Pd2dba3 (58.8 mg, 0.06 mmol) was added to the solution.nbsp;The solution was purged by nitrogen, then heated at 105C overnight.nbsp;Crude product was separarted between water and ethyl acetate.nbsp;The organic layer was concentrated under reduced pressure.nbsp;The crude product was purified on the ISCO(17g silica column, EAhex 0-75%). Then the intermediate was put in 1N HClnbsp;in ether(5mL),.nbsp;The solution was stirred at rt for2hrs.nbsp;Crude product was purified on Gilson(0.1%TFA CH3CNwater 2-35%), 124.8mg final product was obtained as white solid" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)NC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)N5CC[C@H](C5)N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 17.82 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/19/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "485" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00483 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00372 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(O1)C=CC=C2Br" + } + amount { + moles { + value: 0.00372 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.000372 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000186 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 95.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "tert-butyl piperazine-1-carboxylate (0.692 g, 3.72 mmol), ethyl 4-bromobenzofuran-2-carboxylate (1 g, 3.72 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (0.177 g, 0.37 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.170 g, 0.19 mmol) and CESIUM CARBONATE (1.574 g, 4.83 mmol) were heated under argon to 95 C overnight.nbsp;The mixture was allowed to cool. The mixture was diluted with EtOAc and the mixture was filtered through a pad of Celite.nbsp;The filterate was collected and the solvent was removed by rotary evaporation.nbsp;The crude product was added to a silica gel column and was eluted withnbsp;0-50% EtOAc in heptane.nbsp;The collected fractions were combined and the solvent was removed to yield tert-butyl 4-(2-(ethoxycarbonyl)benzofuran-4-yl)piperazine-1-carboxylate (0.990 g, 71.1 %).1H NMR in CDCl3 is consistent with desired productMSnbsp;(m+1) = 375.6.HPLC Peak RT = 3.27 minutes is product.nbsp;Purity = 95%." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(C=CC=C2O1)N3CCN(CC3)C(=O)OC(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 71.15 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/13/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "487" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0372 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.04 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.0286 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(O1)C=CC=C2Br" + } + amount { + moles { + value: 0.0286 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.00286 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.00143 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 95.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "ethyl 4-bromobenzofuran-2-carboxylate (7.7 g, 28.61 mmol), tert-butyl piperazine-1-carboxylate (5.33 g, 28.61 mmol), Tris(dibenzylideneacetone)dipalladium(0) (1.310 g, 1.43 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (1.364 g, 2.86 mmol) and CESIUM CARBONATE (12.12 g, 37.20 mmol) in dioxane (40 mL) was heated under argon to 95 C overnight.nbsp;The mixture was allowed to cool. The mixture was diluted with EtOAc and the mixture was filtered through a pad of Celite.nbsp;The filterate was collected and the solvent was removed by rotary evaporation.nbsp;The crude product was added to a silica gel column and was eluted withnbsp;0-50% EtOAc in heptane.nbsp;The collected fractions were combined and the solvent was removed to yield tert-butyl 4-(2-(ethoxycarbonyl)benzofuran-4-yl)piperazine-1-carboxylate (4.92 g, 45.9 %).MSnbsp;(m+1) = 375.8.HPLC Peak RT = 3.27 minutes is product.nbsp;Purity = 96%." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(C=CC=C2O1)N3CCN(CC3)C(=O)OC(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 45.92 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/17/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "488" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00966 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00743 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(O1)C=CC=C2Br" + } + amount { + moles { + value: 0.00743 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.000743 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000372 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 95.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "ethyl 4-bromobenzofuran-2-carboxylate (2 g, 7.43 mmol), tert-butyl piperazine-1-carboxylate (1.384 g, 7.43 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.340 g, 0.37 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (0.354 g, 0.74 mmol) and CESIUM CARBONATE (3.15 g, 9.66 mmol) were heated under argon to 95 C overnight.nbsp;The mixture was allowed to cool. The mixture was diluted with EtOAc and the mixture was filtered through a pad of Celite.nbsp;The filterate was collected and the solvent was removed by rotary evaporation.nbsp;The crude product was added to a silica gel column and was eluted withnbsp;0-50% EtOAc in heptane.nbsp;The collected fractions were combined and the solvent was removed to yield tert-butyl 4-(2-(ethoxycarbonyl)benzofuran-4-yl)piperazine-1-carboxylate (1.250 g, 44.9 %).MSnbsp;(m+1) = 375.6.HPLC Peak RT = 3.29 minutes is product.nbsp;Purity = 99%." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC2=C(C=CC=C2O1)N3CCN(CC3)C(=O)OC(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 44.92 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/17/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "489" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CCC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00104 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=CC1=O)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000865 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CC(OC2=C(C1)C=CC(=N2)Cl)CC(F)(F)F" + } + amount { + moles { + value: 0.000865 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 8.65e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 8.65e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of 5-(6-amino-2-methoxypyridin-3-yl)-1-methylpyridin-2(1H)-one (0.2 g, 0.86 mmol), 8-chloro-4-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.243 g, 0.86 mmol), Palladium(II) acetate (0.019 g, 0.09 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (0.050 g, 0.09 mmol) and Sodium tert-pentoxide (0.114 g, 1.04 mmol) in dioxane (1.5 mL) was heated by microwave irradiation to 120 C for 30 min.nbsp;The mixture was allowed to cool.nbsp;DCM (5 mL) was added and the mixture was filtered through a short pad of Celite.nbsp;The filtrate was collected and the solvent was removed by rotary evaporation.nbsp;The crude product was added to a silica gel column and was eluted with 0-5% MeOH in DCM.nbsp;The collected fractions were combined and the solvent was removed by rotary evaporation.nbsp;The residue was mitted for separation by chiral SFC to yield 5-(2-methoxy-6-(4-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-ylamino)pyrid-yl)-1-methylpyridin-2(1H)-one (0.055 g, 26.8 %) and 5-(2-methoxy-6-(4-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-ylamino)pyridin-3-yl)-1-methylpyridin-2(1H)-one (0.051 g, 24.80 %).EN04155-91-001:1H NMR in DMSO-d6 is consistent with desired productMSnbsp;(m+1) = 476.1.HPLC Peak RT = 2.48 minutes is product.nbsp;Purity = 97%.EN04155-91-002:1H NMR in DMSO-d6 is consistent with desired productMSnbsp;(m+1) = 476.1.HPLC Peak RT = 2.48 minutes is product.nbsp;Purity = 98%." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CC(OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(C(=O)C=C4)C)OC)CC(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 26.75 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/05/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "490" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00251 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.012 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" + } + amount { + moles { + value: 0.00167 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=C(C=C1F)Br)F" + } + amount { + moles { + value: 0.00209 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00017 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)[PH+](C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5[PH+](C6=CC=CC=C6)C7=CC=CC=C7)C.C1=[C-]C=C(C=C1F)F.Br[Pd+]" + } + amount { + moles { + value: 0.00017 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Pd complexe (147 mg, 0.17 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (600 mg, 1.67 mmol), 1-bromo-3,5-difluorobenzene (0.241 ml, 2.09 mmol) and cesium carbonate (818 mg, 2.51 mmol) dissolved in 1,4-dioxane (12 ml). The resulting suspension was degased with argon and then stirred at 100 C (15:00) for 18 hours.The reaction mixture was allowed to cool to room temperature, filtered and concentrated.The crude product was adsorbed on silica gelnbsp;and purified by flash chromatography on silica gel eluting with 0 to 6% methanol in ethyl acetate. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (314 mg, 39.9 %) as a clear yellow solid.blow yield but LCMS of the crude showed a nice reaction!bLCMS is OK." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 39.87 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/29/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "491" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00113 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" + } + amount { + moles { + value: 0.000753 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=C(C=C1F)Br)F" + } + amount { + moles { + value: 0.000829 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 4e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)[PH+](C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5[PH+](C6=CC=CC=C6)C7=CC=CC=C7)C.C1=[C-]C=C(C=C1F)F.Br[Pd+]" + } + amount { + moles { + value: 4e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Pd complexe (33.2 mg, 0.04 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (270 mg, 0.75 mmol), 1-bromo-3,5-difluorobenzene (0.095 ml, 0.83 mmol) and cesium carbonate (368 mg, 1.13 mmol) dissolved in 1,4-dioxane (5 ml). The resulting suspension was degased with argon and then stirred at 80 C.After 18 hours, lcms showed incomplete reaction: 5% more reactants were added and heating was continued at 100 C for 5 additionnal hours.Lcms showed ~ complete reactionnbsp;after 23 hours.The reaction mixture was allowed to cool to room temperature, filtered and concentrated.The crude product was purified by flash chromatography on silica gel eluting with 0 to 6% methanol in ethyl acetate. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (206 mg, 58.1 %) as a clear yellow foam.LCMS and NMR ar" + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 58.12 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/14/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "492" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00241 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.012 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" + } + amount { + moles { + value: 0.00161 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=C(C=C1F)Br)F" + } + amount { + moles { + value: 0.00201 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00016 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)[PH+](C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5[PH+](C6=CC=CC=C6)C7=CC=CC=C7)C.C1=[C-]C=C(C=C1F)F.Br[Pd+]" + } + amount { + moles { + value: 0.00016 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Pd complexe (142 mg, 0.16 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (577 mg, 1.61 mmol), 1-bromo-3,5-difluorobenzene (0.232 ml, 2.01 mmol) and cesium carbonate (787 mg, 2.41 mmol) dissolved in 1,4-dioxane (12 ml). The resulting suspension was degased with argon and then stirred at 100 C (10:30).After 3 hours, lcms showed complete reaction.The reaction mixture was allowed to cool to room temperature, filtered and concentrated.The crude product was purified by flash chromatography on silica gel eluting with 0 to 6% methanol in ethyl acetate. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (315 mg, 41.6 %) as a clear yellow foam.blow yield but LCMS of the crude showed complete reaction!bLCMS and NMR are OK" + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 41.59 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/05/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "494" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.002 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=COC(=N1)N" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 140.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Pd2(dba)3 (22.89 mg, 0.025 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (43.4 mg, 0.075 mmol), 2,4-dichloropyridine (148 mg, 1.00 mmol), cesium carbonate (651 mg, 2.00 mmol),ethyl 2-aminooxazole-4-carboxylate (156 mg, 1.00 mmol) were added to an oven dried microwave vial, the vial was capped and placed under an inert atmosphere, dioxane (4 mL) was added and the resulting mixture was heated to 140 C for 1 h by microwave irradiation under a nitrogen atmosphere.The crude product was purified by reverse-phase flash chromatography, elution gradient 0 to 100% MeCN in water. Pure fractions were evaporated to dryness to afford ethyl 2-(4-chloropyridin-2-ylamino)oxazole-4-carboxylate (99 mg, 37.0 %) as a pale yellow solid. Conclusion: Yield produced under microwave conditions is essentially identical to overnight reaction with conventional heating. Therefore screening of other aminooxazoles can be carried out under microwave conditions in the interest of time.. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=COC(=N1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 37.02 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/28/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "495" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[K+].[K+]" + } + amount { + moles { + value: 0.00334 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.00245 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.00222 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000111 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 6.67e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Charged a standard microwave vial with a mixture of 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (0.500 g, 2.45 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.611 g, 2.22 mmol), palladium (II) acetate (0.015 g, 0.07 mmol), rac-BINAP (0.069 g, 0.11 mmol), potassium carbonate (0.461 g, 3.34 mmol), and toluene (20 mL).nbsp;The atmosphere was inerted through consecutive vacuum-nitrogen purge cycles, then heated at 120 C for 16 hours.HPLC-UV shows some starting materials remaining (lt;11% at 254 nm).nbsp;The mixture was cooled to room temperature and 20 mL of DCM was added to the vessel.nbsp;The pH was adjusted to pH 2 with 2.0N aqueous HCl and the phases were separated.nbsp;Basified the aqueous with 2.0 M aqueous NaOH and extracted with 2 X 30 mL DCM.nbsp;The organics were combined, dried with magnesium sulfate and concentrated by rotary evaporator to yield EN04092-36-001 (811 mg, 1.833 mmol, 82 %)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=CC=CC=C5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 82.41 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/06/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "496" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000181 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0105 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.00258 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.00258 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000181 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000181 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (528 mg, 2.58 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (710 mg, 2.58 mmol), Sodium tert-butoxide (373 mg, 3.88 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (113 mg, 0.18 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (166 mg, 0.18 mmol) were added to a microwave vial followed by toluene (10.5 mL). The reaction mixture was flushed with nitrogen and the mixture was heated to 100C and stirred overnight. The reaction was complete. The solids were filtered off and washed with ethyl acetate. The organic solution was extracted by sat NaHCO3 solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography using DCM : [DCM:MeOH:NH3=90:10:1] = 100:0 to 60:40 as gradient. The product was obtained as yellow foam 766 mg purity 95-99% depending on wavelength (95% on 220nm). The compound was dissolvn DCM and treated with activated carbon, then filtered and concentrated. The purity was bnot bincreased by the treatment!Preparative purification with Gilson prep was performed, 30-70% gradient was used. The material was collected manually. The fractions were pooled together, concentrated in vacuo then treated with DCM and sat NaHCO3 solution. The phases were separated, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The product was obtained as white foam and was dried overnight in a vacuum oven at 40C.nbsp;nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=CC=CC=C5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 54.92 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/27/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "497" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[K+].[K+]" + } + amount { + moles { + value: 0.0367 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.1 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.0245 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.0245 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00122 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000734 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Charged a round-bottom flask with a mixture of 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (5.0 g, 24.48 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (6.73 g, 24.48 mmol), palladium (II) acetate (0.165 g, 0.73 mmol), rac-BINAP (0.762 g, 1.22 mmol), potassium carbonate (5.08 g, 36.72 mmol), and toluene (100 mL).nbsp;The atmosphere was inerted through consecutive vacuum-nitrogen purge cycles, then heated at 120 C for 16 hours.HPLC-UV shows a small percentage (lt;5%) of starting materials remaining.nbsp;Heating was continued for another 2 hours, then the heating block was removed and the mixture was allowed to cool to room temperature.nbsp;Added 200 mL dichloromethane and adjusted the pH to 2 with 2.0N aqueous HCl.nbsp;Separated the phases and basified the aqueous with 1.0N aqueous sodium hydroxide.nbsp;Extracted with 200 mL DCM, followed by a second extraction with 100 mL DCM.nbsp;The organics were dried with magnesium sulfate and concentr by rotary evaporator to yield EN04092-37-001 (10.9 g, 24.63 mmol, 101 %) as an amber-coloured foam." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=CC=CC=C5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 100.61 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/13/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "498" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[K+].[K+]" + } + amount { + moles { + value: 0.0558 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.15 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.0372 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.0372 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00186 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00112 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Charged a round-bottom flask with a mixture of 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (7.6 g, 37.21 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (10.22 g, 37.21 mmol), palladium (II) acetate (0.251 g, 1.12 mmol), rac-BINAP (1.159 g, 1.86 mmol), potassium carbonate (7.71 g, 55.82 mmol), and toluene (150 mL).nbsp;The atmosphere was inerted through consecutive vacuum-nitrogen purge cycles, then heated at 120 C for 16 hours.HPLC-UV shows lt;9% of starting materials remaining.nbsp;Added an additional 25mg palladium acetate and 116 mg BINAP, then heating was continued for another 2 hours.nbsp;HPLC-UV does not show any additional progress.nbsp;The heating block was removed and the mixture was allowed to cool to room temperature.nbsp;Added 300 mL dichloromethane and adjusted the pH to 2 with 2.0N aqueous HCl.nbsp;Separated the phases and basified the aqueous with 1.0N aqueous sodium hydroxide.nbsp;Extracted with 200 mL DCM, followed by a sd extraction with 100 mL DCM.nbsp;The organics were dried with magnesium sulfate and concentrated by rotary evaporator to yield EN04092-38-001 (16.1 g, 36.4 mmol, 98 %) as an amber-coloured foam." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=CC=CC=C5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 97.77 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/15/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "499" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[K+].[K+]" + } + amount { + moles { + value: 0.0331 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.09 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.022 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.022 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.0011 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000661 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Charged a round-bottom flask with a mixture of 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (4.5 g, 22.03 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (6.05 g, 22.03 mmol), palladium (II) acetate (0.148 g, 0.66 mmol), rac-BINAP (0.686 g, 1.10 mmol), potassium carbonate (4.57 g, 33.05 mmol), and toluene (90 mL).nbsp;The atmosphere s inerted through itrogen purge cycles, then heated at 120 C or 16 hours.HPLC-UV shows lt;5% of starting materials remaining.nbsp;The heating block was removed and the mixture was allowed to cool to room temperature.nbsp;Added 300 mL dichloromethane and adjusted the pH to 2 with 2.0N aqueous HCl.nbsp;Separated the phases and basified the aqueous with 1.0N aqueous sodium hydroxide.nbsp;Extracted with 200 mL DCM, followed by a second extraction with 100 mL DCM.nbsp;The organics were dried with magnesium sulfate and concentrated by rotary evaporator to give EN04092-39-001 (9.90g, 22.37 mmol, 102%).autotext key=quot36C73quot; name=quot;[Samples]quot; index=quot;0quot; field=quot;Samplesquot; type=quot;fieldquot; length=quot;9quot;gt;ber-coloured foam." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=CC=CC=C5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 101.53 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/22/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "500" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000437 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.016 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.00437 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.00437 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000437 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000218 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (0.892 g, 4.37 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (1.20 g, 4.37 mmol), Sodium tert-butoxide (0.630 g, 6.55 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.272 g, 0.44 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (0.200 g, 0.22 mmol) were added to a microwave vial followed by toluene (16 mL). The reaction mixture was flushed with nitrogen and the mixture was heated to 100C and stirred overnight. The reaction was completed. The solids were filtered off and washed with DCM. The organic solution was extracted by sat NaHCO3 solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography using DCM : [DCM:MeOH:NH3=90:10:1] = 100:0 to 60:40 as gradient. The product was obtained as yellow foam 1.55 g with a purity 96-99% depending on wavelength (96% on 220nm). Preparative purificationh Gilson prep was performed, 30-70% gradient was used. The material was collected manually. The fractions were pooled together, concentrated in vacuo then treated with DCM and sat NaHCO3 solution. The phases were separated. The aqueous layer was extracted with DCM 2 more times than once with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The product was obtained as white foam and was dried overnight in a vacuum oven at 50C. According to 1H-NMR 1.5 % ethyl acetate was present in the sample. bEthyl acetate should be avoided for extraction!b The sample was dissolved in DCM and concentrated in vacuo then the process was repeated 2 more times. The product was dried in a vacuum oven overnight at 50C.n" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=CC=CC=C5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 58.78 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/01/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "501" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[K+].[K+]" + } + amount { + moles { + value: 0.0067 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.00372 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.00372 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000186 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000112 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Charged a round-bottom flask with a mixture of 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (0.76 g, 3.72 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (1.022 g, 3.72 mmol), palladium (II) acetate (0.025 g, 0.11 mmol), rac-BINAP (0.116 g, 0.19 mmol), potassium carbonate (0.926 g, 6.70 mmol), and toluene (15 mL).nbsp;The atmosphere was inerted through consecutive vacuum-nitrogen purge cycles, then heated at 110 C under N2(g) for 16 hours. HPLC-UV shows a small percentage (3-6% depending on wavelength) of oxazepine remaining, aminopyridine if fully converted. The mixture was allowed to cool to room temperature. DCM and 2M HCl was added and the orgaic phase were removed. The aqueous phase were basified using solid KOH and a 4M solution. Extracted with DCM, dried oved MgSO4 and concentrated." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=CC=CC=C5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 86.23 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/19/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "502" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[K+].[K+]" + } + amount { + moles { + value: 0.141 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.2 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.0783 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.0783 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00392 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00235 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2011-05-03; 16:30Charged a round-bottom flask with a mixture of 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (16 g, 78.34 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (21.52 g, 78.34 mmol), palladium (II) acetate (0.528 g, 2.35 mmol), rac-BINAP (2.439 g, 3.92 mmol), potassium carbonate (19.49 g, 141.02 mmol), and toluene (200 mL).nbsp;The atmosphere was inerted through consecutive vacuum-nitrogen purge cycles, then heated at 110 C under N2(g).2011-05-04;nbsp;10:52:55HPLC-UV shows a small percentage (3-6% depending on wavelength) of oxazepine remaining, aminopyridine if fully converted. The mixture was allowed to cool to room temperature. DCM and 2M HCl was added and the orgaic phase were removed. The aqueous phase were basified using solid KOH,nbsp;extracted with DCM and concentrated EN04644-87-001 (13 g, 29.4 mmol, 37.5 %) .The remaining organic phase was treated second time with HCl 2M, this aqueous phase ained also product ( 75% according with HPLC). The HCl solution was basified using KOH and extracted with DCM to give EN04644-87-002.EN04644-87-001 (13 g, 29.4 mmol, 37.5 %) (36g of crude) was dissolved in iPrOH (70mL) with heating and the slurry was left over a long weekend (4d). The precipitated obtained (after seeding with a sample from Jacob EN0) had 87% purity. The precipitated obtained (19g) were sent to Daniel for purification." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=CC=CC=C5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 37.5 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/03/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "503" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[K+].[K+]" + } + amount { + moles { + value: 0.0347 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.1 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.0231 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.0231 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00116 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000693 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a 250 mL roundbottomed flask was added 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (5.5 g, 23.11 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (6.50 g, 23.11 mmol), Palladium(II)acetate (0.157 g, 0.69 mmol), rac-BINAP (0.734 g, 1.16 mmol), Potassium carbonate (4.79 g, 34.66 mmol) and toluene (100 mL). The atmosphere was exchanged to nitrogen through consecutive vacuum-nitrogen purge cycles after which the mixture was heated at 120 C for 16 h. Still some starting material left according to HPLC and LCMS (IPC 1), so another 25 mg of Pd(OAc)2 and 116 mg of BINAP was added, and heating continued. After another 4 h, no further progress was detected (IPC 2), so the mixture was allowed to cool to r.t.Dichloromethane (200 mL) was added and pH was adjusted to 2 by addition of 2M HCl (aq) (80 mL was added, but made too acidic). The phases were separated and the aq phase was made basic by addition of 1M NaOH (aq) (ca 70 mL). The aq phase was acted with dichloromethane (200 mL) and re-extracted with another portion of dichloromethane (70 mL). Since the aq phase still contained some product, another portion of 1M NaOH (aq) (20 mL) was added and the aq phase was extracted with dichloromethane (100 mL). The combined organic layers were evaporated and toluene was added to co-evaporate water. The resulting brown solid was dried under vacuum o.n, yielding EN04391-37-001 (12 g, 27.1 mmol, 117 %).To the solid was added EtOAc (55 mL) and the slurry was stirred at r.t for 1 h. Stirring was turned off and the solid was allowed to sediment for 2 h. The solid was filtered off and washed with 2x 12 mL cold EtOAc, yielding EN04391-37-002 (5.7 g, 12.88 mmol, 55.7 %).The mother liquor still contained product so it was concentrated and to the residue was added isopropanol (18 mL, 2 mL g crude). The mixture was heated to dissolve everything (50 C for 5 min) and was then stirred at r.t over night. A white precipitate had formed. The mixture wasled on an ice bath (0-5 C) for 1 h after which the solid was filtered off, washed with 2x10 mL cold isopropanol and dried at 40 C under vacuum, yielding EN04391-37-003 (2.3 g, 5.20 mmol, 22.49 %).EN04391-37-002 and EN04391-37-003 were combined with EN04391-36-002 and EN04391-36-003 and further purified, see page EN04391" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=CC=CC=C5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 78.24 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/12/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "504" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[K+].[K+]" + } + amount { + moles { + value: 0.0378 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.1 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.0252 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.0252 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00126 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000756 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a 250 mL roundbottomed flask was added 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (6 g, 25.21 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (7.10 g, 25.21 mmol), Palladium(II)acetate (0.171 g, 0.76 mmol), rac-BINAP (0.801 g, 1.26 mmol), Potassium carbonate (5.23 g, 37.81 mmol) and toluene (100 mL). The atmosphere was exchanged to nitrogen through consecutive vacuum-nitrogen purge cycles after which the mixture was heated at 120 C for 18 h. Still some starting material left according to HPLC and LCMS (IPC 1), so another 25 mg of Pd(OAc)2 and 116 mg of BINAP was added, and heating continued. After another 3 h, approx. 2% starting material remained according to LCMS (IPC 2), so the mixture was allowed to cool to r.t. Dichloromethane (200 mL) was added and pH was adjusted to 2 by addition of 2M HCl (aq) (140 mL was added, but made too acidic). The phases were separated and the aq phase was made basic by addition of 1M NaOH (aq) (ca 200 mL). Tq phase was extracted with dichloromethane (200 mL) and re-extracted with another portion of dichloromethane (70 mL). Since an oily residue containing product had precipitated upon addition of acid base, the aq phase together with 100 mL dichloromethane was added to the residue in an attempt to dissolve it. More 1M NaOH (aq) was added to assure basic pH and the layers were separated. The combined organic layers were evaporated and the residue was dried under vacuum o.n. EN04391-36-001 (12.2 g, 27.6 mmol, 109 %) was obtained as a brown solid.To the solid was added isopropanol (48 mL, 4 mLg crude prod) and the thick suspension was heated at 95 C. After 30 min, the slurry was allowed to cool to r.t and left stirring over night. The still thick slurry was cooled on an ice bath at 0-5 C for 1 h before it was filtered. The solid was washed with 4x15 mL of cold isopropanol and dried at 40 C under vacuum o.n, yielding EN04391-36-002 (2.05 g, 4.63 mmol, 18.38 %) as a pale yellow solid liquor that still contained product was concentrated. An orange-brown foam was obtained. Toluene was added and evaporated and the residue (8 g) was dissolved in MeCN (13.5 mL) and purified by chromatography (200 g SiO2 in a filter funnel, elutent: EtOAc (750 mL) followed by MeCN (1 L) and MeCN:MeOH 9:1 (1 L)). Fractions 10-13 were combined, concentrated and dried, yielding EN04391-36-003 (5.5 g, 12.43 mmol, 49.3 %) as a solid. EN04391-36-002 and EN04391-36-003 were further purified on page EN04391-38. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=CC=CC=C5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 67.69 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/12/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "507" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000191 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.011 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.00273 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.00273 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000191 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000191 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (558 mg, 2.73 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (750 mg, 2.73 mmol), Sodium tert-butoxide (394 mg, 4.09 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (119 mg, 0.19 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (175 mg, 0.19 mmol) were added to a microwave vial followed by toluene (11 mL). The reaction mixture was flushed with nitrogen and the mixture was heated to 100C and stirred overnight. The reaction was complete. The solids were filtered off and washed with ethyl acetate. The organic solution was extracted by sat NaHCO3 solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography using DCM : [DCM:MeOH:NH3=90:10:1] = 100:0 to 10:90 as gradient. fr1 :160 mg approx 60% purefr2: 804 mg purity 90-99% depending on wavelength, pH and solvent.Preparativrification with Gilson prep was performed on the combined mixture. 30-70% gradient was used. The first batch (38% of the crude) was lost due to the fact that the product gave bnegative UV-signal btherefore didn\'t trigger any collection! The rest of the material was collected manually. The fractions were pooled together, concentrated in vacuo then tretaed with DCM and sat NaHCO3 solution. The phases were separated, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The product was obtained as white foam was dried overnight in a vacuum owen at 50C.nbsp;nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=CC=CC=C5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 32.29 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/20/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "509" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000487 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000324 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC(=NC=C1)C2CN(CC3=C(O2)N=C(C=C3)Cl)C" + } + amount { + moles { + value: 0.000324 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 3.24e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.62e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (66.3 mg, 0.32 mmol), 8-chloro-4-methyl-2-(4-methylpyridin-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (94 mg, 0.32 mmol), Sodium tert-butoxide (46.8 mg, 0.49 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (20.20 mg, 0.03 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (14.85 mg, 0.02 mmol) were added to a microwave vial then toluene (2 mL) was added. The reaction mixture was flushed with nitrogen and the mixture was heated to 100C and stirred overnight. The reaction was complete. The solids were filtered off and washed with DCM. The organic solution was extracted by sat NaHCO3 solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography using DCM : [DCM:MeOH:NH3=90:10:1] = 100:0 to 20:80 as gradient. Beige foam." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CC(=NC=C1)C2CN(CC3=C(O2)N=C(C=C3)NC4=NC(=C(C=C4)C5=CN(N=C5)C)OC)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 43.12 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/25/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "510" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000823 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000549 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN=C(C=C1)C2CN(CC3=C(O2)N=C(C=C3)Cl)C" + } + amount { + moles { + value: 0.000549 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 5.49e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.74e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (0.112 g, 0.55 mmol), 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (0.112 g, 0.55 mmol), Sodium tert-butoxide (0.079 g, 0.82 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.034 g, 0.05 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (0.025 g, 0.03 mmol) were added to a microwave vial then toluene (3 mL) was added. The reaction mixture was flushed with nitrogen and the mixture was heated to 100C and stirred overnight. The reaction was complete. The solids were filtered off and washed with DCM. The organic solution was extracted by sat NaHCO3 solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography using DCM : [DCM:MeOH:NH3=90:10:1] = 100:0 to 20:80 as gradient. Yellow foam." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN=C(C=C1)C2CN(CC3=C(O2)N=C(C=C3)NC4=NC(=C(C=C4)C5=CN(N=C5)C)OC)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 67.71 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/26/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "511" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 2.75e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.00318 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" + } + amount { + moles { + value: 0.000323 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=C(C=C1F)Br)F" + } + amount { + moles { + value: 0.000404 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 2.75e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.29e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (2.90 mg, 0.01 mmol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (120 mg, 0.32 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (15.89 mg, 0.03 mmol), 1-bromo-3,5-difluorobenzene (46.5 l, 0.40 mmol) and cesium carbonate (158 mg, 0.48 mmol) suspended in 1,4-dioxane (3184 l). The resulting suspension was degased with argon and then stirred at 100 C for 20 hours. Purification made by NWAThe reaction mixture was allowed to cool to room temperature, The crude product was adsorbed on silica gel, the solvent was evaporated, and purified by flash chromatography on silica gel eluting with 0 to 10% methanol in ethyl acetate. The solvent was evaporated to dryness, the gum was triturated in Et2Opentane to give a solid; the solid was filtered and dried to affordnbsp;8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (80 mg, 51.2 %) ase solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 51.21 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/31/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "512" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 2.75e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.00318 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" + } + amount { + moles { + value: 0.000323 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=C(C=C1F)Br)F" + } + amount { + moles { + value: 0.000404 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 2.75e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.29e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (2.90 mg, 0.01 mmol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (120 mg, 0.32 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (15.89 mg, 0.03 mmol), 1-bromo-3,5-difluorobenzene (46.5 l, 0.40 mmol) and cesium carbonate (158 mg, 0.48 mmol) suspended in 1,4-dioxane (3184 l). The resulting suspension was degased with argon and then stirred at 100 C for 20 hours. The mixture was evaporated and diluted with DMF.Purification made by KOKOThe reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholinoromene-6-carboxamide (77 mg, 49.3 %)nbsp;as anbsp;beige solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 49.29 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/31/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "513" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0075 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0236 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CCNCC1" + } + amount { + moles { + value: 0.006 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC=C(C=C1)Br" + } + amount { + moles { + value: 0.005 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00025 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00025 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 250 mL round-bottomed flask was ethyl 4-bromobenzoate (816 l, 5 mmol), piperidine (593 l, 6.00 mmol), and CESIUM CARBONATE (2444 mg, 7.50 mmol) in dioxane (2.36E+04 l) to give a white suspension.nbsp;The solution was degassed with N2 (g) for 15 min and then added BINAP (156 mg, 0.25 mmol) and PALLADIUM(II) ACETATE (56.1 mg, 0.25 mmol).nbsp;The reaction was heated to 100 C and stirred under a reflux condenser overnight.nbsp;The reaction was checked by LC-MS (complete), filtered, rinsed with DCM, concentrated in vacuo and onto silica gel.nbsp;Purification by Iscos (25 g.) using 100% hexanes -gt; 40% EtOAc in Hexanes afforded a white solid.nbsp;950 mg of a white solid obtained.nbsp;1H NMR (300 MHz, DMSO-idi6) d ppm 1.28 (t, iJi=7.08 Hz, 3 H) 1.58 (s, 6 H) 3.31 - 3.38 (m, 4 H) 4.23 (q, iJi=7.11 Hz, 2 H) 6.94 (m, iJi=9.06 Hz, 2 H) 7.76 (m, iJi=9.25 Hz, 2 H)LC-MS:nbsp;Rt = 2.98 min.nbsp;Method:nbsp;Short Purity.sp;234.2 [M+H]+. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC=C(C=C1)N2CCCCC2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 81.44 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/29/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "514" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.003 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.00976 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CCNCC1" + } + amount { + moles { + value: 0.0024 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)C1=CN=C(C=C1)Br" + } + amount { + moles { + value: 0.002 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.0001 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.0001 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 100 mL round-bottomed flask was tert-butyl 6-bromonicotinate (516 mg, 2 mmol), piperidine (237 l, 2.40 mmol), and CESIUM CARBONATE (977 mg, 3.00 mmol) in dioxane (9763 l) to give a white suspension.nbsp;The solution was degassed with N2 (g) fo 20 mins.nbsp;PALLADIUM(II) ACETATE (22.45 mg, 0.10 mmol) and BINAP (62.3 mg, 0.10 mmol) were added under N2 (g) and the reaction was heated to 100 C.nbsp;Start Time:nbsp;01-Jul-10 1:10:32 PM -0400.nbsp;The reaction was checked by LC-MS (complete), filtered, rinsed with DCM, concentrated in vacuo.nbsp;u02 July 2010uPurification by Iscos (25 g) using 100% Hexanes -gt; 50% EtOAc in Hexanes afforded a white solid.nbsp;325 mg obtained.nbsp;1H NMR (300 MHz, DMSO-idi6) d ppm 1.51 - 1.57 (m, 12 H) 1.57 - 1.77 (m, 5 H) 3.58 - 3.74 (m, 4 H) 6.78 - 6.92 (m, 1 H) 7.88 (dd, iJi=9.16, 2.36 Hz, 1 H) 8.60 (dd, iJi=2.45, 0.57 Hz, 1 H).LC-MS:nbsp;Rt = 2.37 min.nbsp;Mehort Purity.nbsp;MS ES+:nbsp;263.2 [M+H]+." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)C1=CN=C(C=C1)N2CCCCC2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 61.94 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/30/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "515" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0552 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.1 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.0505 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC(=CC(=C1)Br)C(=O)OC" + } + amount { + moles { + value: 0.0366 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00401 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00401 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a solution of dimethyl 5-bromoisophthalate (10 g, 36.62 mmol) in toluene (100 mL) where BINAP (2.5 g, 4.01 mmol), morpholine (4.4 g, 50.50 mmol), CESIUM CARBONATE (18 g, 55.25 mmol) and PALLADIUM(II) ACETATE (0.9 g, 4.01 mmol) added. The solution was heated to reflux under inert atm for 14h. The silvent was filtered and the filtrate was concentrated. The residue was purified by column chropmatography (Hep:EA) 1:1 to give dimethyl 5-morpholinoisophthalate (8.00 g, 78 %)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC(=O)C1=CC(=CC(=C1)N2CCOCC2)C(=O)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 78.22 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/18/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "516" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0172 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.035 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.0115 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=NC=C1Br)Br" + } + amount { + moles { + value: 0.0127 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000689 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.00023 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of 3,5-dibromopyridine (3.01 mL, 12.66 mmol), morpholine (1.00 g, 11.48 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (0.210 g, 0.23 mmol), sodium 2-methylpropan-2-olate (1.655 g, 17.22 mmol) and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.429 g, 0.69 mmol) in degassed toluene (35 mL) was stirred for 16 hours at 110 C in a sealed vessel under inert atmosphere. Extraction with sat. aq. Na2CO3 solution and AE, then back extraction 2x NaCl sat using DCM. The organics were dried over MgSO4 and evaporated iin vacuoi. The residue (see structure below, LC MS FLA-04227-45-02: 3,5 dimorpholino pyridine) was washed off with diethylether, then AE. The liquors were vaporated iin vacuoi. The residue was purified by chromatography (11 cm SiO2, diameter: 5 cm) eluent: AEhex 2575to 4555 to provide 4-(5-bromopyridin-3-yl)morpholine (1.400 g, 50.2 %) as a yellow solid.1H NMR, LC MS: FLA-04227-45-03. OK-----------------------------------------------------" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1COCCN1C2=CC(=CN=C2)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 50.17 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/12/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "517" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00841 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNCCOC" + } + amount { + moles { + value: 0.00561 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=NC=C1Br)Br" + } + amount { + moles { + value: 0.00617 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00028 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000112 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of 3,5-dibromopyridine (1.468 mL, 6.17 mmol), 2-methoxy-N-methylethanamine (0.602 mL, 5.61 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (0.103 g, 0.11 mmol), sodium 2-methylpropan-2-olate (0.809 g, 8.41 mmol) and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.175 g, 0.28 mmol) in degassed toluene (15 mL) was stirred for 16 hours at 90 C in a sealed vessel under inert atmosphere. LC MS of the crude mixture: FLA 04227-53-01. Extraction with sat. aq. Na2CO3 solution and AE, then back extraction 2x NaCl sat using DCM. The organics were dried over MgSO4 and evaporated iin vacuoi. The residue was purified by chromatography (11 cm SiO2, diameter: 3.5 cm) eluent: AEhex 2575to 4060 to provide 5-bromo-N-(2-methoxyethyl)-N-methylpyridin-3-amine (0.930 g, 67.6 %)nbsp;as a yellow oil.1H NMR, LC MS: FLA-04227-53-02. OK" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(CCOC)C1=CC(=CN=C1)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 67.64 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/20/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "518" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 8.64e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CN1CCCC1=O" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1N)S(=O)(=O)N" + } + amount { + moles { + value: 0.0011 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC(=NC=C1)Cl" + } + amount { + moles { + value: 0.000938 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 8.64e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 5.79e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of 4-aminobenzenesulfonamide (190mg, 1.10 mmol), 2-chloro-4-methoxypyridine (135 mg, 0.94 mmol), diacetoxypalladium (13mg, 0.06 mmol), cesium carbonate (417mg, 1.28 mmol) andnbsp;(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (50 mg, 0.09 mmol) in NMP (2.0 mL) was heatedb in the microwaveb for 10 min at 150 C. LC MS crude mix. FLA-04227-80-01 showed no reaction. Another 30 min at 150C in the microwave provided FLA-04227-80-02 (crude mix.).No product. bDiscard." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=CC(=NC=C1)NC2=CC=C(C=C2)S(=O)(=O)N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/10/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "519" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000697 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.0018 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1N)S(=O)(=O)N" + } + amount { + moles { + value: 0.000581 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)Br" + } + amount { + moles { + value: 0.000581 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 4.65e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.32e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 130.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of 4-aminobenzenesulfonamide (100 mg, 0.58 mmol), bromobenzene (0.061 mL, 0.58 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (26.9 mg, 0.05 mmol), diacetoxypalladium (5.21 mg, 0.02 mmol) and cesium carbonate (227 mg, 0.70 mmol)nbsp;in degassed DMA (1.8 mL) was heatedb uin the microwaveub for 20 min at 130 C. LC MS FLA-04227-96-01 (pH extract 7-8) showed some product and a few bromobenzene left. Heating was continued for 15 min at 150C. LC MS FLA-04227-96-02 (pH extract 7-8) showed reaction stalled. Reaction was stopped. Extraction with AE + ethanol aq. sat NH4Cl (pH7), then back extraction with DCM.The organics were dried over MgSO4 and concentrated iin vacuo. iThe crude product was adsorbed on silica gel 40-60m and purified by flash chromatography on silica gel 15-40m eluting with 2 % of ethanol in dichloromethane (NH3 0.5 %) to provide 4-(phenylamino)benzenesulfonamide (60.0 mg, 41.6 %) as a gum. 1H 4227-96-03: OKbiNote: the product still contains 24% mol DMAibbiCorrected yield: 30%ib" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=CC=C(C=C2)S(=O)(=O)N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 41.61 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/23/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "520" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 3.5e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" + } + amount { + moles { + value: 0.00035 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC(=CC=C1)Br" + } + amount { + moles { + value: 0.000437 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.75e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (3.93 mg, 0.02 mmol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (130 mg, 0.35 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (20.25 mg, 0.03 mmol), 1-bromo-3-methoxybenzene (0.055 ml, 0.44 mmol) and cesium carbonate (171 mg, 0.52 mmol) dissolved in 1,4-dioxane (4 ml). The resulting suspension was degased with argon and then stirred at 100 C for 15 hours.The reaction mixture was allowed to cool to room temperature, filtered and concentrated in V-10 Evaporator (Biotage)The crude product was dissolved in 2ml of DMA.The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 60 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to rdnbsp;8-(1-(3-methoxyphenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (46.0 mg, 27.5 %) as anbsp;solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC=C4)OC)OC(=CC2=O)N5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 27.52 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/10/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "521" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0149 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.03 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)N" + } + amount { + moles { + value: 0.0132 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C(=C1)[N+](=O)[O-])Br" + } + amount { + moles { + value: 0.0104 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000318 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000131 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 200 mL roundbottom flask was charged with 1-bromo-2-nitrobenzene (Alfa Aesar; 2.10 g, 10.40 mmol), Pd2(dba)3 (Aldrich; 119.6 mg, 2.5 mol%), racemic BINAP (Strem; 197.8 mg, 3.1 mol%), and cesium carbonate (Aldrich; 4.87 g, 14.95 mmol).nbsp;The flask was evacuated and backfilled with N2 (3x), and then anhydrous toluene (20 mL) was added.nbsp;Aniline (Acros; 1.20 mL, 13.2 mmol) was added followed by additional toluene (30 mL), and the mixture was allowed to stir at room temperature for 5 minutes before being placed in a 100 C oil bath.After heating overnight, the reaction was allowed to cool and was partitioned between EtOAc and water.nbsp;The aqueous layer was extracted with EtOAc (2x), and the combined organics were concentrated under reduced pressure.nbsp;The crude material was purified by silica gel chromatography (gradient elution; Rf in 90:10 hexanes:EtOAc = 0.54) to give a red-orange solid.nbsp;1.89 g of solid was collected." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=CC=CC=C2[N+](=O)[O-]" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 84.87 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/28/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "522" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000609 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000406 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CSC(=N1)C2CN(CC3=C(O2)N=C(C=C3)Cl)C" + } + amount { + moles { + value: 0.000406 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 4.06e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.06e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To 8-chloro-4-methyl-2-(4-methylthiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (120 mg, 0.41 mmol) in DME (3 mL) were 6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-amine (83 mg, 0.41 mmol), cesium carbonate (198 mg, 0.61 mmol), 2-(Dicyclohexylphosphino)biphenyl (14.22 mg, 0.04 mmol) and Palladium acetate (9.11 mg, 0.04 mmol) added. The reaction was heated to 110C for 180 min under N2 atmosphere. The solids were filtered off and washed with DCM, the solvents were evaporated and the crude product was purified by silica flash chromatography, MeOH, 0-10%, in DCM yielding N-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methyl-2-(4-methylthiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (20.00 mg, 10.63 %)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(N=C(C=C2)NC3=NC4=C(CN(CC(O4)C5=NC(=CS5)C)C)C=C3)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 10.63 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/17/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "523" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000254 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000169 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CSC(=N1)C2CN(CC3=C(O2)N=C(C=C3)Cl)C" + } + amount { + moles { + value: 0.000169 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 1.69e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.69e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To 8-chloro-4-methyl-2-(4-methylthiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (50 mg, 0.17 mmol) in DME (3 mL) were 6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-amine (34.5 mg, 0.17 mmol), cesium carbonate (83 mg, 0.25 mmol), 2-(Dicyclohexylphosphino)biphenyl (5.92 mg, 0.02 mmol) and Palladium acetate (3.80 mg, 0.02 mmol) added. The reaction was heated to 110C for 90 min under N2 atmosphere. The solids were filtered off and washed with DCM, the solvents were evaporated and the crude product was purified by silica flash chromatography, MeOH, 0-10%, in DCM yielding N-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methyl-2-(4-methylthiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (16.00 mg, 20.42 %)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(N=C(C=C2)NC3=NC4=C(CN(CC(O4)C5=NC(=CS5)C)C)C=C3)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 20.42 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/17/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "524" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00862 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.00678 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=C(C=CC(=C1)Br)I" + } + amount { + moles { + value: 0.00616 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000616 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000616 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a solution of methyl 5-bromo-2-iodobenzoate (2.1 g, 6.16 mmol) in DME (15 mL) were morpholine (0.593 mL, 6.78 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.384 g, 0.62 mmol), Palladium acetate (0.138 g, 0.62 mmol) and CESIUM CARBONATE (2.81 g, 8.62 mmol) added. The mixture was heated in the microwave oven for 1h. The solvent was evaporated and the crude product was added to a silica gel column, 0-25% EtOAc in heptane yielding [Products]" + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC(=O)C1=C(C=CC(=C1)Br)N2CCOCC2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 17.85 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/15/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "525" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0116 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.00639 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC(=C(C=C1)I)Br" + } + amount { + moles { + value: 0.00581 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000581 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000581 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a solution of methyl 3-bromo-4-iodobenzoate (1.981 g, 5.81 mmol) in DME (10 mL) were morpholine (0.559 mL, 6.39 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.362 g, 0.58 mmol), Palladium acetate (0.130 g, 0.58 mmol) and CESIUM CARBONATE (3.79 g, 11.62 mmol) added. The mixture was heated in the microwave oven for 12h at 110C. The solids were filtered off through celite, the solvent was evaporated and the crude product was added to a silica gel column, 0-30% EtOAc in heptane yielding methyl 3-bromo-4-morpholinobenzoate (0.566 g, 32.5 %)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC(=O)C1=CC(=C(C=C1)N2CCOCC2)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 32.45 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/15/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "526" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 3.5e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" + } + amount { + moles { + value: 0.00035 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)Br)F" + } + amount { + moles { + value: 0.000437 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.75e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (3.93 mg, 0.02 mmol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (130 mg, 0.35 mmol), 1-bromo-3-fluorobenzene (0.049 ml, 0.44 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (20.25 mg, 0.03 mmol) and cesium carbonate (171 mg, 0.52 mmol) dissolved in 1,4-dioxane (4 ml). The resulting suspension was degased with argon and then stirred at 100 C for 16 hours.The reaction mixture was allowed to cool to room temperature, filtered and concentrated in V-10 Evaporator (Biotage)The crude product was dissolved in 2ml of DMA.The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 60 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to ad 8-(1-(3-fluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (67.0 mg, 41.1 %)nbsp;as anbsp;solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC=C4)F)OC(=CC2=O)N5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 41.12 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/10/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "527" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CCC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00131 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=CC1=O)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.00109 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.00109 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000109 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000109 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (300 mg, 1.09 mmol), 5-(6-amino-2-methoxypyridin-3-yl)-1-methylpyridin-2(1H)-one (253 mg, 1.09 mmol), Palladium(II) acetate (24.51 mg, 0.11 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (63.2 mg, 0.11 mmol) and Sodium tert-pentoxide (144 mg, 1.31 mmol) were mixed in dioxane (3 mL) and run in a microwave reactor for 40 min at 120C. the mixture was filtered thru celite and concetrated. purified using flash column chromatography using 0-6 % MeOH (1% NH3) in DCM." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(C(=O)C=C4)C)OC)C5=CC=CC=C5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 35.11 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/13/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "528" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000145 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN(C)CCOC1=CN=C(C=C1)N" + } + amount { + moles { + value: 0.000966 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(N=CN=C1Cl)N2C=NC3=CC=CC=C32" + } + amount { + moles { + value: 0.000966 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000145 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 4.83e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (44.2 mg, 0.05 mmol) was added to 5-(2-(dimethylamino)ethoxy)pyridin-2-amine (175 mg, 0.97 mmol), 1-(6-chloro-5-methylpyrimidin-4-yl)-1H-benzo[d]imidazole (236 mg, 0.97 mmol), sodium t-butoxide (139 mg, 1.45 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (84 mg, 0.14 mmol) in toluene (10 mL) at 20C under nitrogen. The resulting suspension was stirred at 100 C for 16 hours then cooled to room temperature. LCMS analysis indicates no SM, product peak present. The reaction mixture was diluted with DCMMeOH, filtered and filtrate concentrated iin vacuoi. The residue was dissolved in DCM (100 mL) and washed with water (100 mL). The organic layer was passed through phase separating cartridge and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN Fractions containing the desired compound were evaporated to dryness to afford 6-(1H-benzo[d]imidazol-1-yl)-N-(5-(2-(dimethylamino)ethoxy)pyridin-2-yl)-5-methylpyrimidin-4-amine (67.0 mg, 17.82 %) as a yellow solid. nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(N=CN=C1N2C=NC3=CC=CC=C32)NC4=NC=C(C=C4)OCCN(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 17.82 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/06/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "530" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000216 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.00216 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CC(OC2=C(C1)C=CC(=N2)Cl)CC(F)(F)F" + } + amount { + moles { + value: 0.00216 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" + } + amount { + moles { + value: 0.000216 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" + } + amount { + moles { + value: 0.000108 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A reaction mixture of 8-chloro-4-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.605 g, 2.16 mmol), 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (0.440 g, 2.16 mmol), Cs2CO3 (1.053 g, 3.23 mmol), Tri-t-butylphosphonium tetrafluoroborate (0.063 g, 0.22 mmol) and Bis(dibenzylideneacetone)palladium (0.062 g, 0.11 mmol) in DME (20 mL) was flushed with argon and run in the microwave at 120C for 60 minutes. Have unreacted startingmaterial left. Added Tri-t-butylphosphonium tetrafluoroborate (0.063 g, 0.22 mmol) and Bis(dibenzylideneacetone)palladium (0.062 g, 0.11 mmol) and ran the vial at 120C for another hour. The mixture was filtered through celite and washed with DCM. The solvent was evaporated and the crude prouduct was purified by silica flash chromatography using a gradient of metanol (0 to 5%) in dichloromethane giving N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-(0.483 g, 50.0 %). " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CC(OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)CC(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 49.97 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/20/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "532" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 9.41e-06 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 9.41e-05 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CC(OC2=C(C1)C=CC(=N2)Cl)CC(F)(F)F" + } + amount { + moles { + value: 9.41e-05 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" + } + amount { + moles { + value: 9.41e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" + } + amount { + moles { + value: 4.7e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A reaction mixture of 8-chloro-4-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.044 g, 0.09 mmol), 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (0.019 g, 0.09 mmol), Cs2CO3 (0.046 g, 0.14 mmol), Tri-t-butylphosphonium tetrafluoroborate (2.73 mg, 9.41 mol) and Bis(dibenzylideneacetone)palladium (2.70 mg, 4.70 mol) in DME (2 mL) was flushed with argon and stirred at rt overnight. No product according to LCMS. The reaction mixture was then run in the microwave at 120C for 30 minutes. Have unreacted startingmaterial left. Ran the sample again at 120C for 30 minutes. Doesnt seemnbsp;as if the microwave warmed the vial. Added Tri-t-butylphosphonium tetrafluoroborate (2.73 mg, 9.41 mol) and Bis(dibenzylideneacetone)palladium (2.70 mg, 4.70 mol) and ran the vial at 120C for 1 hr. Reaction complete. The mixture was filtered through celite and washed with DCM. The solvent was evaporated and the crude prouduct was purified by g a gradient of metanol (0 to 5%) in dichloromethane giving N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (0.036 g, 85 %). " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CC(OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)CC(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 85.35 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/16/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "534" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000671 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CC(OC2=C(C1)C=CC(=N2)Cl)CC(F)(F)F" + } + amount { + moles { + value: 0.000671 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 6.71e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 6.71e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "8-chloro-4-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (60 % purity, 314 mg, 0.67 mmol), 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (137 mg, 0.67 mmol), PALLADIUM(II) ACETATE (15.07 mg, 0.07 mmol), 2-(DICYCLOHEXYLPHOSPHINO)BIPHENYL (23.53 mg, 0.07 mmol) and Cs2CO3 (328 mg, 1.01 mmol) were placed in a microwave vial. The vial was capped and flushed with argon. DME (3 mL) was added via a syringe and the resulting mixture was heated to 100C in a microwave apparatus for 2 h. The reaction mixture was diluted with dichloromethane, filtered and concentrated. The residue was purified first by column chromatography using Silica stationary phase and gradient elution with increasing concentration of methanol, from 0 to 8 %, in dichloromethane, and then by reversed phase HPLC to give N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (102 mg, 33.9 %)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CC(OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)CC(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 33.89 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/22/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "536" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00182 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.00121 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CC(OC2=C(C1)C=CC(=N2)Cl)CC(F)(F)F" + } + amount { + moles { + value: 0.00121 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 0.000121 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000121 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A reaction mixture of 8-chloro-4-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.341 g, 1.21 mmol), 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (0.248 g, 1.21 mmol),nbsp;PALLADIUM(II) ACETATE (0.027 g, 0.12 mmol), 2-(DICYCLOHEXYLPHOSPHINO)BIPHENYL (0.043 g, 0.12 mmol) and Cs2CO3 (0.594 g, 1.82 mmol) in DME (2 mL) was degassed and flushed with argon in a microwave vial. The reaction mixture was stirred at 110C for 1 hr. The reaction mixture was filtrated through celite, washed with DCM and concentrated. The crude product was purified by silica flash chromatography using a gradient of methanol (0 to 5%) in DCM giving N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (0.200 g, 36.7 %)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CC(OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)CC(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 36.71 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/18/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "538" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000629 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.00042 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1C(OC2=C(CN1C)C=CC(=N2)Cl)C3=NC(=CS3)C" + } + amount { + moles { + value: 0.00042 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 4.2e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.2e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (0.086 g, 0.42 mmol) in DME (3 mL) were 8-chloro-3,4-dimethyl-2-(4-methylthiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.130 g, 0.42 mmol), cesium carbonate (0.205 g, 0.63 mmol), 2-(Dicyclohexylphosphino)biphenyl (0.015 g, 0.04 mmol) and Palladium acetate (9.42 mg, 0.04 mmol) added. The reaction was heated to 110C for 60 min under argon atmosphere. The reaction mixture was filtered through celite, washed with DCM and the solvents were evaporated. The crude product was purified by silica flash chromatography, MeOH, 0-5%, in DCM yielding N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-3,4-dimethyl-2-(4-methylthiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (0.147 g, 73.4 %). The product was mitted to the prepgroup for chiral separation. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1C(OC2=C(CN1C)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=NC(=CS5)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 73.35 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/01/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "539" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 2.87e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.00333 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" + } + amount { + moles { + value: 0.000338 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)Br)F" + } + amount { + moles { + value: 0.000422 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 2.87e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.48e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (3.33 mg, 0.01 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (121 mg, 0.34 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (16.61 mg, 0.03 mmol), 1-bromo-3-fluorobenzene (0.047 ml, 0.42 mmol) and cesium carbonate (165 mg, 0.51 mmol) suspended in 1,4-dioxane (3.329 ml). The resulting suspension was degased with argon and then stirred at 100 C for 20 hours i(iiUPLCMS ON showed that the SM was almost consumed). iThe reaction mixture was allowed to cool to room temperature, the crude product was adsorbed on silica gelnbsp;and purified by flash chromatography on silica gel eluting with 0 to 7% Propanol-CH2Cl2. The solvent was evaporated to dryness to afford methyl 8-(1-(3-fluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (120 mg, 79 %) as anbsp;yellow oil which solidified on standing." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC=C4)F)OC(=CC2=O)N5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 78.55 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/28/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "540" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000358 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.00894 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=C(C(=C1)Cl)C(=O)OC)Br" + } + amount { + moles { + value: 0.00894 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000358 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000179 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;Palladium(II) acetate (0.040 g, 0.18 mmol), methyl 2-chloro-4-methoxy-5-morpholinobenzoate (2.042 g, 80 %), cesium carbonate (4.08 g, 12.52 mmol) and racemic 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.223 g, 0.36 mmol) were mixed together in a round bottom flask and evacuated then purged with nitrogen. Morpholine (0.780 mL, 8.94 mmol) and degassed toluene (15 mL) were added and the resulting suspension (orangered) was degassed and purged with nitrogen 3 times. The mixture was heated to 100 C under nitrogen overnight. The mixture was allowed to cool to ambient temperature and filtered, washing with EtOAc. The filtrate was concentrated and the crude residue (a dark orange gum) wasnbsp;purified by flash silica chromatography, elution gradient 0 to 40% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-chloro-4-methoxy-5-morpholinobenzoate (2.042 g, 80 %) as a pale yellowcream crystalline solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=C(C=C(C(=C1)Cl)C(=O)OC)N2CCOCC2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 79.91 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/01/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "541" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000213 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.00532 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=C(C(=C1)Cl)C(=O)OC)Br" + } + amount { + moles { + value: 0.00532 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000213 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000106 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;Methyl 5-bromo-2-chloro-4-methoxybenzoate (1.486 g, 5.32 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.132 g, 0.21 mmol), palladium(II) acetate (0.024 g, 0.11 mmol) and cesium carbonate (2.425 g, 7.44 mmol) were mixed together and evacuated then purged with nitrogen. Toluene (10 mL) and morpholine (0.464 mL, 5.32 mmol) were added and the mixture evacuated and purged with nitrogen several times. The suspension (red) was heated to 100 C for 18 hours under nitrogen. The mixture was allowed to cool to ambient temperature and filtered, washing with EtOAc. The filtrate was concentrated to provide an orange residue. The crude product was purified by flash silica chromatography, elution gradient 0 to 35% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-chloro-4-methoxy-5-morpholinobenzoate (0.826 g, 54.4 %) as a cream crystalline solid. Lower than expected yield (previously recorded 80% EN04398-06).....not sure what has happened." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=C(C=C(C(=C1)Cl)C(=O)OC)N2CCOCC2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 54.38 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/21/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "542" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000332 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.03 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.00829 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=C(C(=C1)Cl)C(=O)OC)Br" + } + amount { + moles { + value: 0.00829 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000332 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000166 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;Cesium carbonate (3.78 g, 11.61 mmol), methyl 5-bromo-2-chloro-4-methoxybenzoate (2.317 g, 8.29 mmol), palladium(II) acetate (0.037 g, 0.17 mmol) and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.206 g, 0.33 mmol) were combined and evacuated and purged with nitrogen (3 times).Degassed toluene (30 mL) and morpholine (0.723 mL, 8.29 mmol) was added and the resulting suspension was evacuated and purged with nitrogen several times. The reaction mixture was heated to 100 C under nitrogen for 22 hours. The reaction was allowed to cool to ambient temperature and filtered through a celite pad, washing with EtOAc. The filtrate was concentrated and the crude product purified by flash silica chromatography, elution gradient 10 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-chloro-4-methoxy-5-morpholinobenzoate (1.865 g, 79 %) as a cream crystalline solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=C(C=C(C(=C1)Cl)C(=O)OC)N2CCOCC2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 78.74 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/20/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "543" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000175 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC2=C(C=NN2C=C1)C3=NC(=NC=C3Cl)N" + } + amount { + moles { + value: 0.000125 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)[N+](=O)[O-])Br" + } + amount { + moles { + value: 0.000125 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 1e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 7.5e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "iCrude SM used i2-bromo-1-methoxy-4-nitrobenzene (0.029 g, 0.13 mmol), 5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (0.031 g, 0.125 mmol) and cesium carbonate (0.057 g, 0.18 mmol) were suspended in dry dioxane (2 mL) the mixture degassed with nitrogen for 10 minutes. TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (6.87 mg, 7.50 mol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (5.79 mg, 10.00 mol) were added and the mixture was sealed into a microwave tube. The reaction was heated to 150 C for 2 hours in the microwave reactor and cooled to RT. Possibly product - not very much. The reaction was heated to 150 C for 10 hours in the microwave reactor and cooled to RT. Product now c4%, both starting materials still present.No" + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)[N+](=O)[O-])NC2=NC=C(C(=N2)C3=C4C=CC=CN4N=C3)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/07/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "544" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000175 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC2=C(C=NN2C=C1)C3=NC(=NC=C3Cl)N" + } + amount { + moles { + value: 0.000125 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)[N+](=O)[O-])Br" + } + amount { + moles { + value: 0.000125 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 3.75e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "iCrude SM used i2-bromo-1-methoxy-4-nitrobenzene (0.029 g, 0.13 mmol), 5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (0.031 g, 0.125 mmol) and cesium carbonate (0.057 g, 0.18 mmol) were suspended in dry dioxane (2 mL) the mixture degassed with nitrogen for 10 minutes. TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.034 g, 0.04 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.029 g, 0.05 mmol) were added and the mixture was sealed into a microwave tube. The reaction was heated to 150 C for 2 hours in the microwave reactor and cooled to RT. Possibly product - not very much. The reaction was heated to 150 C for 10 hours in the microwave reactor and cooled to RT. Product now c4%, both starting materials still present.Not contin" + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)[N+](=O)[O-])NC2=NC=C(C(=N2)C3=C4C=CC=CN4N=C3)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/22/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "546" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 4.05e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1C[C@@H](C2=NC(=NN2C1)N)C3=CC=C(C=C3)F" + } + amount { + moles { + value: 0.000405 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C(=O)CC1=CC=C(C=C1)Br" + } + amount { + moles { + value: 0.000405 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 4.05e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.05e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "8-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine (94 mg, 0.40 mmol), 2-(4-bromophenyl)-N,N-dimethylacetamide (103 mg, 0.40 mmol), Cesium carbonate (198 mg, 0.61 mmol), Palladium(II) acetate (9.09 mg, 0.04 mmol) and 2-(Dicyclohexylphosphino)biphenyl (14.18 mg, 0.04 mmol) were added to a 0.5-2 mL microwave vial. The vial was capped and flushed with nitrogen. dioxane (3 mL) was added and the vial was flushed with additional nitrogen before it was heated by microwave irradiation at 120C for 1.5h. The reaction mixture was cooled to r.t. and water and EtOAc were added and the layers were separated. The aqueous phase was extracted with EtOAc (3x). The combined organic phases were washed with brine, dried (phase separator) and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography using a gradient of 0-3% MeOH in EtOAc over 12 min. The desired fractions were combined to result in 2-(4-(8-(4-fluorophenyl)-5,6,7,8-teydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)phenyl)-N,N-dimethylacetamide (51.0 mg, 32.0 %)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(C)C(=O)CC1=CC=C(C=C1)NC2=NN3CCCC(C3=N2)C4=CC=C(C=C4)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 32.03 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/14/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "551" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00072 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000554 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CC(OC2=C(C1)C=CC(=N2)Cl)C3CC(C3)(F)F" + } + amount { + moles { + value: 0.000554 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000166 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 8.31e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 145.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium(II) acetate (0.019 g, 0.08 mmol) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.096 g, 0.17 mmol) were added to a degassed solution of 8-chloro-2-(3,3-difluorocyclobutyl)-4-methyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.160 g, 0.55 mmol), 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (0.113 g, 0.55 mmol) and Cesium carbonate (0.058 mL, 0.72 mmol) in dry dioxane (15 mL). The reaction was heated in a microwave oven at 145C for 1h. About 50% of product. The reaction was heated at 145C for another 30 min. About 45% of product. The reaction was interrupted and the reaction mixture was pooled with the corresponding mixture in EN04426-52. The reaction mixture was filtered through a plug of celite. The celite was washed with DCM. The solvents were evaporated and the crude was purified by ISCO on a 25 g column with an increased gradient of DCMMeOH (9010) 0-50% in DCM) to give 0.176 g (35%) of the product. The enatiomers were also separated (see EN04426-" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CC(OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5CC(C5)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 69.57 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "12/01/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "552" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[K+].[K+]" + } + amount { + moles { + value: 0.0405 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.1 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=NC(=C1)Cl)Cl" + } + amount { + moles { + value: 0.0135 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C=C1Cl)N)C#N" + } + amount { + moles { + value: 0.0135 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.0027 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00135 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 112.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of 2,6-dichloropyridine (2 g, 13.51 mmol), 2-amino-4-chlorobenzonitrile (2.062 g, 13.51 mmol), PALLADIUM(II) ACETATE (0.303 g, 1.35 mmol), BINAP (1.683 g, 2.70 mmol) and potassium carbonate (5.60 g, 40.54 mmol) in toluene (100 mL) was stirred at reflux under N2 for 5hrs. LCMS detected major peak as desire product. The resulting suspension was cooled, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography of the residue on silica gel using 15% to 20% ethyl acetate in hexane, then 100% ethyl acetate as eluent gave the crude product which was recrystallized from methanolDCM to yield a light yellow solid as desired product 4-chloro-2-(6-chloropyridin-2-ylamino)benzonitrile (3.34 g, 93 %)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC(=NC(=C1)Cl)NC2=C(C=CC(=C2)Cl)C#N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 93.49 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/18/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "553" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0191 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=CC(=N1)S(=O)(=O)C)N" + } + amount { + moles { + value: 0.0127 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC(=O)N1CCC(CC1)OC2=C(C(=NC=N2)Cl)OC" + } + amount { + moles { + value: 0.0127 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3OC4=CC=CC=C4P(C5=CC=CC=C5)C6=CC=CC=C6" + } + amount { + moles { + value: 0.000508 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000254 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 60.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Bis[(2-diphenylphosphino)phenyl] ether (0.274 g, 0.51 mmol) was added in one portion to Palladium(II) acetate (0.057 g, 0.25 mmol) in toluene (5 mL) (degassed by bubbling N2 through it for 30 minutes) at 20C under nitrogen (this mixture was also degassed by vacuum N2 six times). After a few minutes a yellow suspension had formed. This was added by pipette to a mixture of isopropyl 4-(6-chloro-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate (4.19 g, 12.71 mmol),nbsp;2-methyl-6-(methylsulfonyl)pyridin-3-amine (2.366 g, 12.71 mmol) and Sodium tert-butoxide (2.333 mL, 19.06 mmol) in toluene (40 mL) at 60C under nitrogen. The resulting mixture was degassed using N2 vacuum six times. The resulting suspension was stirred at 60 C for 18 hours. Sodium tert-butoxide (2.333 mL, 19.06 mmol) was added to the reaction mixture followed by another amount of pre-formed catalyst using Bis[(2-diphenylphosphino)phenyl] ether (0.274 g, 0.51 mmol) was added in one portion to Palladium(II) acetate (0.0mol) in toluene (5 mL) as above. The mixture was heated at 60C for 7 hours then further catalyst added using Bis[(2-diphenylphosphino)phenyl] ether (0.274 g, 0.51 mmol) was added in one portion to Palladium(II) acetate (0.057 g, 0.25 mmol) in toluene (5 mL) as above. The mixture was stirred at 60C for 18 hours. Work up was by diluting with water (30 ml) and DCM (100 ml) then filtering through a pad of celite and washing through well with DCM (6 x 50 ml). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography (330g column), elution gradient 0 to 100% EtOAc in heptane (material applied in DCM). Pure fractions were evaporated to dryness to leave a yellow solid, EN05005-04-01. The solid was triturated with Et2O (20 ml) and the solid filtered off and washed with Et2O (2 x 10ml) then heptane ( 2 x 10ml) to afford isopropyl 4-(5-methoxy-6-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)pyrimidin-4-yloxy)piperidrboxylate (4.78 g, 78 %), EN05005-04-02, as a white solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=CC(=N1)S(=O)(=O)C)NC2=C(C(=NC=N2)OC3CCN(CC3)C(=O)OC(C)C)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 78.45 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/03/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "554" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00145 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.001 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=CC(=N1)S(=O)(=O)C)N" + } + amount { + moles { + value: 0.000964 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC(=O)N1CCC(CC1)OC2=C(C(=NC=N2)Cl)OC" + } + amount { + moles { + value: 0.000964 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3OC4=CC=CC=C4P(C5=CC=CC=C5)C6=CC=CC=C6" + } + amount { + moles { + value: 3.86e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.93e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 60.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Bis[(2-diphenylphosphino)phenyl] ether (0.021 g, 0.04 mmol) was added in one portion to Palladium(II) acetate (4.33 mg, 0.02 mmol) in toluene (1 mL) (degassed by bubbling N2 through it for 30 minutes) at 20C under nitrogen. After a few minutes a yellow suspension had formed. This added in one portion by pipette to a mixture of isopropyl 4-(6-chloro-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate (0.318 g, 0.96 mmol),nbsp;2-methyl-6-(methylsulfonyl)pyridin-3-amine (0.180 g, 0.96 mmol) and Sodium tert-butoxide (0.177 mL, 1.45 mmol) in toluene (3 mL) at 60C under nitrogen. The resulting mixture was degassed using N2 vacuum six times. The resulting suspension was stirred at 60 C for 18 hours. Work up was by diluting with water (10 ml) and DCM (10 ml) then filtering through a pad of celite and washing through well with DCM (6 x 10 ml). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography ( elution gradient 0 to 100% EtOAc in heptane (material applied in DCM). Pure fractions were evaporated to dryness to afford isopropyl 4-(5-methoxy-6-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)pyrimidin-4-yloxy)piperidine-1-carboxylate (0.231 g, 50.0 %) as a slightly off white foam. Trituration with Et2O (10 ml) and sctratching gave a free flowing white suspension. The solvent was removed under reduced pressure to give a white powder." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=CC(=N1)S(=O)(=O)C)NC2=C(C(=NC=N2)OC3CCN(CC3)C(=O)OC(C)C)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 49.95 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/17/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "556" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00202 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CN" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 0.00012 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 8.08e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "palladium(II) acetate (0.018 g, 0.08 mmol), (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (0.066 g, 0.12 mmol), sodium tert-butoxide (0.194 g, 2.02 mmol), phenylmethanamine (0.110 mL, 1.01 mmol) and 2,4-dichloropyridine (0.151 mL, 1.01 mmol) were suspended in DME (4 mL) and sealed into a microwave tube. The reaction was heated to 80 C for 30 minutes in the microwave reactor and cooled to RT. nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CNC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/18/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "557" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00203 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CN" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000122 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000101 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;phenylmethanamine (0.111 mL, 1.01 mmol), 2,4-dichloropyridine (0.151 mL, 1.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (70.4 mg, 0.12 mmol) and cesium carbonate (660 mg, 2.03 mmol) were stirred in 1,4-dioxane (5 mL).nbsp;The mixture was purged with nitrogen for 10 minutes.nbsp;Palladium(II) acetate (22.76 mg, 0.10 mmol) was added and sealed into a microwave tube. The reaction was heated to 100 C for 1 hour in the microwave reactor and cooled to RT. The reaction was heated to 100 C for 1 hour in the microwave reactor and cooled to " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CNC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/12/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "558" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00202 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)CN" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 0.00012 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 8.08e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;palladium(II) acetate (0.018 g, 0.08 mmol), (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (0.066 g, 0.12 mmol), sodium tert-butoxide (0.194 g, 2.02 mmol), 2-methylpropan-1-amine (0.100 mL, 1.01 mmol) and 2,4-dichloropyridine (0.151 mL, 1.01 mmol) were suspended in DME (4 mL) and sealed into a microwave tube. The reaction was heated to 80 C for 30 minutes in the microwave reactor and cooled to RT. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)CNC1=NC=CC(=C1)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/17/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "560" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 7.16e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.001 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC2=C(N1)C=C(C=C2)OC(F)(F)F" + } + amount { + moles { + value: 5.11e-05 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)COC2=CC(=CC=C2)Br" + } + amount { + moles { + value: 7.87e-05 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C1=CC=CC=C1C2=CC=CC=C2)C(C)(C)C" + } + amount { + moles { + value: 1.53e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.02e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "EN04773-53, iBuchwald coupling, toluene and bromideiThe indole from 4773-25, 1-(benzyloxy)-3-bromobenzene,Pd2(dba)3, JohnPhos and KOtBu were dissolved in toluene. The mixture was warmed at 100 C for 2h. Ca 60% conversion according to LCMS (product at 2.31 min). This conversion rate seemed faster than for the corresponding aryliodide. Big bacth was performed in 4773-54." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CC2=C(N1C3=CC(=CC=C3)OCC4=CC=CC=C4)C=C(C=C2)OC(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 59.07 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/01/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "561" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0338 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.2 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC2=C(N1)C=C(C=C2)OC(F)(F)F" + } + amount { + moles { + value: 0.0242 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)COC2=CC(=CC=C2)Br" + } + amount { + moles { + value: 0.029 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C1=CC=CC=C1C2=CC=CC=C2)C(C)(C)C" + } + amount { + moles { + value: 0.00242 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.00121 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "EN04773-54, iBuchwald coupling, toluene and bromideiThe indole from 4773-41, 1-(benzyloxy)-3-bromobenzene,Pd2(dba)3 (5mol%), JohnPhos (10mol%) and KOtBu (1.4eq) were dissolved in toluene. The mixture was warmed at 80 C for 40 hours.* The reaction was carefully monitored and analysis data from 2h, 4, 16 and 40 h are attached. According to LCMS there were ca 75% conversion to the product. The mixture was washed with water, concentrtaed and purified by silica column (HepEtOAc 6:1). The collected fractions contained product (6 g, 62.5% yield) but had some impurity (see TLC and NMR). Nevertheless Friedel crafts acylation was performed without further purifications. See e.g. 4773-56.###*JohnPhos, pd2(dba)3 and sodium tertbutoxide had been dissolved in toluene and was portionwise added to the reaction mixture during the first 16h. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CC2=C(N1C3=CC(=CC=C3)OCC4=CC=CC=C4)C=C(C=C2)OC(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 62.48 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/02/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "562" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000298 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNC1" + } + amount { + moles { + value: 0.0149 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1C#N)Br" + } + amount { + moles { + value: 0.00744 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000298 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000223 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "4-bromobenzonitrile (1.355 g, 7.44 mmol) and Sodium tert-butoxide (1.073 g, 11.17 mmol)nbsp;were mixed in toluene (10 mL) and degassed by passing nitrogen for 5 min. Thennbsp;Azetidine (1 mL, 14.89 mmol),nbsp;9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (0.172 g, 0.30 mmol) and Palladium(II) acetate (0.050 g, 0.22 mmol)were added and thenbsp;mixture was heated innbsp;oilbath at 100C for 15h. The reaction was complete by GCMS. Filtration through celite washing with CH2Cl2 and evaporation gave a crude product (1g).nbsp;Purification by chromatography on silica (0-50 % EtOAc in heptane) gave the desired product 4-(azetidin-1-yl)benzonitrile (0.730 g, 62.0 %)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CN(C1)C2=CC=C(C=C2)C#N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 61.99 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/02/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "564" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00872 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.027 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00581 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=CC=N1)Br" + } + amount { + moles { + value: 0.00581 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 0.000581 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000291 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium acetate (65 mg, 0.29 mmol) and RuPhos (271mg, 0.58mmol) were dissolved in toluene (10 mL), degassed and purged with nitrogen and warmed to 50C for 15 minutes. In a separate vessel, were mixed 3-bromo-2-methyl pyridine (1.00g, 5.81 mmol), BOC-piperazine (1.08g, 5.81mmol), sodium tertbutoxide and toluene (17 mL). The mixture was degassed, purged with nitrogen and warmed to 50C.The catalyst was transferred to the reaction vessel and the mixture degassed and purged with nitrogen. The reaction was heated at 100C overnight under nitrogen.The mixture was filtered through GFF paper, washing with MeOH. The filtrate was concentrated to provide a dark brown gum.The gum was purified by flash silica chromatography, elution gradient 30 to 80% EtOAc in heptane. Pure fractions were evaporated to provide the desired product as a gum (1.492g, 93%).Rf (1:1 EtOAchept" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=CC=N1)N2CCN(CC2)C(=O)OC(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 92.54 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/19/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "565" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0174 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.04 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.0116 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=CC=N1)Br" + } + amount { + moles { + value: 0.0116 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 0.00116 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000581 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "RuPhos (0.543 g, 1.16 mmol) and palladium (II) acetate (0.131 g, 0.58 mmol) were suspended in toluene (15 mL) at ambient temperature. The resulting mixture was degassed and purged several times and warmed to 50C under nitrogen for 20 mins.In a separate vessel were mixed 3-bromo-2-methylpyridine (2 g, 11.63 mmol), tert-butyl 4-(2-methylpyridin-3-yl)piperazine-1-carboxylate (2.67 g, 83 %), sodium tertbutoxide (1.676 g, 17.44 mmol) and toluene. The mixture was degassed and purged with nitrogen several times and warmed to 50C. The catalyst solution was added to the reaction vessel and the resulting mixture degassed and purged wtih nitrogen. The reaction was heated at 100C overnight.The reaction mixture was allowed to cool to ambient temperature and filtered through GFF paper, washing with MeOH. The filtrate was concentrated to provide the crude material. This was purified by flash silica chromatography, elution gradient 20 to 70% EtOAc in heptane. Pure fractions were o dryness to afford tert-butyl 4-(2-methylpyridin-3-yl)piperazine-1-carboxylate (2.67 g, 83 %) as a pale yellow oil.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=CC=N1)N2CCN(CC2)C(=O)OC(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 82.86 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/16/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "566" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00015 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.001 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC2=C(N1)C=C(C=C2)OC(F)(F)F" + } + amount { + moles { + value: 0.000107 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC(=CC=C1)Br" + } + amount { + moles { + value: 0.000128 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C1=CC=CC=C1C2=CC=CC=C2)C(C)(C)C" + } + amount { + moles { + value: 2.41e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 8.02e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "EN04773-51, iBuchwald coupling,ibi J. Med. Chem. 2009, page 3846-3854 (exactly same reaction).ibThe indole from 4773-41, 1-bromo-3-methoxybenzenee,Pd2(dba)3, JohnPhos and KOtBu were dissolved in toluene. The mixture was warmed at 120 C for 1h and ~65% conversion was observed on NMR*(see attached NMR). Reaction seems to work fine and assumed better yield than in 4773-50. This could be due to that bromides generally perform better than iodines in the Buchwald coupling. This test reaction was thrown away.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CC2=C(N1C3=CC(=CC=C3)OC)C=C(C=C2)OC(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 65.49 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/23/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "567" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0424 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.3 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@@H]1CNC[C@@H](N1)C" + } + amount { + moles { + value: 0.0424 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1Br)I" + } + amount { + moles { + value: 0.0283 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00566 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00283 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "sodium 2-methylpropan-2-olate (4.08 g, 42.42 mmol) was added to (2R,6S)-2,6-dimethylpiperazine (4.84 g, 42.42 mmol) in dioxane (300 mL) at 21Cnbsp;under nitrogen. Stirred for 5 mins. 1-bromo-4-iodobenzene (8 g, 28.28 mmol) added, followed by diacetoxypalladium (0.635 g, 2.83 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (3.27 g, 5.66 mmol). Reaction evacuated and refilled with nitrogen several times. Heated at 90C for 18hours.nbsp;Diluted with ethyl acetate and filtered through celite. The organic layer was washed with water ( 500ml) and then dried over Na2SO4, filterednbsp;and reduced in volume. Filtered - lcms messy. Dissolved in DCM and combined with the filtrate - adsorbed onto silica.The crude product was purified by flash silica chromatography, elution gradient 0 to 30% MeOH in EtOAc. Pure fractions were evaporated to dryness to afford (3S,5R)-1-(4-bromophenyl)-3,5-dimethylpiperazine (4.69 g, 61.6 %) as a yellow solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@@H]1CN(C[C@@H](N1)C)C2=CC=C(C=C2)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 61.61 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/25/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "568" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0053 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.04 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@@H]1CNC[C@@H](N1)C" + } + amount { + moles { + value: 0.0053 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1Br)I" + } + amount { + moles { + value: 0.00353 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000707 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000353 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "sodium 2-methylpropan-2-olate (0.510 g, 5.30 mmol) was added to (2R,6S)-2,6-dimethylpiperazine (0.605 g, 5.30 mmol) in dioxane (40 mL) at 21Cnbsp;under nitrogen. Stirred for 5 mins. 1-bromo-4-iodobenzene (1 g, 3.53 mmol) added, followed by diacetoxypalladium (0.079 g, 0.35 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.409 g, 0.71 mmol). Reaction evacuated and refilled with nitrogen several times. Heated at 90C for 18hours. left to cool ow.The reaction mixture was diluted with EtOAc (250 mL), and washed sequentially with water (150 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% MeOH in EtOAc. Pure fractions were evaporated to dryness to afford (3S,5R)-1-(4-bromophenyl)-3,5-dimethylpiperazine (0.420 g, 44.1 %) as a yellow solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@@H]1CN(C[C@@H](N1)C)C2=CC=C(C=C2)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 44.14 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/22/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "569" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00201 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" + } + amount { + moles { + value: 0.00187 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C(=C1)F)C2=CC=C(C=C2)Br)F" + } + amount { + moles { + value: 0.00134 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.000134 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000134 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "PdOAc2 (0.030 g, 0.13 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.064 g, 0.13 mmol) were added in one portion tonbsp;a degassed solution of 4\'-bromo-2,6-difluorobiphenyl (0.36 g, 1.34 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (0.355 g, 1.87 mmol) and cesium carbonate (0.654 g, 2.01 mmol) in toluene (10 mL) at 20Cnbsp;under nitrogen. The resulting suspension was stirred at 120 C for 50 hours.The reaction mixture was diluted with EtOAc (150 mL)nbsp;and water (150 mL) and the biphasic mixture was filtered through celite. The organic layer was separated and washed sequentially with water (150 mL) and saturated brine (150 mL). The organic layer was evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-N-(2-(tert-butyldimethylsilyloxy)propyl)-2\',6\'-difluorobiphenyl-4-amine (0.300 g, 59.4 %) as a yellow so" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@H](CNC1=CC=C(C=C1)C2=C(C=CC=C2F)F)O[Si](C)(C)C(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 59.39 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/13/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "570" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00019 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.022 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" + } + amount { + moles { + value: 0.00223 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=C(C=C1F)Br)F" + } + amount { + moles { + value: 0.00279 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00019 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 8.93e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (0.020 g, 0.09 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (0.8g, 2.23 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.110 g, 0.19 mmol), 1-bromo-3,5-difluorobenzene (0.321 ml, 2.79 mmol) and cesium carbonate (1.091 g, 3.35 mmol) suspended in 1,4-dioxane (22.00 ml). The resulting suspension was degased with argon and then stirred at 100 C for 20 hours. imaybe not complete but have to go forwardiThe reaction mixture was allowed to cool to room temperature, the insoluble were removed by filtration and the filtrate concentrated.The crude product was adsorbed on silica gelnbsp;and purified by flash chromatography on silica gel eluting with 0 to 6% methanol in ethyl acetate. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (0.760 g, 66.2 %) as anbsp;beige foam." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 66.17 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/18/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "571" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 2.96e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" + } + amount { + moles { + value: 0.000349 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=C(C=C1F)Br)F" + } + amount { + moles { + value: 0.000384 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 2.96e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.4e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (3.13 mg, 0.01 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (125 mg, 0.35 mmol), 1-bromo-3,5-difluorobenzene (0.044 ml, 0.38 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (17.15 mg, 0.03 mmol) and cesium carbonate (170 mg, 0.52 mmol) dissolved in 1,4-dioxane (2 ml). The resulting suspension was degased with argon and then stirred at 100 C for 10 hours.The reaction mixture was allowed to cool to room temperature. The reaction mixture was quenched with water and extracted with dichloromethane (2 x 10 ml). The combined organic phases were dried over magnesium sulfate and concentrated to afford the crude product as a orangeyellow oil.The crude product was purified by flash chromatography on silica gel eluting with 0 to 10% methanol in dichloromethane. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carbote (118 mg, 71.9 %) as a yellow gum." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 71.91 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/28/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "572" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000315 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.036 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" + } + amount { + moles { + value: 0.0037 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=C(C=C1F)Br)F" + } + amount { + moles { + value: 0.00463 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000315 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000148 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (0.033 g, 0.15 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (1.326 g, 3.7 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.182 g, 0.31 mmol), 1-bromo-3,5-difluorobenzene (0.533 ml, 4.63 mmol) and cesium carbonate (1.808 g, 5.55 mmol) suspended in 1,4-dioxane (36 ml). The resulting suspension was degased with argon and then stirred at 100 C over the WE (66hours).Albeit Lcms showed ~ 7% SM remaining, the reaction was stopped. The reaction mixture was allowed to cool to room temperature, the insolubles were removed by filtration and the filtrate concentrated. The crude product was adsorbed on silica gelnbsp;and purified by flash chromatography on silica gel eluting with 2 to 5% methanol in ethyl acetate. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (1.172 g, 67.3 %) as anbsp;beige foam." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 67.33 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/01/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "573" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 5.58e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.008 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" + } + amount { + moles { + value: 0.000558 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=C(C=C1F)Br)F" + } + amount { + moles { + value: 0.000698 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 5.58e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.79e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (6.26 mg, 0.03 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (200 mg, 0.56 mmol), 1-bromo-3,5-difluorobenzene (0.080 ml, 0.70 mmol) and cesium carbonate (273 mg, 0.84 mmol) dissolved in 1,4-dioxane (8 ml). The resulting suspension was degased with argon and then stirred at 100 C (15:00) for 18 hours.The reaction mixture was allowed to cool to room temperature, filtered and concentrated.The crude product was adsorbed on silica gelnbsp;and purified by flash chromatography on silica gel eluting with 0 to 6% methanol in ethyl acetate. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (137 mg, 52.2 %) as a clear yellow foam.LCMS and NMR are OK." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 52.18 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/12/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "574" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 5.58e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.008 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" + } + amount { + moles { + value: 0.000558 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=C(C=C1F)Br)F" + } + amount { + moles { + value: 0.000698 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 5.58e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.79e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (6.26 mg, 0.03 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (200 mg, 0.56 mmol), 1-bromo-3,5-difluorobenzene (0.080 ml, 0.70 mmol) and cesium carbonate (273 mg, 0.84 mmol) dissolved in 1,4-dioxane (8 ml). The resulting suspension was degased with argon and then stirred at 100 C (18:00) for 15 hours.The reaction mixture was allowed to cool to room temperature, filtered and concentrated.The crude product was adsorbed on silica gelnbsp;and purified by flash chromatography on silica gel eluting with 0 to 6% methanol in ethyl acetate. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (173 mg, 65.9 %) as a clear yellow foam.LCMS and NMR are OK." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 65.89 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/12/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "575" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000251 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0161 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" + } + amount { + moles { + value: 0.00251 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=C(C=C1F)Br)F" + } + amount { + moles { + value: 0.00314 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000251 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000126 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (0.028 g, 0.13 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (0.9 g, 2.51 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.145 g, 0.25 mmol), 1-bromo-3,5-difluorobenzene (0.361 ml, 3.14 mmol) and cesium carbonate (1.227 g, 3.77 mmol) suspended in 1,4-dioxane (16.05 ml). The resulting suspension was degased with argon and then stirred at 100 C (18:00) for 15 hours.The reaction mixture was allowed to cool to room temperature, concentrated in presence of silica gel and purified by flash chromatography on silica gel eluting with 0 to 10% methanol in ethyl acetate. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (0.792 g, 67.0 %) as an yellow foam." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 67.04 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/04/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "576" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0586 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.25 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" + } + amount { + moles { + value: 0.0391 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=C(C=C1F)Br)F" + } + amount { + moles { + value: 0.0488 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00391 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00195 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (0.439 g, 1.95 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (14 g, 39.06 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.260 g, 3.91 mmol), 1-bromo-3,5-difluorobenzene (5.62 ml, 48.83 mmol) and cesium carbonate (19.09 g, 58.60 mmol) suspended in 1,4-dioxane (250 ml). The resulting suspension was degased with argon and then stirred at 100 C for 16 hours.The reaction mixture was allowed to cool to room temperature, concentrated in presence of silica gel and purified by Chromatography on silica gelnbsp;(Novasep)nbsp;eluting with 0 to 10% methanol in ethyl acetate. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (10.30 g, 56.0 %) as an yellow foam." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 56.04 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/07/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "577" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000195 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0009 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC2=C(N1)C=C(C=C2)OC(F)(F)F" + } + amount { + moles { + value: 0.000139 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)COC2=CC(=CC=C2)I" + } + amount { + moles { + value: 0.000167 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C1=CC=CC=C1C2=CC=CC=C2)C(C)(C)C" + } + amount { + moles { + value: 3.14e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.05e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "EN04773-50, iBuchwald coupling,ibi J. Med. Chem. 2009, page 3846-3854 (changed: solvent to dioxane and bromide to iodide).ibThe indole from 4773-41, 1-(benzyloxy)-3-iodobenzene, Pd2(dba)3, JohnPhos and KOtBu were dissolved in toluene. The mixture was warmed at 120 C for 1hand ~40% conversion was observed on NMR. The reaction mixture was further heated at 80 C for 16h and 40 h, see attached 1H-NMR for reaction progress. A comparison with 4773-51 shows that using dioxane or iodide gives a lower yield (slower reaction). Switching the solvent to toluene was explored in 4773-52. The reaction in this experiment showed that the Buchwald conditions worked. Reaction mixture was thrown aw" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CC2=C(N1C3=CC(=CC=C3)OCC4=CC=CC=C4)C=C(C=C2)OC(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 40.17 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/23/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "578" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000651 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC2=C(N1)C=C(C=C2)OC(F)(F)F" + } + amount { + moles { + value: 0.000465 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)COC2=CC(=CC=C2)I" + } + amount { + moles { + value: 0.000558 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C1=CC=CC=C1C2=CC=CC=C2)C(C)(C)C" + } + amount { + moles { + value: 0.000167 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 5.58e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "EN04773-52, iBuchwald coupling, toluene and iodideiThe indole from 4773-25, 1-(benzyloxy)-3-iodobenzene,Pd2(dba)3, JohnPhos and KOtBu were dissolved in toluene. The mixture was warmed at 120 C for 1h and 50% conversion was observed on NMR*(see attached NMR). The mixture was warmed further 15h at 120C, still starting material left but the reaction mixture was directly applied to a silica column (heptane 3:1). Product was collected in fraction 22-23 (see attached NMR). Only 19.3 mg (10.45% yield) could be collected but NMR showed correct product. Test reaction with bromide was performed in 4773-53.#########################*Small amount from reaction mixture was dissolved in CDCl3 and 1HNMR analysis was perfor" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CC2=C(N1C3=CC(=CC=C3)OCC4=CC=CC=C4)C=C(C=C2)OC(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 10.45 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/25/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "579" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00602 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0075 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2" + } + amount { + moles { + value: 0.00301 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=NC=C1Br)C(F)(F)F" + } + amount { + moles { + value: 0.0015 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000361 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.00015 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 50 ml round bottom equipped with stir bar was charged with BINAP (225 mg, 0.36 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (138 mg, 0.15 mmol) dissolved in 1,4-dioxane (7.500 mL).nbsp;This was degassed and purged with nitrogen and stirred at RT for 10 mins.nbsp;3-bromo-5-(trifluoromethyl)pyridine (340 mg, 1.50 mmol) followed by tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (597 mg, 3.01 mmol) andnbsp;sodium tert-butoxide (578 mg, 6.02 mmol) were added, and the reaction was stirred at 80 C for 2 hrs. The crude material was loaded on a Snap KP-SIL 100g column and purified on a Biotage Isolera One instrument, eluting with 10% to 35% ethyl acetate in heptane to provide tert-butyl 5-(5-(trifluoromethyl)pyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (425 mg, 82 %) as an oil." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CC2CC1CN2C3=CN=CC(=C3)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 82.28 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/14/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "581" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00885 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0107 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00442 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=NC=C1Br)C(F)(F)F" + } + amount { + moles { + value: 0.00221 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000531 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000221 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 100 ml round bottom equipped with stir bar was charged with (S)-BINAP (331 mg, 0.53 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (203 mg, 0.22 mmol) dissolved in 1,4-dioxane (10.700 mL).nbsp;This was degassed and purged with nitrogen and stirred at RT for 10 mins.nbsp;3-bromo-5-(trifluoromethyl)pyridine (500 mg, 2.21 mmol) followed by tert-butyl piperazine-1-carboxylate (824 mg, 4.42 mmol) andnbsp;sodium tert-butoxide (850 mg, 8.85 mmol) were added, and the reaction was stirred at 80 C for 2 hrs. The crude material was loaded on a Snap KP-SIL 100g column and purified on a Biotage Isolera One instrument, eluting with 10% to 30% ethyl acetate in heptane to provide tert-butyl 4-(5-(trifluoromethyl)pyridin-3-yl)piperazine-1-carboxylate (630 mg, 86 %) as an oil." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CN=CC(=C2)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 85.94 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/15/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "584" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[K+].[K+]" + } + amount { + moles { + value: 0.033 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC#N" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCNCC" + } + amount { + moles { + value: 0.033 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1C#N)Br" + } + amount { + moles { + value: 0.011 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.0011 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000549 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 160.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "4-Bromobenzonitrile (2.000 g, 10.99 mmol), diethylamine (3.41 mL, 32.96 mmol) and POTASSIUM CARBONATE (4.56 g, 32.96 mmol) were mixed in dry acetonitrile (10 mL) under argon in a microwave vial. The vial was sealed and heated with microvawes for 60 minutes at 160C. Added diethylamine (3.41 mL, 32.96 mmol) and heated at 160C for 3 hours. Added Palladium(II) acetate (0.123 g, 0.55 mmol) and 2-(Dicyclohexylphosphino)-2\',4\',6\'-tri-i-propyl-1,1\'-biphenyl (0.524 g, 1.10 mmol), purged with argon for 5 minutes and heated in an oil bath at 100C for 24 hours. The reaction was cooled to rt and partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (40 mL). The layers were separated and the aqueous phase extracted with EtOAc (100 mL). The organics were combined, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography on silica gel gave 4-(diethylamino)benzonitrile (0.750 g," + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCN(CC)C1=CC=C(C=C1)C#N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 39.17 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/03/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "585" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000906 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.0021 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)S(=O)(=O)N)N" + } + amount { + moles { + value: 0.000755 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=N1)Cl" + } + amount { + moles { + value: 0.000755 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 6.04e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.02e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 130.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of 3-aminobenzenesulfonamide (130mg, 0.75 mmol), 2-chloropyrazine (0.067 mL, 0.75 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (34.9 mg, 0.06 mmol), diacetoxypalladium (6.78 mg, 0.03 mmol) and cesium carbonate (295 mg, 0.91 mmol)nbsp;in degassed DMA (2.1 mL) was heatedb uin the microwaveub for 15 min at 130 C. LC MS FLA-04665-01-01 (pH extract 6-7) showed some product and few sulfanilamide left. Reaction was stopped. Extraction with AE + ethanol aq. sat NH4Cl (pH7), then back extraction with DCM.The organics were dried over MgSO4 and concentrated iin vacuo. iThe crude product was adsorbed on silica gel 40-60m and purified by flash chromatography on silica gel 15-40m eluting with 3.5 % of ethanol in dichloromethane (NH3 0.5 %) to provide 3-(pyrazin-2-ylamino)benzenesulfonamide (80 mg, 42.3 %) as a colourless solid. 1H NMR, LC MS FLA-04665-0" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)S(=O)(=O)N)NC2=NC=CN=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 42.34 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/28/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "586" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000767 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.0019 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)S(=O)(=O)N)N" + } + amount { + moles { + value: 0.000639 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=NC=N1)Br" + } + amount { + moles { + value: 0.000639 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 5.11e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.56e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 130.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of 3-aminobenzenesulfonamide (110mg, 0.64 mmol), 5-bromopyrimidine (102 mg, 0.64 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (29.6 mg, 0.05 mmol), diacetoxypalladium (5.74 mg, 0.03 mmol) and cesium carbonate (250 mg, 0.77 mmol)nbsp;in degassed DMA (1.9 mL) was heatedb uin the microwaveub for 35 min at 130C. LC MS FLA-04665-12-01 (pH extract 6-7) showed some product. Reaction was stopped. Extraction with AE + ethanol aq. sat NH4Cl (pH7), then back extraction with DCM.The organics were dried over MgSO4 and concentrated iin vacuo. iThe crude product was adsorbed on silica gel 40-60m and purified by flash chromatography on silica gel 15-40m eluting with 3.5 % of ethanol in dichloromethane (NH3 0.5 %) to provide 3-(pyrimidin-5-ylamino)benzenesulfonamide (30.0 mg, 18.77 %) as a yellow solid. 1H NMR,LC MS: FLA-04665-12" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)S(=O)(=O)N)NC2=CN=CN=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 18.77 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/05/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "587" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000633 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1C[C@@H](C2=NC(=NN2C1)N)C3=CC=C(C=C3)F" + } + amount { + moles { + value: 0.000422 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1CC#N)Br" + } + amount { + moles { + value: 0.000422 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 3.99e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "8-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine (98 mg, 0.42 mmol), 2-(4-bromophenyl)acetonitrile (83 mg, 0.42 mmol), Cesium carbonate (206 mg, 0.63 mmol), Palladium(II) acetate (9.47 mg, 0.04 mmol) and 2-(Dicyclohexylphosphino)biphenyl (14.79 mg, 0.04 mmol) were added to a 2-5 mL microwave vial. The vial was capped and flushed with nitrogen. dioxane (2 mL) was added and the vial was flushed with additional nitrogen before it was heated by microwave irradiation at 120C for 1.5h. PALLADIUM(II) ACETATE (10 mg, 0.04 mmol) and 2-(DICYCLOHEXYLPHOSPHINO)BIPHENYL (14 mg, 0.04 mmol) were added and the mixture was heated for 45+30 min at 120 in a microwave reactor.Water (2 ml) and dichloromethane (10 ml) was added and the mixture was added to a phase separator tube. The organic phase was collected and evaporated. The solvents were evaporated and the residue was purified by column chromatography on silica eluting with gradients of methanol and ammonia in dichloromethane. The swere evaporated to give EN04671-48-001 (55 mg, 0.158 mmol, 37.5 %). Ca 88% pure according to LC-UV. The residue was dissolved in MeCN (2 ml) and the solution was passed through a syringe filter. Water was added to give a cloudy mixture (sample-002). Not possible to isolate solid by filtration. The solvents were evaporated to give EN04671-48-002. Not pure. EtOAc (2ml) and DCM (0.5 ml) and two drops of methanol were added. Most solid into solution. The mixture was passed through a syringe filter. The filter was rinsed with EtOAc (1 ml). Heptane was added until a solid started to form. The mixture was left for 1 h (sample -003). The mixture was filtered, everything passed through the filter. The solvents were evaporated and the residue was dissolved in MeCN and purified by preparative HPLC. Fr 1-2 were pooled and evaporated to give EN04671-48-004 (6.7 mg, 0.019 mmol, 4.57 %). Fr 3-6 were pooled and evaporated." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CC(C2=NC(=NN2C1)NC3=CC=C(C=C3)CC#N)C4=CC=C(C=C4)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 42.09 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/14/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "588" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000103 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.006 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCC[C@@H]1COC2=CN=C(C=C2)N" + } + amount { + moles { + value: 0.000689 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C2C(=C1)N=CN2C3=CC(=NC=N3)Cl" + } + amount { + moles { + value: 0.000689 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000103 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 3.45e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (31.6 mg, 0.03 mmol) was added to (R)-5-((1-methylpyrrolidin-2-yl)methoxy)pyridin-2-amine (143 mg, 0.69 mmol), 1-(6-chloropyrimidin-4-yl)-1H-benzo[d]imidazole (159 mg, 0.69 mmol), sodium t-butoxide (99 mg, 1.03 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (59.8 mg, 0.10 mmol) in toluene (6 mL) at 20C under nitrogen. The resulting suspension was stirred at 100 C for 16 hours then cooled to room temperature. LCMS analysis indicates no SM, product peak present. The reaction mixture was concentrated iin vacuoi. The residue was dissolved in DCM (100 mL) and washed with water (100 mL). The organic layer was passed through phase separating cartridge and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford a yellow gum. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD 5 silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (R)-6-(1H-benzo[d]imidazol-1-yl)-N-(5-((1-methylpyrrolidin-2-yl)methoxy)pyridin-2-yl)pyrimidin-4-amine (39.0 mg, 14.09 %) as an pale yellow solid. Experiment was re-opened on 08062012 to record additional data for publication. 13C and HRMS data recorded as separate sections rather than within sample details due to ELN conflict when trying to sign and close with redundant project code.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CCC[C@@H]1COC2=CN=C(C=C2)NC3=CC(=NC=N3)N4C=NC5=CC=CC=C54" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 14.09 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/18/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "589" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00957 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.05 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCCC12OCCO2" + } + amount { + moles { + value: 0.00798 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC(=CN=C1)Br" + } + amount { + moles { + value: 0.00798 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.000479 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000479 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "1105 2011 07:58:54 +0200A mixture of 3-bromo-5-methoxypyridine (1.5 g, 7.98 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (1.023 ml, 7.98 mmol), palladium(II) acetate (0.107 g, 0.48 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.228 g, 0.48 mmol) in toluene (38.3 ml) and tBuOH (7.65 ml) was evacuated and flashed with N2 several times. Then sodium 2-methylpropan-2-olate (0.920 g, 9.57 mmol) was added and the reaction mixture was heated to 100C for 2hrs.LCMS showed complete conversion. Reaction mixture had turned black.The reaction mixture was filtered through celite. The celite was washed with DCM. The combined filtrates were concentrated to yield 2.2g of brown oil, which starts to crystalise patially.Crude NMR showed only little unreacted amine (ca. 14%).The crude was purified by flash:The residue was purified by automated flash chromatography on a 100gnbsp;column. A gradient from 40%nbsp;tonbsp;100% of EA in Hep over 12CV, EA over 6CV was used as mobile phase. The product was collected using the wavelength 254 nm.1.5g of desired product were obtained as a light yellow oil." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=CN=CC(=C1)N2CCC3(CC2)OCCO3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 75.12 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/11/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "590" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0349 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CN=C1)N" + } + amount { + moles { + value: 0.038 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CN=C1)Br" + } + amount { + moles { + value: 0.0316 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 2.43e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.43e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Stock solution: 2.43 M solution of CyPF-tBuPd(OAc)2 (1:1) in DME.pyridin-3-amine (3.57 g, 37.98 mmol) was dissolved in DME (10 mL). To the mixture was added 10 mL of stock solution, and sodium tert-butoxide (4.26 g, 44.30 mmol). 5 min later, to the mixtue was added a solution of 3-bromopyridine (3.05 mL, 31.65 mmol) in DME (10 mL). The mixture was heated at 100 C overnight. LCMS1 showed the result after 1 h heating. LCMS2 showed the result after 18 h heating, which showed the product formation, and the starting material 3-BrPy. LCMS3 showed the result after 40 h heating.nbsp;LCMS4 was after 60h. To the mixture was added 50 mL DCM and acetic acid (2 mL, 34.94 mmol). The mixture was stirred for 10 min, and then was filtered. The filtrate was concentrated, and the compound was purified by preparative HPLC on a XBridge C18 column (10 m 250x50 ID mm) using a gradient of 0-60% acetonitrile in H2OACNNH3 9550.2 buffer over 20 minutes with a flow of 100 mLmin. The compounds were dby UV at 254nm (LCMS5). After freezing-dried overnight, product dipyridin-3-ylamine (0.540 g, 9.97 %) was obtained.nbsp;nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC(=CN=C1)NC2=CN=CC=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 9.97 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/03/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "591" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.007 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CN=C1)N" + } + amount { + moles { + value: 0.006 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CN=C1)Br" + } + amount { + moles { + value: 0.005 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 4.86e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.86e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Stock solution: 2.43 M solution of CyPF-tBuPd(OAc)2 (1:1) in DME.3-bromopyridine (0.482 mL, 5.00 mmol) was dissolved in DME (10 mL). To the solution was added 2mL of stock solution, and sodium tert-butoxide (0.673 g, 7.00 mmol). To the mixture was added a solution of pyridin-3-amine (0.565 g, 6.00 mmol) in DME (10 mL). The mixture was heated at 90 C overnight. LCMS showed the product formation, but the starting material 3-BrPy was still . To the mixture was added 2 mL stock solution additionally, and the mixture was heated at 90 C for another 2h, but LCMS did not show improvement. The mixture was filtered. The filtrate was concentrated, and the compound was purified by preparative HPLC on a XBridge C18 column (10 m 250x50 ID mm) using a gradient of 0-50% acetonitrile in H2OACNNH3 9550.2 buffer over 15 minutes with a flow of 100 mLmin. The compounds were detected by UV at 254nm. To the fractions (ca. 60mL) were added 5 mL of HOAc. The product was freezing-dried to give the prdin-3-ylamine (0.031 g, 3.62 %). " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC(=CN=C1)NC2=CN=CC=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 3.62 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/30/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "592" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0623 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CN=C1)N" + } + amount { + moles { + value: 0.0747 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CN=C1)Br" + } + amount { + moles { + value: 0.0623 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 2.43e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.43e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Stock solution: 2.43 M solution of CyPF-tBuPd(OAc)2 (1:1) in DME.3-bromopyridine (6 mL, 62.28 mmol) was dissolved in DME (10 mL). To the solution was added 10 mL of stock solution, and sodium tert-butoxide (8.38 g, 87.19 mmol). To the mixture was added a solution of pyridin-3-amine (7.03 g, 74.74 mmol) in DME (10 mL). The mixture was heated at 100 C overnight. LCMS showed the product formation, and the starting material 3-BrPy . To the mixture was added 4 mL stock solution additionally, and the mixture was heated at 100 C for another 5h. LCMS showed more impurities peaks. The mixture was filtered. The filtrate was concentrated, and the compound was purified by preparative HPLC on a XBridge C18 column (10 m 250x50 ID mm) using a gradient of 0-50% acetonitrile in H2OACNNH3 9550.2 buffer over 15 minutes with a flow of 100 mLmin. The compounds were detected by UV at 254nm. To the fractions (ca. 1000mL) were added 20 mL of HOAc. The product was freezing-dried to give the 1.56 g out NMR1 showed that there was 5 eq. acetic acid in the crude. The residue was dissolved in 10 mL methanol. To the solution was added 10 mL of aq. ammonia solution, and the crude was freezing-dried overnight to give the product dipyridin-3-ylamine (1.300 g, 12.19 %) .nbsp;nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC(=CN=C1)NC2=CN=CC=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 12.19 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "12/01/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "594" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000648 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0025 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1C[C@@H](C2=NC(=NN2C1)N)C3=CC=C(C=C3)F" + } + amount { + moles { + value: 0.000435 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC=C(C=C1)Br" + } + amount { + moles { + value: 0.000438 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 4.51e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.37e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "8-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine (101 mg, 0.43 mmol), 4-bromo-N,N-dimethylbenzamide (100 mg, 0.44 mmol), Cesium carbonate (211 mg, 0.65 mmol), Palladium(II) acetate (9.8 mg, 0.04 mmol) and 2-(Dicyclohexylphosphino)biphenyl (15.8 mg, 0.05 mmol) were added to a microwave vial. The vial was capped and flushed with nitrogen. Dioxane (2.5 mL) was added and the vial was flushed with additional nitrogen before it was irradiated in a microwave reactor at 120 C for 1.5 h. The reaction mixture was diluted with dichloromethane and filtered through a pad of diatomaceous earth. The pad was rinced repeatedly with dichloromethane, then the solvents were removed iin vacuoi. Handed over to the preparative chromatography group for purification (see attached report). The desired fractions were pooled and concentrated iin vacuoi. The residue was partitioned between water and dichloromethane (x1), the organic layer was passed through a phase separator and concentrated n vacuoi. The residue was redissolved in acetonitrile and water was added. Freeze-dried over weekend to give 4-(8-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-N,N-dimethylbenzamide (67.5 mg, 40.9 %)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC=C(C=C1)NC2=NN3CCCC(C3=N2)C4=CC=C(C=C4)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 40.91 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/15/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "595" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 3.5e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" + } + amount { + moles { + value: 0.00035 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=C(C=C1F)Br)C#N" + } + amount { + moles { + value: 0.000437 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.75e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (3.93 mg, 0.02 mmol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (130 mg, 0.35 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (20.25 mg, 0.03 mmol), 3-bromo-5-fluorobenzonitrile (88 mg, 0.44 mmol)nbsp;and cesium carbonate (171 mg, 0.52 mmol) dissolved in 1,4-dioxane (4 ml). The resulting suspension was degased with argon and then stirred at 100 C (18:00) for 15 hours.The reaction mixture was allowed to cool to room temperature, filtered and concentrated in V-10 Evaporator (Biotage)The crude product was dissolved in 2ml of DMA.The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 60 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated tyness to afford 8-(1-(3-cyano-5-fluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (90 mg, 52.4 %)nbsp;as anbsp;solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)C#N)F)OC(=CC2=O)N5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 52.42 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/10/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "596" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 3.5e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" + } + amount { + moles { + value: 0.00035 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)Br" + } + amount { + moles { + value: 0.000437 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.75e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (3.93 mg, 0.02 mmol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (130 mg, 0.35 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (20.25 mg, 0.03 mmol), bromobenzene (0.046 ml, 0.44 mmol) and cesium carbonate (171 mg, 0.52 mmol) dissolved in 1,4-dioxane (4 ml). The resulting suspension was degased with argon and then stirred at 100 C (18:00) for 15 hours.The reaction mixture was allowed to cool to room temperature, filtered and concentrated in V-10 Evaporator (Biotage)The crude product was dissolved in 2ml of DMA.The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 60 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afforsp;N,N-dimethyl-2-morpholino-4-oxo-8-(1-phenylpyrrolidin-2-yl)-4H-chromene-6-carboxamide (59.0 mg, 37.7 %) as anbsp;solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC=CC=C4)OC(=CC2=O)N5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 37.67 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/10/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "597" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000841 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" + } + amount { + moles { + value: 0.000673 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1F)Br" + } + amount { + moles { + value: 0.000841 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 6.73e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.37e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (7.56 mg, 0.03 mmol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (250 mg, 0.67 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (38.9 mg, 0.07 mmol), 1-bromo-4-fluorobenzene (0.092 ml, 0.84 mmol) and cesium carbonate (329 mg, 1.01 mmol) dissolved in 1,4-dioxane (5 ml). The resulting suspension was degased with argon and then stirred at 100 C for 15 hours.The reaction mixture was allowed to cool to room temperature and concentrated.The crude product was dissolved in 2ml of DMA.The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 60 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-(4-fluorophenyl)pyrrolidin-2-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (47.0 mg, 15.00 %) as anbsp;solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC=C(C=C4)F)OC(=CC2=O)N5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 15.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/06/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "599" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 6.73e-06 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" + } + amount { + moles { + value: 6.73e-05 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1F)Br" + } + amount { + moles { + value: 8.41e-05 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 6.73e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.37e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (0.756 mg, 3.37 mol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (25 mg, 0.07 mmol), [Reactants], 1-bromo-4-fluorobenzene (9.24 l, 0.08 mmol) and cesium carbonate (32.9 mg, 0.10 mmol) dissolved in 1,4-dioxane (1.5 ml). The resulting suspension was degased with argon and then stirred at 100 C for 15 hours.The reaction mixture was allowed to cool to room temperature and concentrated.The crude product was dissolved in 2ml of DMA.The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 60 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-(4-fluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carbo mg, 19.15 %) as anbsp;solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC=C(C=C4)F)OC(=CC2=O)N5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 19.15 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/20/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "600" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 6.73e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" + } + amount { + moles { + value: 0.000673 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1F)Br" + } + amount { + moles { + value: 0.000841 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 6.73e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.37e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (7.56 mg, 0.03 mmol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (250 mg, 0.67 mmol), biphenyl-2-yldicyclohexylphosphine (23.59 mg, 0.07 mmol), 1-bromo-4-fluorobenzene (0.092 ml, 0.84 mmol) and cesium carbonate (329 mg, 1.01 mmol) dissolved in 1,4-dioxane (5 ml). The resulting suspension was degased with argon and then stirred at 100 C for 15 hours.The reaction mixture was allowed to cool to room temperature and concentrated.The crude product was dissolved in DMA.The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 60 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-(4-fluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholinoxo-4H-chromene-6-carboxamide (155 mg, 49.5 %) as anbsp;gum200mg (155mg from EN05368-13 and 45mg from EN04870-97) was sent to the collection and purified by chiral separation by Fiona Bell." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC=C(C=C4)F)OC(=CC2=O)N5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 49.47 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/21/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "601" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 1.35e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" + } + amount { + moles { + value: 0.000135 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1F)Br" + } + amount { + moles { + value: 0.000168 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 1.35e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 6.73e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (1.511 mg, 6.73 mol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (50 mg, 0.13 mmol), biphenyl-2-yldicyclohexylphosphine (4.72 mg, 0.01 mmol), 1-bromo-4-fluorobenzene (0.018 ml, 0.17 mmol) and cesium carbonate (65.8 mg, 0.20 mmol) dissolved in 1,4-dioxane (1.5 ml). The resulting suspension was degased with argon and then stirred at 100 C for 15 hours.The reaction mixture was allowed to cool to room temperature and concentrated.The crude product was dissolved in 2ml of DMA.The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 60 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-(4-fluorophenyl)pyrrolidin-2-yl)-N,N-dimethyholino-4-oxo-4H-chromene-6-carboxamide (10.00 mg, 15.96 %) as anbsp;gum." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC=C(C=C4)F)OC(=CC2=O)N5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 15.96 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/20/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "602" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000437 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" + } + amount { + moles { + value: 0.00035 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1F)Br" + } + amount { + moles { + value: 0.000437 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.75e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (3.93 mg, 0.02 mmol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (130 mg, 0.35 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (20.25 mg, 0.03 mmol), 1-bromo-4-fluorobenzene (0.048 ml, 0.44 mmol) and cesium carbonate (171 mg, 0.52 mmol) dissolved in 1,4-dioxane (4 ml). The resulting suspension was degased with argon and then stirred at 100 C for 15 hours.The reaction mixture was allowed to cool to room temperature, filtered and concentrated in V-10 Evaporator (Biotage)The crude product was dissolved in 2ml of DMA.The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 60 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to af 8-(1-(4-fluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (31.0 mg, 19.03 %) as anbsp;solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC=C(C=C4)F)OC(=CC2=O)N5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 19.03 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/10/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "603" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00785 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)CN.Cl" + } + amount { + moles { + value: 0.00524 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=NC(=C1N)Br)F" + } + amount { + moles { + value: 0.00262 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000262 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000262 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 50 mL round-bottomed flask 2-bromo-5-fluoropyridin-3-amine (500 mg, 2.62 mmol) ethyl 2-aminoacetate hydrochloride (731 mg, 5.24 mmol)nbsp;BINAP (163 mg, 0.26 mmol) palladium(II) acetate (58.8 mg, 0.26 mmol)nbsp;CESIUM CARBONATE (2559 mg, 7.85 mmol) were taken.The solids were mixed well and degassed.The toluene was taken in another RB and degassed using Nitrogen.The degassed toluene was then added to the solids.The resulting RM was heated to reflux for 16 hrs.The reaction was monitored by LCMS, which indicated starting material only and no required product.Therefore, the batch was discarded. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)CNC1=C(C=C(C=N1)F)N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/19/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "604" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00244 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C1=CC=CC=C1)N" + } + amount { + moles { + value: 0.00175 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=N1)Cl" + } + amount { + moles { + value: 0.00175 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000227 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000227 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 70.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a solution of 1-phenylethanamine (212 mg, 1.75 mmol) and 2-chloropyrazine (200 mg, 1.75 mmol) in toluene (10 mL) while bubbling N2 was added binap (141 mg, 0.23 mmol), sodium tert-butoxide (235 mg, 2.44 mmol) and palladium(II) acetate (51.0 mg, 0.23 mmol). The reaction mixure was heated at 70 oC for 3 hours. The reaction was concentrated, partitioned between ethyl acetate and water. The aqueous phase was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated.nbsp;The crude material was loaded on a 40g silica gel column and purified on a Teledyne Isco instrument, eluting with 20% to 70% ethyl acetate in heptane to provide N-(1-phenylethyl)pyrazin-2-amine (148 mg, 42.5 %) as a solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C1=CC=CC=C1)NC2=NC=CN=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 42.54 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/21/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "605" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 5.11e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CS(=O)(=O)C1=CC=C(C=C1)N" + } + amount { + moles { + value: 0.000426 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)Cl)C" + } + amount { + moles { + value: 0.000426 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 5.11e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.98e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 10 mL microwave reactor 3-(2-chloropyridin-4-yloxy)-2,6-dimethylpyridine (100 mg, 0.43 mmol) andnbsp;4-(methylsulfonyl)aniline (73.0 mg, 0.43 mmol) were dissolved in DMA (3 mL) to give a tan solution.To the resultant solution Cesium carbonate (0.068 mL, 0.85 mmol) was added and sparged with nitrogen for 1 minute. Then Palladium(II) acetate (6.70 mg, 0.03 mmol) and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (29.6 mg, 0.05 mmol) were added and the reaction mixture was sealed. The reaction was heated to150 C for 25 minutes in the biotage microwave.The reaction was cooled to room temperature and LCMS shows reaction was completed. Reaction mixture was filtered through Celite Bed and washed with Dichloromethane. Filtrate was jected to concentration to get DMA solution which was given to analytical department to purify using Mass based HPLC. After purification compound was isolated to get pale yellow solid ofnbsp; 4-(2,6-dimethylpyridin-3-yloxy)-N-(4-(methylsulfonyl)phenyl)pyridin-2-amine (80 50.8 %)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)NC3=CC=C(C=C3)S(=O)(=O)C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 50.82 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/07/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "606" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 5.11e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1CCNS(=O)(=O)C2=CC=C(C=C2)N" + } + amount { + moles { + value: 0.000426 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)Cl)C" + } + amount { + moles { + value: 0.000426 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 5.11e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.98e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 10 mL microwave reactor 3-(2-chloropyridin-4-yloxy)-2,6-dimethylpyridine (100 mg, 0.43 mmol) andnbsp;4-amino-N-(2-morpholinoethyl)benzenesulfonamide (122 mg, 0.43 mmol) were dissolved in DMA (5 mL) to give a tan solution.To the resultant solution Cesium carbonate (0.068 mL, 0.85 mmol) was added and sparged with nitrogen for 1 minute. Then Palladium(II) acetate (6.70 mg, 0.03 mmol) and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (29.6 mg, 0.05 mmol) were added and the reaction mixture was sealed. The reaction was heated to150 C for 25 minutes in the biotage microwave.The reaction was cooled to room temperature and LCMS shows reaction was completed. Reaction mixture was filtered through Celite Bed and washed with Dichloromethane. Filtrate was jected to concentration to get DMA solution which was given to analytical department to purify using Mass based HPLC. After purification compound was isolated to get pale yellow solid ofnbsp; 4-(4-(2,6-dimethylpyridin-3-yloxy)pyridin-2-ylamino)-N-(2-holinoethyl)benzenesulfonamide (125 mg, 60.7 %)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)NC3=CC=C(C=C3)S(=O)(=O)NCCN4CCOCC4)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 60.66 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/11/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "607" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 5.11e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(COC)NS(=O)(=O)C1=CC=C(C=C1)N" + } + amount { + moles { + value: 0.000426 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)Cl)C" + } + amount { + moles { + value: 0.000426 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 5.11e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.98e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 10 mL microwave reactor 3-(2-chloropyridin-4-yloxy)-2,6-dimethylpyridine (100 mg, 0.43 mmol) andnbsp;4-amino-N-(1-methoxypropan-2-yl)benzenesulfonamide (104 mg, 0.43 mmol) were dissolved in DMA (3 mL) to give a brown solution.To the resultant solution Cesium carbonate (0.068 mL, 0.85 mmol) was added and sparged with nitrogen for 1 minute. Then Palladium(II) acetate (6.70 mg, 0.03 mmol) and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (29.6 mg, 0.05 mmol) were added and the reaction mixture was sealed. The reaction was heated to150 C for 25 minutes in the biotage microwave.The reaction was cooled to room temperature and LCMS shows reaction was completed. Reaction mixture was filtered through Celite Bed and washed with Dichloromethane. Filtrate was jected to concentration to get DMA solution which was given to analytical department to purify using Mass based HPLC. After purification compound was isolated to get pale yellow solid ofnbsp;4-(4-(2,6-dimethylpyridin-3-yloxy)pyridin-2-ylamino)-Nmethoxypropan-2-yl)benzenesulfonamide (98 mg, 52.0 %)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)NC3=CC=C(C=C3)S(=O)(=O)NC(C)COC)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 51.97 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/11/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "608" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00288 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0065 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCC1CN" + } + amount { + moles { + value: 0.00192 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)I)Br" + } + amount { + moles { + value: 0.00192 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000288 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000144 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium (II) acetate (0.032 g, 0.14 mmol) and racemic-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.179 g, 0.29 mmol) were suspended in toluene (3 mL). The mixture was evacuated and purged with nitrogen, and warmed to 50C.In a separate vessel, 2-bromo-4-iodo-1-methoxybenzene (0.6 g, 1.92 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (0.221 g, 1.92 mmol) and sodium-t-butoxide (0.276 g, 2.88 mmol) were suspended in toluene (3.5 mL). The resulting mixture was evacuated, purged with nitrogen and warmed to 50C. After ~30 mins, the catalyst mixture was transferred to the reaction vessel. The reaction was evacuated and purged with nitrogen and heated at 80C overnight. The mixture was filtered and purified by flash silica chromatography, elution 30% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 3-bromo-4-methoxy-N-((tetrahydro-2H-pyran-4-yl)methyl)aniline (0.060 g, 10.42 %) as a brown solid. 60mg of product formed by LC-MS and major product is unknown buttain pyran signals in NMR and not SM iodide." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)NCC2CCOCC2)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 10.42 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/27/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "609" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00671 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCC1CN" + } + amount { + moles { + value: 0.00447 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)I)Br" + } + amount { + moles { + value: 0.00447 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000358 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000336 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium (II) acetate (0.075 g, 0.34 mmol) and racemic-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.223 g, 0.36 mmol) were suspended in dioxane (5mL). The mixture was evacuated and purged with nitrogen, and warmed to 50C.In a separate vessel, 2-bromo-4-iodo-1-methoxybenzene (1.4 g, 4.47 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (0.547 mL, 4.47 mmol) and sodium-t-butoxide (0.645 g, 6.71 mmol) were suspended in dioxane (5ML). The resulting mixture was evacuated, purged with nitrogen and warmed to 50C. After ~30 mins, the catalyst mixture was transferred to the reaction vessel. The reaction was evacuated and purged with nitrogen and heated at 80C overnight. Very little product and mainly SM so reaction ab" + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)NCC2CCOCC2)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/03/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "610" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000427 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.035 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" + } + amount { + moles { + value: 0.00502 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)Br)F" + } + amount { + moles { + value: 0.00502 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000427 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000201 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (0.045 g, 0.20 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (1.8 g, 5.02 mmol), methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (1.8 g, 5.02 mmol) and cesium carbonate (2.455 g, 7.53 mmol) dissolved in 1,4-dioxane (35 ml). The resulting suspension was degased with argon and then stirred at 100 C for 11 hours.The reaction mixture was allowed to cool to room temperature, filtered and concentrated.The crude product was purified by flash chromatography on silica gel eluting with 0 to 20% methanol in ethyl acetate (on 50 min). The solvent was evaporated to dryness to afford methyl 8-(1-(3-fluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (1.610 g, 70.8 %) as a clear yellow foam." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC=C4)F)OC(=CC2=O)N5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 70.85 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/18/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "611" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 2.96e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" + } + amount { + moles { + value: 0.000349 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC(=CC=C1)Br" + } + amount { + moles { + value: 0.000384 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 2.96e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.4e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (3.13 mg, 0.01 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (125 mg, 0.35 mmol), 1-bromo-3-methoxybenzene (0.049 ml, 0.38 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (17.15 mg, 0.03 mmol) and cesium carbonate (170 mg, 0.52 mmol) dissolved in 1,4-dioxane (2 ml). The resulting suspension was degased with argon and then stirred at 100 C for 11 hours.The reaction mixture was allowed to cool to room temperature. The reaction mixture was quenched with water and extracted with dichloromethane (2 x 10 ml). The combined organic phases were dried over magnesium sulfate and concentrated to afford the crude product as a orangeyellow oil.The crude product was purified by flash chromatography on silica gel eluting with 0 to 10% methanol in dichloromethane. The solvent was evaporated to dryness to afford methyl 8-(1-(3-methoxyphenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate mg, 55.6 %) as a yellow gum." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=CC=CC(=C1)N2CCCC2C3=CC(=CC4=C3OC(=CC4=O)N5CCOCC5)C(=O)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 55.55 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/28/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "612" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000948 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)CN1CCNCC1" + } + amount { + moles { + value: 0.000632 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1Br)Br" + } + amount { + moles { + value: 0.00158 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 3.79e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.26e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 85.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a reaction vial, 1,4-dibromobenzene (0.373 g, 1.58 mmol), methyl 2-(piperazin-1-yl)acetate (0.100 g, 0.63 mmol), CS2CO3 (0.309 g, 0.95 mmol), and BINAP (0.024 g, 0.04 mmol) were taken up in 1,4-dioxane (1.5 ml).nbsp;Argon was bubbled through the solution for 1 minute.nbsp;Pd2(dba)3 (0.012 g, 0.01 mmol) was added, followed by additional purging with argon.nbsp;The vial was capped and placed on the heater-shaker.nbsp;The reaction was stirred (450 rpm) at 100 C overnight. LCMS at this point did not indicate any formation of the dp.nbsp;Experiment not progressed." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC(=O)CN1CCN(CC1)C2=CC=C(C=C2)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/04/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "613" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0461 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1CCNCC1" + } + amount { + moles { + value: 0.0154 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=CC(=C1)Br)F" + } + amount { + moles { + value: 0.0154 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000922 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000569 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 100 mL round-bottomed flask methyl piperidine-4-carboxylate (2.2 g, 15.36 mmol),4-bromo-1-fluoro-2-methylbenzene (1.954 mL, 15.36 mmol),Pd2(dba)3 (0.521 g, 0.57 mmol),BINAP (0.574 g, 0.92 mmol) and sodium tert-butoxide (4.43 g, 46.09 mmol) was taken in toluene (10 mL) under N2.The resulting reaction was stirred at 110 C for 3 hrs.LCMS did not show product MS.Material was discrded." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=CC(=C1)N2CCC(CC2)C(=O)OC)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/13/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "614" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.014 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.01 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CC2=C(C1=O)C=C(C=C2)Br" + } + amount { + moles { + value: 0.01 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.0001 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 60.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In an oven-dried RB flask was added Tris(dibenzylideneacetone)dipalladium(0) (0.046 g, 0.05 mmol) and rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.062 g, 0.10 mmol). The flask was evacuated and back-filled with nitrogen. Anhydrous toluene (3 mL) was added and the mixture was stirred at rt for 10 min to give a purple solution. 6-bromo-2-methylisoindolin-1-one (2.261 g, 10 mmol), 1-Boc-piperazine (1.863 g, 10.00 mmol) and Sodium tert-butoxide (1.714 mL, 14.00 mmol) were added in one portion followed by anhydrous toluene (15 mL). The flask was evacuated and back-filled with nitrogen and the resulting mixture was stirred at 60 C under a nitrogen atmosphere for 2 days. LCMS shows 10% conversion. Tris(dibenzylideneacetone)dipalladium(0) (0.183 g, 0.20 mmol) and 2-Dicyclohexylphosphino-2\',6\'-diisopropoxybiphenyl (0.187 g, 0.40 mmol) (RuPhos) were added and the mixture was heated to 80 C and stirred for 5 h. LCMS shows complete conversion. When cooled to rt the mixture was diluted with EtOAc (25 stirred for 1 h. The solid was filtered off and washed with EtOAc (50 mL). The filtrate was washed with saturated aqueous Na2CO3 (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated. The crude producr was purified on a silica gel column eluted with 20-100% EtOAc in Heptane to give a yellow solid; tert-butyl 4-(2-methyl-3-oxoisoindolin-5-yl)piperazine-1-carboxylate (1.890 g, 57.0 %)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC3=C(CN(C3=O)C)C=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 57.03 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/30/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "615" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00015 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)O" + } + amount { + volume { + value: 0.000241 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.000105 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=NC(=C1Br)Cl)Cl" + } + amount { + moles { + value: 0.0001 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 4e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 25.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2011-05-18r1 was checked by NMR and LCMS:Vial a:3-bromo-2,6-dichloropyridine (0.023 g, .1 mmol), morpholine (9.15 l, 0.11 mmol), Pd2dba3 (1.831 mg, 2.00 mol),4-(2,6-dichloropyridin-3-yl)morpholine (0.00 g) were mixed innbsp;tBuOH (0.241 ml) in microwave vial. The vial was flushed with N2 and sealed and the mix was strd at rt.Vial b: As above, but in PhCF3.1100:start2011-05-190800: LCMS: around 50% r1 in both vials.vial a: new peak at 1.53 min (20%), at 2.90 min (17%) and some small peaks as well.vial b: new peak at 1.54 min (32%), 2.61 min (25%) and at 2.90 min (5%) and some small peaks as well.MW100 degr20 min. LCMS, pH3: vial a: 1.17 min: new peak (8-9%, not integrated); 2.11 min: new peak (31%), no right mass track.vial b: 1.17 min: new, small peak; 2.11 min: new peak (17%), no right mass track.The peak from the 2.11 peak is relatively higher in vial a than in b. ation: r1 has logD 3.60, product has logD 1.92.Any Br-gt;H? Check of ret time of 2,6-diCl-pyridine (commercial ref. material): 1.86 min. NO such thing.at rt over night2011-05-200800: LCMS: around 50% r1 in both vials.MW100 degr20 min. LCMS: vial a: 1.17 min (8%); 1.51 min (ca. 5%); 2.12 min (32%); 2.47 min (r1 peak; 38%) + other small peaks.vial b: 1.54 min (19%); 2.12 min (21%); 2.48 (24%); 2.90 min (11%).The crudes were mixed, concentrated and kept at rt over night.2011-05-21Passed thru Si-plug with MeOH. NMR on crude: very messy. Scrutiny of the arom. region did not show anything that seemed like the right product.Not taken further." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1COCCN1C2=C(N=C(C=C2)Cl)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/16/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "616" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 1e-06 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1CCOC1" + } + amount { + volume { + value: 0.000474 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.0003 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=NC(=C1Br)Cl)Cl" + } + amount { + moles { + value: 5e-05 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 2e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "sodium tert-butoxide (0.012 g, 0.13 mmol), were transfered to a microwave vial. Pd2dba3 (0.916 mg, 1.00 mol),dicyclohexyl(2\',6\'-diisopropoxybiphenyl-2-yl)phosphine (0.933 mg, 2.00 mol),nbsp;(2-DICYCLOHEXYLPHOSPHINO-2\',6\'-DIISOPROPYL-1,1\'-BIPHENYL)[2-(2-AMINOETHYL)PHENYL]PALLADIUM(II) (0.729 mg, 1.00 mol) were added. 3-bromo-2,6-dichloropyridine (0.011 g, .05 mmol) in tetrahydrofuran (0.474 ml) was added. The vial was flushed with N2, sealed, and the reaction mix was heated on an oil bath at 100 C.2011-10-050900: interrupted, cooled-LCMS, 5 min method, pH11:1H NMR on crude:not good spectra.2011-10-06The mix was filtered thru Si-plug and conc. 1H NMR and COSY.Very complex. Lower rection temp and time needed. Discarded.----Info from -25:2011-09-18Lit. ref: Maiti,D....Buchwald, S. iChem. Sci.i b2011b, i2i, 57sodium tert-butoxidemmol), were transfered to a microwave vial. Pd2dba3 (1.831 mg, 2.00 mol),dicyclohexyl(2\',6\'-diisopropoxybiphenyl-2-yl)phosphine (1.867 mg, 4.00 mol), (2-DICYCLOHEXYLPHOSPHINO-2\',6\'-DIISOPROPYL-1,1\'-BIPHENYL)[2-(2-AMINOETHYL)PHENYL]PALLADIUM(II) (1.457 mg, 2.00 mol) were added. [Reactants] in tetrahydrofuran (0.948 ml) was added. The vial was flushed with N2, sealed, and the reaction mix was heated on an oil bath at 100 C.2115: start2011-09-190915: LCMS, 5 min method, pH11: some r1 remained3.62 major peak1200: heating at 120 degr2011-09-201400 lcms:5 min method, pH11: right mass peak appeared at 0.12 and 0.18 min.! seeemed very unlikely4.20 still peak, probabaly r1 ,but difficult to say since no iionizationThis was a test experiment, starting from a mix of r1 and one monost. starting material. Repeated with pure r1, see -66.Report Cannot be finalized, since this program" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1COCCN1C2=C(N=C(C=C2)Cl)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/01/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "620" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0266 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCCC12OCCO2" + } + amount { + moles { + value: 0.0266 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=NC(=CC=C1)Br" + } + amount { + moles { + value: 0.0266 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.0266 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.0266 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: nan + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "The same procedure as EN03653-93-01." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=CC=CC(=N1)N2CCC3(CC2)OCCO3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 69.11 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/30/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "621" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0051 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)N" + } + amount { + moles { + value: 0.00408 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC(=CC(=C1)Br)Br" + } + amount { + moles { + value: 0.0034 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00051 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00034 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "aniline (0.380 g, 4.08 mmol), methyl 3,5-dibromobenzoate (1.000 g, 3.40 mmol), Pd(OAc)2 (0.076 g, 0.34 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.295 g, 0.51 mmol) and CESIUM CARBONATE (1.663 g, 5.10 mmol) were stirred in toluene (10 mL) and degassed with nitrogen for 15 minutes. The mixture was then heated at 110 C under nitrogen fornbsp;24 hours. No evidence of any significant amount of product (ester or acid) therfore abandaned." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC(=O)C1=CC(=CC(=C1)Br)NC2=CC=CC=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/06/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "622" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000326 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=C(C=C1F)F)CN" + } + amount { + moles { + value: 0.0093 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC=C(C=C1)Br" + } + amount { + moles { + value: 0.00465 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000326 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000233 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "methyl 4-bromobenzoate (1 g, 4.65 mmol), (3,5-difluorophenyl)methanamine (1.100 mL, 9.30 mmol) and Cesium carbonate (1.515 g, 4.65 mmol) were mixed in toluene (4 mL) and degassed by bubbling nitrogen through solution. Palladium acetate (0.052 g, 0.23 mmol) and rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.203 g, 0.33 mmol) were added and the vial was capped and heated at 100C over 5 days. Workup by dilution with EtOAc, washing with water, then extraction with 2M HCl. The HCl extract was neutralized with 2M NaOH and extracted with EtOAc and the EtOAc phase was dried (K2CO3) and evaporated to give the crude product. The identity of product was doubtful but it was already used in exp 60-68." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC(=O)C1=CC=C(C=C1)NCC2=CC(=CC(=C2)F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/09/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "623" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000586 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=C(C=C1F)F)CN" + } + amount { + moles { + value: 0.0167 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC=C(C=C1)Br" + } + amount { + moles { + value: 0.00837 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000586 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000419 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "methyl 4-bromobenzoate (1.8 g, 8.37 mmol), (3,5-difluorophenyl)methanamine (1.980 mL, 16.74 mmol) and Cesium carbonate (2.73 g, 8.37 mmol) were mixed in toluene (4 mL) and degassed by bubbling nitrogen through solution. Palladium acetate (0.094 g, 0.42 mmol) and rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.365 g, 0.59 mmol) were added and the vial was capped and heated at 100C over 5 days. Workup by dilution with EtOAc, washing with water, then extraction with 2M HCl. The HCl extract was neutralized with 2M NaOH and extracted with EtOAc and the EtOAc phase was dried (K2CO3) and evaporated to give the crude product. The desired amine was not the compound isolated. Discarded." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC(=O)C1=CC=C(C=C1)NCC2=CC(=CC(=C2)F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/19/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "624" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000465 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCC2=CC=CC=C21" + } + amount { + moles { + value: 0.00093 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC=C(C=C1)Br" + } + amount { + moles { + value: 0.000465 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 3.26e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.33e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "methyl 4-bromobenzoate (100 mg, 0.47 mmol), [Reactants] and Cesium carbonate (152 mg, 0.47 mmol) were mixed in toluene (4 mL) and degassed by bubbling nitrogen through solution. Palladium acetate (5.22 mg, 0.02 mmol) and rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (20.27 mg, 0.03 mmol) were added and the vial was capped and heated at 100C over 5 days. Product had formed in mixture. Workup by dilution with EtOAc, washing with water, then extraction with 2M HCl. The HCl extract was neutralized with 2M NaOH and extracted with EtOAc and the EtOAc phase was dried (K2CO3) and evaporated to give the crude product. No product. Discarded." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC(=O)C1=CC=C(C=C1)N2CCC3=CC=CC=C3C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/09/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "625" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00119 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1N)N2C=CN=C2" + } + amount { + moles { + value: 0.000597 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CC(OC2=C(C1=O)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.000398 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 3.98e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.98e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "8-chloro-4-methyl-2-phenyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (115 mg, 0.40 mmol), 4-(1H-imidazol-1-yl)aniline (95 mg, 0.60 mmol), PdOAc2 (8.94 mg, 0.04 mmol), biphenyl-2-yldicyclohexylphosphine (13.96 mg, 0.04 mmol) and CS2CO3 (389 mg, 1.19 mmol)nbsp;were placed in a microwave vial equipped with a stirring bar. The vial was capped and flushed with argon. DME (1.5 mL) was added via a syringe and the mixture was heated to 100C in a microwave apparatus for 1 h. The residue was diluted with ethyl acetate and filtered through a short plug og Celite. The filtrate was evaporated and the residue was purified by HPLC to give 62 mg of the product as a solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CC(OC2=C(C1=O)C=CC(=N2)NC3=CC=C(C=C3)N4C=CN=C4)C5=CC=CC=C5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 37.83 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/15/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "628" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[K+]" + } + amount { + moles { + value: 0.004 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.005 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=CC=C1C(F)(F)F)CN2C(=NC3=C(C=C(C=C32)Br)C(=O)OC)C" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CCCCP(CCCC)CCCC" + } + amount { + moles { + value: 0.0002 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 9.99e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: nan + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "methyl 6-bromo-2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-4-carboxylate (441 mg, 1.00 mmol) was taken up with morpholine (435 l, 5.00 mmol), potassium tert-butoxide (449 mg, 4.00 mmol), tri-n-butylphosphine (49.3 l, 0.2 mmol) and palladium(II) acetate (22.44 mg, 0.10 mmol) in dioxane (10ml) and heated for 18 hrs at 100C. The reaction profile showed no required product and only dimer adduct to be present.the reaction was therefore ab" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=CC=C1C(F)(F)F)CN2C(=NC3=C(C=C(C=C32)N4CCOCC4)C(=O)OC)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/29/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "629" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.002 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)N" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=NC(=C1)Cl)C(F)(F)F" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 160.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: To test strate scope in 5-ester stituted 2-aminooxazole coupling.TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.87 mg, 0.02 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (43.4 mg, 0.075 mmol), cesium carbonate (651 mg, 2.00 mmol), ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol) and 2-chloro-6-(trifluoromethyl)pyridine (181 mg, 1.00 mmol) were placed in an oven dried microwave vial. The vial was then capped and placed under an inert atmosphere. Dioxane (4 mL) was added and the mixture was heated to 160 C for 1 h under microwave irradiation. LCMS of the crude reaction mixture indicated the presence of the desired product.DCM (10 mL) was added to the crude reaction mixture together with C-18 silica (2 g), and the solvent was removed under reduced pressure. The solid residue was then placed in a dry-load tube prior to chromatography. The crude product was purified by reverse-phase flash chromatography on C-18 silica, elution gradient 30 to 80% MeCNwater (1% ammonium hydroxide). Pure fractions were evaporated to dryness to afford ethyl 2-(6-(trifluoromethyl)pyridin-2-ylamino)oxazole-5-carboxylate (204 mg, 67.8 %) as a beige solid. Conclusion: The desired product was isolated in moderate yield and high purity." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)NC2=CC=CC(=N2)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 67.78 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/27/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "630" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.002 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)N" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1C#N)Cl" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 160.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: To test strate scope in 5-ester stituted 2-aminooxazole coupling.TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.87 mg, 0.02 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (43.4 mg, 0.075 mmol), cesium carbonate (651 mg, 2.00 mmol), ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol) and 2-chloroisonicotinonitrile (138 mg, 1.00 mmol) were placed in an oven dried microwave vial. The vial was then capped and placed under an inert atmosphere. Dioxane (4 mL) was added and the mixture was heated to 160 C for 1 h under microwave irradiation. LCMS of the crude reaction mixture indicated the presence of the desired product as well as a significant amount of amine starting material.DCM (10 mL) was added to the crude reaction mixture together with C-18 silica (2 g), and the solvent was removed under reduced pressure. The solid residue was then placed in a dry-load tube prior to chromatography. The crude product was purified by reverse-phase flash chromatograph C-18 silica, elution gradient 20 to 60% MeCN in water (1% ammonium hydroxide). Pure fractions were evaporated to dryness to afford ethyl 2-(4-cyanopyridin-2-ylamino)oxazole-5-carboxylate (155 mg, 60.1 %) as a beige solid. Conclusion: The desired product was isolated in moderate yield." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)C#N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 60.08 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/27/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "631" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.002 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)N" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=NC(=C1)Cl" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 160.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: To test the strate scope in 5-ester stituted 2-aminooxazole coupling.TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.87 mg, 0.02 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (43.4 mg, 0.075 mmol), cesium carbonate (651 mg, 2.00 mmol), ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol) and 2-chloropyridine (113 mg, 1.00 mmol) were placed in an oven dried microwave vial. The vial was then capped and placed under an inert atmosphere. Dioxane (4 mL) was added and the mixture was heated to 160 C for 1 h under microwave irradiation. LCMS of the crude reaction mixture indicated the presence of the desired product.DCM (10 mL) was added to the crude reaction mixture together with C-18 silica (2 g), and the solvent was removed under reduced pressure. The solid residue was then placed in a dry-load tube prior to chromatography. The crude product was purified by reverse-phase flash chromatography on C-18 silica, elution gradient 10 to 60% MeCN in water (1% amum hydroxide). Pure fractions were evaporated to dryness to afford ethyl 2-(pyridin-2-ylamino)oxazole-5-carboxylate (88 mg, 37.8 %) as a beige solid. Conclusion: The desired product was isolated in moderate yield, but in only 84% purity based on LCMS." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)NC2=CC=CC=N2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 37.77 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/27/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "632" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.002 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)N" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=NC=C1[N+](=O)[O-])Cl" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.49e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 160.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: Test of strate scope in couple of ester stituted aminooxazole To an oven-dried microwave vial was added ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol), cesium carbonate (651 mg, 2.00 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.87 mg, 0.02 mmol) 2-chloro-5-nitropyridine (158 mg, 1.00 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (43.4 mg, 0.07 mmol) and the vial was capped and purged with nitrogen. dioxane (4 mL) (degassed) was added and the reaction mixture was heated to 160 C for 1 h under microwave irradiation. LCMS of the crude reaction mixture indicated that the desired product had been formed while only a trace of the amine starting material remained.DCM (20 mL) was added to the crude reaction mixture together with silica (2 g) and the solvent was removed under reduced pressure. The resulting residue was then placed in a dry-load tube prior to chromatography.The crude product was purified by flash silica chromraphy, elution gradient 0 to 2.5% methanolic ammonia in DCM. Pure fractions were evaporated to dryness to afford ethyl 2-(5-nitropyridin-2-ylamino)oxazole-5-carboxylate (238 mg, 86 %) as a orange solid. nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)NC2=NC=C(C=C2)[N+](=O)[O-]" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 85.62 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/22/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "633" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000907 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CC(NC1)C2=CC(=CC3=C2OC(=CC3=O)N4CCOCC4)C(=O)N5CCOCC5" + } + amount { + moles { + value: 0.000605 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1F)Br" + } + amount { + moles { + value: 0.000756 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 6.05e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.02e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (6.79 mg, 0.03 mmol) was added to a stirred mixture of 6-(morpholine-4-carbonyl)-2-morpholino-8-(pyrrolidin-2-yl)-4H-chromen-4-one (250 mg, 0.60 mmol), biphenyl-2-yldicyclohexylphosphine (21.19 mg, 0.06 mmol), 1-bromo-4-fluorobenzene (0.083 ml, 0.76 mmol) and cesium carbonate (296 mg, 0.91 mmol) dissolved in 1,4-dioxane (5 ml). The resulting suspension was degased with argon and then stirred at 100 C for 15 hours.The reaction mixture was allowed to cool to room temperature and concentrated.The crude product was dissolved in DMA.The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 60 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-(4-fluorophenyl)pyrrolidin-2-yl)-6-(morpholine-4-carbonyl)-2pholino-4H-chromen-4-one (140 mg, 45.6 %) as anbsp;gum.The product was sent to the collection and purified by chiral separation by Fiona Bell." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CC(N(C1)C2=CC=C(C=C2)F)C3=CC(=CC4=C3OC(=CC4=O)N5CCOCC5)C(=O)N6CCOCC6" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 45.62 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/27/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "634" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.002 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)N" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(C=C1)Cl" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 160.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: Test of scope in the coupling of ester stituted aminooxazoleTo an oven-dried microwave vial was added ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol), cesium carbonate (651 mg, 2.00 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.87 mg, 0.02 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (43.4 mg, 0.075 mmol) and the vial was capped and purged with nitrogen. ethyl 6-chloronicotinate (185 mg, 1.00 mmol) and dioxane (4 mL) (degassed) were added and the reaction mixture was heated to 160 C for 1 h under microwave irradiation.LCMS of the crude reaction mixture indicated that the desired product had formed with minimal formation of side-products.DCM (20 mL) was added to the crude reaction mixture together with silica (2 g). The solvent was removed under reduced pressure and the resulting residue was placed in a dry-load tube prior to chromatography.The crude product was purified by flash silica chromatography, elution gradient 05% Methanolic ammonia in DCM. Pure fractions were evaporated to dryness to afford the desired product (270 mg, 88% isolated yield in 86% purity). This solid was triturated with hot MeCN and allowed to cool to room temperature to give a solid which was collected by filtration and dried under vacuum to give ethyl 2-(5-(ethoxycarbonyl)pyridin-2-ylamino)oxazole-5-carboxylate (205 mg, 67.2 %) as a cream solid. Conclusion: The desired product was isolated in moderate yield and high purity." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(C=C1)NC2=NC=C(O2)C(=O)OCC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 67.21 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/04/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "635" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.002 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)N" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(N=C(C=N1)Cl)C#N" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 160.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: Test of scope in the coupling of ester stituted aminooxazoleTo an oven-dried microwave vial was added ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol), 6-chloropyrazine-2-carbonitrile (139 mg, 1.00 mmol), cesium carbonate (651 mg, 2.00 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.87 mg, 0.02 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (43.4 mg, 0.075 mmol) and the vial was capped and purged with nitrogen. dioxane (4 mL) (degassed) was added and the reaction mixture was heated to 160 C for 1 h under microwave irradiation.DCM (20 mL) was added to the crude reaction mixture together with silica (2 g) and the solvent was removed under reduced pressure. The resulting residue was added to a dry-load tube prior to chromatography.The crude product was purified by flash silica chromatography, elution gradient 0 to 1% methanolic ammonia in DCM.. Pure fractions were evaporated to dryness to afford ethyl 2-(6-cyanopyrazin-2-ylamino)oxazole-5-carbate (121 mg, 46.7 %) as a cream solid. nbsp;Conclusion: The desired product was formed in moderate yield purity." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)NC2=NC(=CN=C2)C#N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 46.72 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/13/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "636" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0015 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC=CN1C2=CC=C(C=C2)N" + } + amount { + moles { + value: 0.00072 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CC(OC2=C(C1=O)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.0006 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "8-chloro-4-methyl-2-phenyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (173 mg, 0.60 mmol), 4-(2-methyl-1H-imidazol-1-yl)aniline (125 mg, 0.72 mmol), PdOAc2 (13.47 mg, 0.06 mmol), biphenyl-2-yldicyclohexylphosphine (21.03 mg, 0.06 mmol) and cesium carbonate (489 mg, 1.50 mmol)nbsp;were placed in a microwave vial equipped with a stirring bar. The vial was capped, DME (4 mL) was added, the vial was flushed with nitrogen via a syringe and the mixture was heated to 100C in a microwave reactor for 1 h. The residue was diluted with CH2Cl2 and filtered through a short plug of Celite. The filtrate was evaporated and the residue was purified by ISCO column chromatography on silica (gradient elution 0-6% methanol in dichloromethane) to give 4-methyl-8-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-2-phenyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (105 mg, 41.1 %).68 mg given to Per Svensson crystallography." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC=CN1C2=CC=C(C=C2)NC3=NC4=C(C=C3)C(=O)N(CC(O4)C5=CC=CC=C5)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 41.13 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/23/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "637" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000883 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC=CN1C2=CC=C(C=C2)N" + } + amount { + moles { + value: 0.000412 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CC(OC2=C(C1=O)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.000294 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 2.94e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.94e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: " were placed in a microwave vial equipped with a stirring bar. The vial was capped and flushed with argon. DME (2 mL) was added via a syringe and the mixture was heated to 100C in a microwave apparatus for 1h. The reaction mixture was filtered, the solvent was evaporated and the residue was purified by HPLC to give 53 mg (42 % yield) of the product as a solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC=CN1C2=CC=C(C=C2)NC3=NC4=C(C=C3)C(=O)N(CC(O4)C5=CC=CC=C5)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 42.31 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/22/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "638" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00269 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC=CN1C2=CC=C(C=C2)N" + } + amount { + moles { + value: 0.00108 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CC(OC2=C(C1=O)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.000897 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 8.97e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 8.97e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Not continued." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC=CN1C2=CC=C(C=C2)NC3=NC4=C(C=C3)C(=O)N(CC(O4)C5=CC=CC=C5)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 74.93 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/11/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "640" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000244 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CS(=O)(=O)CC1=CC(=CC=C1)N" + } + amount { + moles { + value: 0.000974 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=CC(=C1)F)C2=NC(=NC=C2F)Cl" + } + amount { + moles { + value: 0.000974 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000244 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000195 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine (0.25 g, 0.97 mmol), 3-((methylsulfonyl)methyl)aniline (0.180 g, 0.97 mmol), cesium carbonate (1.270 g, 3.90 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.141 g, 0.24 mmol)and Pd2(dba)3 (0.178 g, 0.19 mmol) were suspended in degassed 1,4-dioxane (3 mL) at ambient temperature. The resulting mixture was degassed, purged with nitrogen and heated at 100 C for 3 hours after which time reaction was shown to be complete by LC-MS. The mixture was allowed to cool overnight. The reaction mixture was diluted with water (250 mL), and extracted with DCM (250 mL).nbsp;The organic was dried over MgSO4, filtered and evaporated to afford crude product.nbsp;The crude product was purified by flash silica chromatography, elution 50% ethyl acetate in Heptane. Fractions were evaporated to dryness to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 50 mm diameter, 150th), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-(3-((methylsulfonyl)methyl)phenyl)pyrimidin-2-amine (0.200 g, 50.6 %) as a white solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=C(C=CC(=C1)F)C2=NC(=NC=C2F)NC3=CC=CC(=C3)CS(=O)(=O)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 50.64 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/01/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "641" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00665 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.00266 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=NC=C1Br)CO" + } + amount { + moles { + value: 0.00266 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000199 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 6.65e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 10 mL Microwave vial was (5-bromopyridin-2-yl)methanol (500 mg, 2.66 mmol), morpholine (0.233 mL, 2.66 mmol),cesium carbonate (2166 mg, 6.65 mmol), Pd2(dba)3 (60.9 mg, 0.07 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (115 mg, 0.20 mmol) in dioxane (10 mL) () to give a brown suspension. The reaction mixture was heated to 110 C for 3h.The reaction mixture was passed over Celite and washed with ethylacetate. The Filtrate was concentrate to dryness to get as a syrupy brown liquid. Water 30ml was added and extracted with ethylacetate (20x 2)ml. THe organic layers are collected, dried over Sodium Sulphate and concentrated to get as a liquid.The crude product was added to a silica gel column and was eluted with ethylacetate 0-70%nbsp;Pure Collected fractions are evaporated to get as a (5-morpholinopyridin-2-yl)methanol (100 mg, 19.36 %)colorless liquid .The compound was carried to next step." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1COCCN1C2=CN=C(C=C2)CO" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 19.36 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/12/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "642" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000823 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.06 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@@H]1CNCCN1" + } + amount { + moles { + value: 0.0216 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C=C1F)C(F)(F)F)Br" + } + amount { + moles { + value: 0.0206 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000823 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000412 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "1-bromo-4-fluoro-2-(trifluoromethyl)benzene (5 g, 20.58 mmol), (R)-2-methylpiperazine (2.164 g, 21.61 mmol), sodium tert-butoxide (3.95 g, 41.15 mmol) and BINAP (0.512 g, 0.82 mmol) in anhydrous toluene (60 mL) was degassed under vacuum with inlet of nitrogen. TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.377 g, 0.41 mmol) was added, the mixture again degassed. The resulting suspension was stirred at 100 C for 6 hours under nitrogen.LCMS: Product formed.Cooled and evaporated. Residue diluted with diethyl ether (75 mL), filtered through Celite and the filtrates extracted with 2M HCl (2x30 mL). The combined aqueous layers were basified with solid NaOH to pH ~10, extracted with diethyl ether (2x50 mL), the organic extracts washed with water (2x10 mL) and brine, dried over mgSO4, filtered and evaporated to give crude product (3.2g, 59%) as an orange oil which was used without further purification." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@@H]1CN(CCN1)C2=C(C=C(C=C2)F)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/06/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "643" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00165 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.1 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@@H]1CNCCN1" + } + amount { + moles { + value: 0.0432 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C=C1F)C(F)(F)F)Br" + } + amount { + moles { + value: 0.0412 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00165 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000823 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "1-bromo-4-fluoro-2-(trifluoromethyl)benzene (10 g, 41.15 mmol), (R)-2-methylpiperazine (4.33 g, 43.21 mmol), sodium tert-butoxide (7.91 g, 82.31 mmol) and BINAP (1.025 g, 1.65 mmol) in anhydrous toluene (100 mL) was degassed under vacuum with inlet of nitrogen. TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.754 g, 0.82 mmol) was added, the mixture again degassed. The resulting suspension was stirred at 100 C for 4 hours under nitrogen.LCMS: Product formed.Heated for a further 2 hours.LCMS: Reaction complete.Cooled and evaporated. Residue diluted with diethyl ether (75 mL), filtered through Celite and the filtrates extracted with 2M HCl (2x30 mL). The combined aqueous layers were basified with solid NaOH to pH ~10, extracted with diethyl ether (2x50 mL), the organic extracts washed with water (2x10 mL) and brine, dried over MgSO4, filtered and evaporated to give crude product (3.2g, 59%) as an orange oil which was used without further purification." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@@H]1CN(CCN1)C2=C(C=C(C=C2)F)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/09/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "644" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "[O-]P(=O)([O-])[O-].[K+].[K+].[K+]" + } + amount { + moles { + value: 0.00208 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.006 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)N" + } + amount { + moles { + value: 0.00178 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "B1(OC(C(O1)(C)C)(C)C)C2=CC(=CC(=C2)Cl)C(=O)OC" + } + amount { + moles { + value: 0.00148 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" + } + amount { + moles { + value: 4.45e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.48e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "aniline (0.162 mL, 1.78 mmol) was added to methyl 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (440mg, 1.48 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (13.59 mg, 0.01 mmol), tri-tert-butylphosphine (10.80 L, 0.04 mmol) and potassium phosphate (441 mg, 2.08 mmol) in degassed DME (6 mL) at 20C under nitrogen. The reaction was stirred at 100 C for 2 days. The reaction mixture was diluted with Et2O (50 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution 10 to 60% EtOAc in " + } + outcomes { + products { + identifiers { + type: SMILES + value: "B1(OC(C(O1)(C)C)(C)C)C2=CC(=CC(=C2)NC3=CC=CC=C3)C(=O)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 2.29 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/19/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "645" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "[O-]P(=O)([O-])[O-].[K+].[K+].[K+]" + } + amount { + moles { + value: 0.000455 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)N" + } + amount { + moles { + value: 0.00395 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "B1(OC(C(O1)(C)C)(C)C)C2=CC(=CC(=C2)Cl)C(=O)OC" + } + amount { + moles { + value: 0.00303 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" + } + amount { + moles { + value: 0.000455 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000152 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "aniline (0.360 mL, 3.95 mmol) was added to methyl 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (900 mg, 3.03 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (139 mg, 0.15 mmol), [Reactants] and potassium phosphate (1546 mg, 7.28 mmol) in degassed DME (10 mL) at 20C under nitrogen. The reaction was stirred at 100 C for 24 hours. The reaction mixture was allowed to cool then filtered through celite, washing with ethyl acetate. The filtrate was evaporated under reduced pressure to give a brown residue.Not progressed any furt" + } + outcomes { + products { + identifiers { + type: SMILES + value: "B1(OC(C(O1)(C)C)(C)C)C2=CC(=CC(=C2)NC3=CC=CC=C3)C(=O)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/06/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "647" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[K+].[K+]" + } + amount { + moles { + value: 0.000751 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C2=C(N1C)C=CC(=C2)N)Cl" + } + amount { + moles { + value: 0.000275 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1CN2CC(C2)O)C3=NC(=NC=C3)Cl" + } + amount { + moles { + value: 0.00025 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 2.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.25e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 40 mL scintillation vial charged with 3-chloro-1,2-dimethyl-1H-indol-5-amine (53.6 mg, 0.28 mmol), 1-((1-(2-chloropyrimidin-4-yl)-3-methyl-1H-pyrazol-4-yl)methyl)azetidin-3-ol (70mg, 0.25 mmol), palladium(II) acetate (2.81 mg, 0.01 mmol), dicyclohexyl(2\',4\',6\'-triisopropyl-[1,1\'-biphenyl]-2-yl)phosphine (x--phos) (11.93 mg, 0.03 mmol) and Dioxane (3 mL) After being degassed by nitrogen bubbling , the reaction mixture was heated to 100 C for 5 hours. LCMS analysis indicated no desired product and chloropyrimidine starting material was decomposed. The reaction mixture was discarded.nbsp;Need to reverse the sequence." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C2=C(N1C)C=CC(=C2)NC3=NC=CC(=N3)N4C=C(C(=N4)C)CN5CC(C5)O)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/31/2014" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "648" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00783 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCCN1" + } + amount { + moles { + value: 0.0157 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C(=C1)Cl)Br" + } + amount { + moles { + value: 0.00522 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000261 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000261 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a stirred sol of 1-bromo-2-chlorobenzene (0.606 mL, 5.22 mmol) in toluene (10 mL) was added Pd2(dba)3 (0.239 g, 0.26 mmol), BINAP (0.163 g, 0.26 mmol), sodium tert-butoxide (0.753 g, 7.83 mmol) and piperazine (1.350 g, 15.67 mmol) and the resulting sol was heated at 110 C for 16h.Cooled to rt, filtered through a celeite pad, volatiles were evaporated off and residue was column chromatographed (DCM:MeOH 90:10) to afford 1-(2-chlorophenyl)piperazine (0.450 g, 43.8 %) as a gum." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CN(CCN1)C2=CC=CC=C2Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 43.8 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/22/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "649" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00783 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCCN1" + } + amount { + moles { + value: 0.0157 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C(=C1)Cl)Br" + } + amount { + moles { + value: 0.00522 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000261 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000261 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a stirred sol of 1-bromo-2-chlorobenzene (0.606 mL, 5.22 mmol) in toluene (10 mL) was added Pd2(dba)3 (0.239 g, 0.26 mmol), BINAP (0.163 g, 0.26 mmol), sodium tert-butoxide (0.753 g, 7.83 mmol) and piperazine (1.350 g, 15.67 mmol) and the resulting sol was heated at 110 C for 16 h.Filtered through a celeite pad amp; crude mixture was purified by column chromatography to afford (DCM:MeOH 90:10) to afford 1-(2-chlorophenyl)piperazine (0.600 g, 58.4 %) as a brown gum." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CN(CCN1)C2=CC=CC=C2Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 58.41 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/23/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "651" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0113 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1CNC1" + } + amount { + moles { + value: 0.00469 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1Br)Br" + } + amount { + moles { + value: 0.00469 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 9.38e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.69e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "3-methylazetidine (0.5 g, 4.69 mmol), diacetoxypalladium (10.53 mg, 0.05 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.058 g, 0.09 mmol) and cesium carbonate (3.67 g, 11.26 mmol), degassed toluene (15 mL) were heated at 100 C over the weekend. The RM was filtered and washed with EtOAc the filtrate was then concentrated and the crude product purified by flash silica chromatography, elution gradient 20 to 30% EtOAc in heptane. Purest fractions were collected and combined with EN05604-93. The combined product was then recrystalised from EtOAc to give 1-(4-bromophenyl)-3-methylazetidine (0.899 g, 85 %)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1CN(C1)C2=CC=C(C=C2)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 84.74 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/29/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "652" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00241 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.016 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CC1CNC2=CC=C(C3=CC=CC=C32)Cl.Cl" + } + amount { + moles { + value: 0.0012 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1CC1C(=O)C2=C(C=C(C=N2)Br)OC" + } + amount { + moles { + value: 0.001 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 7.02e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 5.01e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 70.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Repeat from Orexa Patent write up and cfnbsp;uEN06741-39\\ReactionubuAim:-u bto Prepare target for further useb. NB. the SM is either the (R,R) or (S,S) isomerbethyl 2-(5-bromo-3-methoxypicolinoyl)cyclopropanecarboxylate (0.329 g, 1.00 mmol), 4-chloro-N-(cyclopropylmethyl)naphthalen-1-amine, HCl (0.323 g, 1.20 mmol), PALLADIUM(II) ACETATE (0.011 g, 0.05 mmol), rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthalene (0.044 g, 0.07 mmol) and cesium carbonate (0.784 g, 2.41 mmol) were mixed in toluene (16 mL), purged with nitrogen and stirred in a sealed tube at 70 C for 19 hours.The reaction mixture was diluted with EtOAc (20 ml), filtered through a celite pad and concentrated to give 902 mgnbsp;brown oil.TLC (1 : 1 - EtOAc : n-heptane) see diagram UV onlyThe residue was absorbed onto a samplet and purified on a 25 g Biotage SNAP column, eluting with a step-wise gradient from 0 : 10 to 4 : 6 EtOAc : n-heptane using a Thomson pump collecting 25 ml tions.nbsp;Pure fractions were evaporated to give 318 mg of orange solid - the product eluted with the 4 : 6 mixture. The front spot was probably binap bis oxideLCMS (pH = 3) Rt = 1.66 min (85% by UV),nbsp;mz: 479 (MH+). 1H NMR (DMSO-d6) - looks ok - Aromatics are ok - aliphatics more or less ok but 1 proton missing but there are a number of small peaks as well!buConclusion:u- bOK to use for further reactions - See EN06995-01" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1CC1C(=O)C2=C(C=C(C=N2)N(CC3CC3)C4=CC=C(C5=CC=CC=C54)Cl)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 66.22 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/20/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "653" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000951 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N" + } + amount { + moles { + value: 0.00679 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CN=C1)CN2C=CC3=C2C=C(C=C3)Br" + } + amount { + moles { + value: 0.00453 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.000951 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000317 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "6-bromo-1-(pyridin-3-ylmethyl)-1H-indole (1.3 g, 4.53 mmol), cesium carbonate (2.213 g, 6.79 mmol),nbsp;tert-butyl carbamate (0.796 g, 6.79 mmol), dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.453 g, 0.95 mmol) and PALLADIUM(II) ACETATE (0.071 g, 0.32 mmol) were placed under a nitrogen atmosphere. dry degassed dioxane (20 mL) was added and the reaction was warmed to 110 C (using microwave). After reaction completion (3h) the the reaction was diluted with EtOAc(20mL) and water (10mL) and the organic layer was separated. The aqueous layer was washed with a further portion of EtOAc(10mL) and the combined organic layers were dried (MgSO4), filtered and evaporated to afford crude product.The crude product was purified by flash silica chromatography, elution gradient 30 to 70% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 1-(pyridin-3-ylmethyl)-1H-indol-6-ylcarbamate (1.200 g, 82 %) as a colourless gum. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC1=CC2=C(C=C1)C=CN2CC3=CN=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 81.96 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/25/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "654" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000522 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N" + } + amount { + moles { + value: 0.000522 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CN=C1)CN2C=CC3=C2C=C(C=C3)Br" + } + amount { + moles { + value: 0.000348 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 7.31e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.44e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "6-bromo-1-(pyridin-3-ylmethyl)-1H-indole (0.1 g, 0.35 mmol), cesium carbonate (0.170 g, 0.52 mmol),nbsp;tert-butyl carbamate (0.061 g, 0.52 mmol), dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.035 g, 0.07 mmol) and PALLADIUM(II) ACETATE (5.47 mg, 0.02 mmol) were placed under a nitrogen atmosphere. dry degassed dioxane (2 mL) was added and the reaction was warmed to 100 C (using microwave). After reaction completion (2.5h) the the reaction was diluted with EtOAc(20mL) and water (10mL) and the organic layer was separated. The aqueous layer was washed with a further portion of EtOAc(10mL) and the combined organic layers were dried (MgSO4), filtered and evaporated to afford crude product.The crude product was purified by flash silica chromatography, elution gradient 30 to 70% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 1-(pyridin-3-ylmethyl)-1H-indol-6-ylcarbamate (0.094 g, 83 %) as a colourless gum. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC1=CC2=C(C=C1)C=CN2CC3=CN=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 83.47 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/24/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "655" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0218 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.08 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C(=C1)N)Br" + } + amount { + moles { + value: 0.0164 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC=C(C=C1)I" + } + amount { + moles { + value: 0.0156 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00125 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000779 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-Bromoaniline (1.851 mL, 16.35 mmol) and ethyl 4-iodobenzoate (2.60 mL, 15.58 mmol) were dissolved in toluene (argon bubbled through for 10 min) (80 mL). To the stirred mixture were palladium acetate (0.175 g, 0.78 mmol), rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.776 g, 1.25 mmol) and cesium carbonate (7.10 g, 21.81 mmol) added, argon bubbled through the reaction for 2 min and heated then at 100 C for 3 h. The reaction was not complete (the reaction was checked on a worked-up portion on GCMS and the product was 20% on GCMS). The following were added to the cooled reaction mixture: rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (400 mg) and palladium acetate (100 mg) and then argon bubbled through the reaction for 1 min and heated then at 100 C overnight. The reaction was checked on a worked-up portion on GCMS =gt; 85% product.nbsp;The following were added to the cooled reaction mixture: rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (200 mg) and palladium acetate (50 mg) and then bbled through the reaction for 1 min and heated then at 100 C for 3 h =gt; done.The reaction was poured on a filter-funnel (silica, packed in toluene, eluted with toluene, Rf 0.32). The product came out in fractions 5-8 (Note 1) and they were pooled and the solvent was removed on the rotovap to give ethyl 4-(2-bromophenylamino)benzoate (3.00 g, 60.2 %) as a light brown oil." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC=C(C=C1)NC2=CC=CC=C2Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 60.16 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "12/05/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "657" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000624 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@@H]1CN(CCN1)C(=O)OC(C)(C)C" + } + amount { + moles { + value: 0.000499 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CN=C1)Br" + } + amount { + moles { + value: 0.000418 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 8.32e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.16e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (9.34 mg, 0.04 mmol) and RuPhos (0.039 g, 0.08 mmol) were suspended in 1,4 dioxane (5 mL), degassed and stirred at 50 C for 10 minutes.nbsp;Thennbsp;(R)-tert-butyl 3-methylpiperazine-1-carboxylate (0.100 g, 0.50 mmol), 3-bromopyridine (0.040 mL, 0.42 mmol) and cesium carbonate (0.203 g, 0.62 mmol) were added and the reaction mixture was stirred at 100 C for 16 h.nbsp;LCMS showed only 5% conversion to desired product.nbsp;This was part of a screen and Ruphos, sodium tert-butoxide in toluene gave far better conversion so this was abando" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@@H]1CN(CCN1C2=CN=CC=C2)C(=O)OC(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/09/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "658" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00949 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@@H]1CN(CCN1)C(=O)OC(C)(C)C" + } + amount { + moles { + value: 0.00949 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CN=C1)Br" + } + amount { + moles { + value: 0.00633 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000316 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000158 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 85.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.145 g, 0.16 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.183 g, 0.32 mmol) were added to a mixture of Sodium tert-butoxide (0.912 g, 9.49 mmol), 3-bromopyridine (0.610 mL, 6.33 mmol),(R)-tert-butyl 3-methylpiperazine-1-carboxylate (1.901 g, 9.49 mmol) andnbsp;toluene (20 mL) under nitrogen. The mixture was heated at 85 C for 16 hours before being cooled to RT and filtered through celite. The filtrate was concentrated and the reaction mixture was seperated by flash silica chromatography, elution gradient 20 to 40% EtOAc in heptane. No product was isolated.. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@@H]1CN(CCN1C2=CN=CC=C2)C(=O)OC(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/29/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "659" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00749 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.025 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@@H]1CN(CCN1)C(=O)OC(C)(C)C" + } + amount { + moles { + value: 0.00499 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CN=C1)Br" + } + amount { + moles { + value: 0.00499 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000499 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;uRepeat of reaction EN05798-78uDiacetoxypalladium (0.112 g, 0.50 mmol) and dicyclohexyl(2\',6\'-diisopropoxybiphenyl-2-yl)phosphine (0.466 g, 1.00 mmol) were dissolved in toluene (15 mL) at ambient temperature under nitrogen. The mixture was degassed and purged with nitrogen several times and heated to 50C for 20 mins.In a separate vessel, were mixed 3-bromopyridine (0.789 g, 4.99 mmol), sodium 2-methylpropan-2-olate (0.720 g, 7.49 mmol), (R)-tert-butyl 3-methylpiperazine-1-carboxylate (1g, 4.99 mmol) and toluene (10 mL). The mixture was degassed and purged with nitrogen several times.The catalyst mixture was added to the reaction vessel and the resulting mixture was degassed and purged with nitrogen, and heated at 100 C under nitrogen overnight.The reaction mixture was filtered through celite, washing with EtOAcMeOH. The filtrate was concentrated and the residue purified by flash silica chromatography, elution gradient 20 to 100% EtOAc in heptane. Purens were evaporated to dryness to afford (R)-tert-butyl 3-methyl-4-(pyridin-3-yl)piperazine-1-carboxylate (1.426 g, 103 %) as a pale orange gum. [Rf ~ 0.1 in 1:1 EtOAchept]Note: Trace Ruphos contaminating productnbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@@H]1CN(CCN1C2=CN=CC=C2)C(=O)OC(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 102.97 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/10/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "661" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000911 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000304 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.000304 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 3.04e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.04e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A solution of (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (83 mg, 0.30 mmol) and 6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-amine (62.0 mg, 0.30 mmol) in DME (3 mL) was added to a microwave vial containing palladium(II) acetate (6.82 mg, 0.03 mmol), 2-(Dicyclohexylphosphino)biphenyl (10.64 mg, 0.03 mmol) and CS2CO3 (297 mg, 0.91 mmol) under an athmosphere of argon. The resulting mixture was heated to 100C in a microwave apparatus for 2 h. The reaction mixture was diluted with dichloromethane and methanol and filtered through a plug of Celite. The solvents were evaporated and the residue was purified by HPLC to give 21 mg of the title product (16 % Yield)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(N=C(C=C2)NC3=NC4=C(CN(C[C@H](O4)C5=CC=CC=C5)C)C=C3)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 15.63 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/23/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "663" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00103 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N" + } + amount { + moles { + value: 0.00103 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC(=C(N=C1)Cl)F" + } + amount { + moles { + value: 0.000687 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 6.87e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 6.87e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (15.42 mg, 0.07 mmol) and(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (39.8 mg, 0.07 mmol)nbsp;were added to a degassed mixture of 2-chloro-3-fluoro-5-methylpyridine (100 mg, 0.69 mmol), tert-butyl carbamate (121 mg, 1.03 mmol) and cesium carbonate (336 mg, 1.03 mmol) in dioxane (10 mL) at 21C.nbsp;The resulting mixture was stirred at 100 C for 16 hours.Filtered through celite and adsorbed onto silica.The crude product was purified by flash silica chromatography, elution gradient 0 to 50% DCM in heptane. Pure fractions were evaporated to dryness to afford sm by HNMRAbandoned.nbsp;nbsp;p" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CC(=C(N=C1)NC(=O)OC(C)(C)C)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 25.74 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/02/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "664" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "[OH-].[Na+]" + } + amount { + moles { + value: 0.00103 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N" + } + amount { + moles { + value: 0.000893 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC(=C(N=C1)Cl)F" + } + amount { + moles { + value: 0.000687 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 6.87e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 6.87e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (15.42 mg, 0.07 mmol) and(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (39.8 mg, 0.07 mmol)nbsp;were added to a degassed mixture of 2-chloro-3-fluoro-5-methylpyridine (100 mg, 0.69 mmol), tert-butyl carbamate (105 mg, 0.89 mmol) and 2-chloro-3-fluoro-5-methylpyridine (100 mg, 0.69 mmol) in dioxane (10 mL) at 21C.nbsp;The resulting mixture was stirred at 100 C for 2 hours.Cooled. Adsorbed onto silica.The crude product was purified by flash silica chromatography, elution gradient 10 to 30% DCM in heptane. Pure fractions were evaporated to dryness to afford tert-butyl 3-fluoro-5-methylpyridin-2-ylcarbamate (40.0 mg, 25.7 %) as a cream solid. not pure enough to registernbsp;nbsp;p" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CC(=C(N=C1)NC(=O)OC(C)(C)C)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 25.74 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/06/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "665" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.7 [N-arylation with Ar-X] Chloro N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0079 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H](C1)C(=O)N" + } + amount { + moles { + value: 0.00263 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CCC2=C(C=NN2CC1)C3=CC(=NC=C3F)Cl" + } + amount { + moles { + value: 0.00263 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000527 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.[Pd]" + } + amount { + moles { + value: 0.000263 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Tetrakis(triphenylphosphine)palladium(0) (0.304 g, 0.26 mmol) was added to 3-(2-chloro-5-fluoropyridin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepine (0.700 g, 2.63 mmol), tert-butyl ((1R,3S)-3-carbamoylcyclohexyl)carbamate (0.638 g, 2.63 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.305 g, 0.53 mmol) and Cesium carbonate (2.58 g, 7.90 mmol) innbsp;1,4-dioxane (10 mL)Degassed for 5 mins under nitrogen and the resulting suspension was stirred at 120 C for 17 hours in the microwave reactor. The reaction mixture was partitioned between water (20ml) and ethyl acetate (100ml) filtered and separated. The organics were absorbed onto silica and purified by flash silica chromatography, elution gradient 1:1 EtOAc in heptane. Pure fractions were evaporated to dryness to afford tert-butyl ((1R,3S)-3-((5-fluoro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate (0.900 g, 72.4 %) as a white solid. Product is crude so used directly in the next step." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H](C1)C(=O)NC2=NC=C(C(=C2)C3=C4CCCCCN4N=C3)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 72.45 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/09/2015" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "666" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0254 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.06 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1CCNCC1" + } + amount { + moles { + value: 0.0212 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1Br)Br" + } + amount { + moles { + value: 0.0212 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00159 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.00053 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 85.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A suspension of ethyl piperidine-4-carboxylate (3.27 mL, 21.20 mmol), 1,4-dibromobenzene (5 g, 21.20 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.485 g, 0.53 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.990 g, 1.59 mmol) and Sodium Tert-Butoxide (2.444 g, 25.43 mmol) in anhydrous toluene (60 mL) was stirred at 85 C under nitrogen for 16 hours.nbsp;The reaction was cooled to ambient temperature, diluted with Ether (100 mL) and filtered through celite.nbsp;The filtrate was evaporated in vacuo to yield crude product.nbsp;The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in heptane.nbsp;Pure fractions were evaporated to dryness to afford ethyl 1-(4-bromophenyl)piperidine-4-carboxylate (3.91 g, 59.1 %) as a yellow oil. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1CCN(CC1)C2=CC=C(C=C2)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 59.1 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/17/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "667" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00743 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.03 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1CCNC1" + } + amount { + moles { + value: 0.00619 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1Br)Br" + } + amount { + moles { + value: 0.00619 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000465 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000155 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 85.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A suspension of methyl pyrrolidine-3-carboxylate (800 mg, 6.19 mmol), 1,4-dibromobenzene (1461 mg, 6.19 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (142 mg, 0.15 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (289 mg, 0.46 mmol) and Sodium Tert-Butoxide (714 mg, 7.43 mmol) in anhydrous toluene (30 mL) was stirred at 85 C under nitrogen for 4 hours.nbsp;The reaction was cooled to ambient temperature, diluted with Ether (100 mL) and filtered through celite.nbsp;The filtrate was evaporated in vacuo to yield crude product.nbsp;The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in heptane.nbsp;Pure fractions were evaporated to dryness to afford methyl 1-(4-bromophenyl)pyrrolidine-3-carboxylate (513 mg, 29.1 %) as a yellow solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC(=O)C1CCN(C1)C2=CC=C(C=C2)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 29.15 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/24/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "668" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0195 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.06 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1CCNC1" + } + amount { + moles { + value: 0.0163 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1Br)Br" + } + amount { + moles { + value: 0.0163 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00122 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000406 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 85.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A suspension of methyl pyrrolidine-3-carboxylate (2.1 g, 16.26 mmol), 1,4-dibromobenzene (3.84 g, 16.26 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.372 g, 0.41 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.759 g, 1.22 mmol) and Sodium Tert-Butoxide (1.875 g, 19.51 mmol) in anhydrous toluene (60 mL) was stirred at 85 C under nitrogen for 16 hours.nbsp;The reaction was cooled to ambient temperature, diluted with Ether (100 mL) and filtered through celite.nbsp;The filtrate was evaporated in vacuo to yield crude product.nbsp;The crude product was purified by flash silica chromatography, elution gradient 5 to 20% EtOAc in heptane.nbsp;Pure fractions were evaporated to dryness to afford methyl 1-(4-bromophenyl)pyrrolidine-3-carboxylate (1.460 g, 31.6 %) as a yellow solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC(=O)C1CCN(C1)C2=CC=C(C=C2)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 31.6 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/28/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "671" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00451 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00205 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)NC1=CC(=C(C=C1)OC)Br" + } + amount { + moles { + value: 0.00205 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 0.00041 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000205 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A solution of N-(3-bromo-4-methoxyphenyl)acetamide (0.5 g, 2.05 mmol) dissolved in toluene (5 mL) was treated with tert-butyl piperazine-1-carboxylate (0.382 g, 2.05 mmol), diacetoxypalladium (0.046 g, 0.20 mmol), dicyclohexyl(2\',6\'-diisopropoxybiphenyl-2-yl)phosphine (0.191 g, 0.41 mmol) and sodium 2-methylpropan-2-olate (0.433 g, 4.51 mmol)nbsp;in a sealed tube. The resulting mixture was degassed and stirred at 100 C for 8 hours in a microwave. The mixture was pre-absorbed onto silica. The crude product was purified by flash silica chromatography, elution 50% ethyl acetate in Heptane. Pure fractions were evaporated to dryness to afford intermediate. The intermediate was dissolved in 4M HCl in dioxane (10mL) and stirred at RT overnight. The mixture was evaporated to give N-(4-methoxy-3-(piperazin-1-yl)phenyl)acetamide (0.260 g, 50.9 %) as a tan solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)NC1=CC(=C(C=C1)OC)N2CCNCC2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 50.91 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/31/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "672" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000177 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0025 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCN(CC1)CC2=CC(=CC=C2)N" + } + amount { + moles { + value: 0.000177 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)NC(=O)C2=CC3=C(C=C2)OCCO3)NC(=O)C4=CN=C(C=C4)Cl" + } + amount { + moles { + value: 0.000118 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.08e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 3.54e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of 6-chloro-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)nicotinamide (50 mg, 0.12 mmol),3-((4-methylpiperazin-1-yl)methyl)aniline (36.3 mg, 0.18 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4.10 mg, 7.08 mol),TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (3.24 mg, 3.54 mol),sodium 2-methylpropan-2-olate (17.01 mg, 0.18 mmol) in toluene (2 mL)IPA (0.500 mL)was degassed with nitrogen and heated at reflux for 18 hours.The reaction mixture was filtered and filtered solid washed with ethyl acetate. The organic filtrate was washed with water (50ml), and organic layer dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamlphenyl)-6-(3-((4-methylpiperazin-1-yl)methyl)phenylamino)nicotinamide (18.10 mg, 25.9 %) as a beige solid. nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)NC(=O)C2=CC3=C(C=C2)OCCO3)NC(=O)C4=CN=C(C=C4)NC5=CC=CC(=C5)CN6CCN(CC6)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 25.89 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/21/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "675" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00127 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0065 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCC1CN" + } + amount { + moles { + value: 0.000848 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)I)Br" + } + amount { + moles { + value: 0.000848 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000127 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 6.36e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium (II) acetate (14.28 mg, 0.06 mmol) and racemic-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (79 mg, 0.13 mmol) were suspended in toluene (3 mL). The mixture was evacuated and purged with nitrogen, and warmed to 50C.In a separate vessel, 1-bromo-3-iodobenzene (240 mg, 0.85 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (98 mg, 0.85 mmol) and sodium-t-butoxide (122 mg, 1.27 mmol) were suspended in toluene (3.5 mL). The resulting mixture was evacuated, purged with nitrogen and warmed to 50C. After ~30 mins, the catalyst mixture was transferred to the reaction vessel. The reaction was evacuated and purged with nitrogen and heated at 80C overnight.This reaction was combined with EN06953-06 for purification.The mixture was filtered and purified by flash silica chromatography, elution gradient 0 to 40% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 3-bromo-N-((tetrahydro-2H-pyran-4-yl)methyl)aniline (71.0 mg, 31.0 %) as a colourless ostallised on standing. The main impurity was isolated (EN06953-09-02) but this was not identified; assume it is BINAP or the catalyst- ligand complex. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1COCCC1CNC2=CC(=CC=C2)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 30.98 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/22/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "677" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.9 [N-arylation with Ar-X] Iodo N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0119 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.137 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)N" + } + amount { + moles { + value: 0.014 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC(=CC(=C1)I)Br" + } + amount { + moles { + value: 0.014 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.0014 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.0014 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (0.314 g, 1.40 mmol) and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.871 g, 1.40 mmol) were added to a degassed mixture of methyl 3-bromo-5-iodobenzoate (4.77 g, 13.99 mmol), aniline (2.55 ml, 13.99 mmol) and cesium carbonate (3.87 g, 11.89 mmol) in toluene (137 ml) under nitrogen. The resulting mixture was stirred at 110 C for 18 hours. The resulting mixture was evaporated to dryness and the residue was diluted with EtOAc (150 mL), and washed with water (100 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 15% EtOAc in heptane. Pure fractions were evaporated to dryness to afford methyl 3-bromo-5-(phenylamino)benzoate (1.735 g, 40.5 %) as a pale yellow solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC(=O)C1=CC(=CC(=C1)Br)NC2=CC=CC=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 40.51 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/19/2016" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "678" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000977 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CN=C1)CN" + } + amount { + moles { + value: 0.000537 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Pyridin-3-ylmethanamine (58.1 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford N2-phenyl-N4-(pyridin-3-ylmethyl)pyridine-2,4-diamine (80 mg, 59.2 %) as an off white solid.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)NCC3=CN=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 59.25 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/05/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "680" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.7 [N-arylation with Ar-X] Chloro N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00113 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H](C1)C(=O)N" + } + amount { + moles { + value: 0.000452 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1(CC2=NC=C(N2C1)C3=CC(=NC=C3F)Cl)C" + } + amount { + moles { + value: 0.000376 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.53e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.[Pd]" + } + amount { + moles { + value: 3.76e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Tetrakis(triphenylphosphine)palladium(0) (43.5 mg, 0.04 mmol) was added to 3-(2-chloro-5-fluoropyridin-4-yl)-6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (100 mg, 0.38 mmol), tert-butyl ((1R,3S)-3-carbamoylcyclohexyl)carbamate (109 mg, 0.45 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (43.6 mg, 0.08 mmol) and Cesium carbonate (368 mg, 1.13 mmol) in 1,4-dioxane (5.98 ml).nbsp;Degassed for 5 mins under nitrogen and the resulting suspension was stirred at 120 C for 3 hours in the microwave reactor. The reaction mixture was partitioned between water (20ml) and DCM (40ml) and separated using a phase separation cartridge.nbsp;The organics were absorbed onto silica and purified by flash silica chromatography, elution gradient 0 to 60% EtOAc in heptane. Pure fractions were evaporated to dryness to afford starting material (100mg)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1(CC2=NC=C(N2C1)C3=CC(=NC=C3F)NC(=O)[C@H]4CCC[C@H](C4)NC(=O)OC(C)(C)C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 80.01 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/07/2015" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "681" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 4.84e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1CCNCC1" + } + amount { + moles { + value: 0.000678 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC(=NC=C1Br)Cl" + } + amount { + moles { + value: 0.000484 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 4.84e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.42e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.18 mg, 0.02 mmol) was added to a degassed mixture of ethyl piperidine-4-carboxylate (0.105 mL, 0.68 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)(xantphos) (28.0 mg, 0.05 mmol) and ethyl 1-(6-chloro-4-methylpyridin-3-yl)piperidine-4-carboxylate and sodium 2-methylpropan-2-olate (65.2 mg, 0.68 mmol) in toluene (3 mL). The resulting suspension was stirred at 100 C for 20 hours under nitrogen. LCMS indicated little reaction so reaction abandoned. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1CCN(CC1)C2=CN=C(C=C2C)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/21/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "682" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 9.69e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1CCNCC1" + } + amount { + moles { + value: 0.000678 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC(=NC=C1Br)Cl" + } + amount { + moles { + value: 0.000484 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 9.69e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.84e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A solution of diacetoxypalladium (10.87 mg, 0.05 mmol) and dicyclohexyl(2\',6\'-diisopropoxy-[1,1\'-biphenyl]-2-yl)phosphine (45.2 mg, 0.10 mmol) dissolved in toluene (3 mL) was degassed and heated to 50C for 30 minutes before adding ethyl piperidine-4-carboxylate (0.105 mL, 0.68 mmol), 5-bromo-2-chloro-4-methylpyridine (100 mg, 0.48 mmol) and sodium 2-methylpropan-2-olate (74.5 mg, 0.77 mmol) under nitrogen. The mixture was heated to 100C for 2 hours. nbsp;LCMS indicated little product so reaction abandon" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1CCN(CC1)C2=CN=C(C=C2C)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/23/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "683" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000977 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC=CC=C1CN" + } + amount { + moles { + value: 0.000537 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.91e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(2-methoxyphenyl)methanamine (73.7 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford N4-(2-methoxybenzyl)-N2-phenylpyridine-2,4-diamine (90 mg, 60.3 %) as an off-white solid.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=CC=CC=C1CNC2=CC(=NC=C2)NC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 60.32 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/05/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "684" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000977 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC=CC=C1CN" + } + amount { + moles { + value: 0.000537 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.91e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(2-methoxyphenyl)methanamine (73.7 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness and purified by C18 silica chromatography, elution gradient 40 to 70% MeCN in Water + 1% NH4OH. Fractions containproduct were evaporated to dryness to afford N4-(2-methoxybenzyl)-N2-phenylpyridine-2,4-diamine (16.00 mg, 10.72 %) as a yellow gum.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=CC=CC=C1CNC2=CC(=NC=C2)NC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 10.72 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/01/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "685" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000852 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CN" + } + amount { + moles { + value: 0.000469 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000426 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Phenylmethanamine (50.2 mg, 0.47 mmol), 4-chloro-N-(4-methoxyphenyl)pyridin-2-amine (100 mg, 0.43 mmol) and sodium 2-methylpropan-2-olate (82 mg, 0.85 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (28.4 mg, 0.05 mmol) and diacetoxypalladium (7.65 mg, 0.03 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford N4-benzyl-N2-(4-methoxyphenyl)pyridine-2,4-diamine (77 mg, 59.2 %) as an off-white solid.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=CC=C(C=C1)NC2=NC=CC(=C2)NCC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 59.17 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/01/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "687" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[K+].[K+]" + } + amount { + moles { + value: 0.0027 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.008 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C2=C(N1C)C=CC(=C2)N)Cl" + } + amount { + moles { + value: 0.000988 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NN(C=C1C=O)C2=NC(=NC=C2)Cl" + } + amount { + moles { + value: 0.000898 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 8.98e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.49e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 40 mL scintillation vial charged with 3-chloro-1,2-dimethyl-1H-indol-5-amine (192 mg, 0.99 mmol), 1-(2-chloropyrimidin-4-yl)-3-methyl-1H-pyrazole-4-carbaldehyde (200mg, 0.90 mmol), palladium(II) acetate (10.08 mg, 0.04 mmol), dicyclohexyl(2\',4\',6\'-triisopropyl-[1,1\'-biphenyl]-2-yl)phosphine (x--phos) (42.8 mg, 0.09 mmol) and Dioxane (8mL) After being degassed by nitrogen bubbling , the reaction mixture was heated 100 C for 6 hours. At this stage most of the starting material was consumed.nbsp;The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water and brine. The organic layer separated, dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography (Isco, Hexaneethyl acetate, 0-100%, 25 minutes) to give 1-(2-((3-chloro-1,2-dimethyl-1H-indol-5-yl)amino)pyrimidin-4-yl)-3-methyl-1H-pyrazole-4-carbaldehyde (221 mg, 64.6 %) as a yellow solid. LCMS (2 minute, Acid _CV10.olp method) 381 (M + 1), 1.27 minutes." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C2=C(N1C)C=CC(=C2)NC3=NC=CC(=N3)N4C=C(C(=N4)C)C=O)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 64.6 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/07/2014" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "689" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00139 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=C2C(=CC(=C1F)F)NC(=O)C=C2Cl" + } + amount { + moles { + value: 0.000464 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C[C@H]1C[C@@H](CCN1C(=O)C2=C(N(N=C2)C)Cl)N.C(=O)(C(F)(F)F)O" + } + amount { + moles { + value: 0.000464 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 4.64e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.64e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 140.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "4-chloro-6,7-difluoroquinolin-2(1H)-one (100 mg, 0.46 mmol) was taken in a microwave tube. Added ((2S,4R)-4-amino-2-methylpiperidin-1-yl)(5-chloro-1-methyl-1H-pyrazol-4-yl)methanone 2,2,2-trifluoroacetate (172 mg, 0.46 mmol), followed by the addition of Palladium (II) acetate (10.41 mg, 0.05 mmol), racemic-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (28.9 mg, 0.05 mmol), Cesium carbonate (111 mL, 1.39 mmol), N,N\'-Diisopropylethylamine (242 mL, 1.39 mmol).nbsp;toluene (10 mL) was added and jected to microwave with the following parameters.Temperaturenbsp;140 CTime 60 minutesAfter the completion of the reaction, dissolved the compound in methanol and purified by column" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@H]1C[C@@H](CCN1C(=O)C2=C(N(N=C2)C)Cl)NC3=CC(=O)NC4=CC(=C(C=C43)F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 49.46 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/28/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "690" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00835 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.06 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=C2C(=CC(=C1F)F)NC(=O)C=C2Cl" + } + amount { + moles { + value: 0.00278 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C[C@H]1C[C@@H](CCN1C(=O)C2=C(N(N=C2)C)Cl)N.C(=O)(C(F)(F)F)O" + } + amount { + moles { + value: 0.00417 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000278 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000278 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 140.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "((2S,4R)-4-amino-2-methylpiperidin-1-yl)(5-chloro-1-methyl-1H-pyrazol-4-yl)methanone 2,2,2-trifluoroacetate (1548 mg, 4.17 mmol) was taken in a 100ml single necked flask equipped with a reflux condenser connected to nitrogen source. Added 4-chloro-6,7-difluoroquinolin-2(1H)-one (600 mg, 2.78 mmol), followed by the addition of racemic-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (173 mg, 0.28 mmol), Palladium (II) acetate (62.5 mg, 0.28 mmol),nbsp;and Cesium carbonate (668 mL, 8.35 mmol). toluene (60 mL) was added followed by the addition of N,N\'-Diisopropylethylamine (1454 mL, 8.35 mmol).The contents of the flask were purged with nitrogen for 5 minutes and heate at 140 C for overnight.After the completion of the reaction, added methanol, and adsorbed on silica gel, and purified by reverse phase column." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@H]1C[C@@H](CCN1C(=O)C2=C(N(N=C2)C)Cl)NC3=CC(=O)NC4=CC(=C(C=C43)F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 23.08 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/01/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "692" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000977 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1CN)F" + } + amount { + moles { + value: 0.000537 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(4-fluorophenyl)methanamine (67.3 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford N4-(4-fluorobenzyl)-N2-phenylpyridine-2,4-diamine (86 mg, 60.0 %) as an off-white solid.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)NCC3=CC=C(C=C3)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 60.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/01/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "693" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00802 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCC1CN" + } + amount { + moles { + value: 0.00535 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC=C(C=C1)Br" + } + amount { + moles { + value: 0.00535 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000802 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000401 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium (II) acetate (0.090 g, 0.40 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.464 g, 0.80 mmol) were suspended in toluene (3 mL). The mixture was evacuated and purged with nitrogen, and warmed to 50C.In a separate vessel, 1-bromo-4-methoxybenzene (1 g, 5.35 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (0.654 mL, 5.35 mmol) and sodium-t-butoxide (0.771 g, 8.02 mmol) were suspended in toluene (7 mL). The resulting mixture was evacuated, purged with nitrogen and warmed to 50C. After ~30 mins, the catalyst mixture was transferred to the reaction vessel. The reaction was evacuated and purged with nitrogen and heated at 80C overnight. The mixture was diluted with water (250 mL), and extracted with ethyl acetate (200 mL).nbsp;The organic was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH antions were evaporated to dryness to afford 4-methoxy-N-((tetrahydro-2H-pyran-4-yl)methyl)aniline (0.270 g, 22.82 %) as a brown oil. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=CC=C(C=C1)NCC2CCOCC2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 22.82 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/29/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "694" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 5.86e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CN" + } + amount { + moles { + value: 0.000537 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 5.86e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.91e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Phenylmethanamine (57.6 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. 2-Dicyclohexylphosphino-2\',6\'-di-i-propoxy-1,1\'-biphenyl (27.4 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by preparative HPLC (Waters SunFire column, 5 silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness N4-benzyl-N2-phenyl-2,4-diamine (17.80 mg, 13.23 %) as an off-white solid. nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 13.23 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/11/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "695" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 5.86e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CN" + } + amount { + moles { + value: 0.000537 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=C(C=CC(=C2P(C3CCCCC3)C4CCCCC4)OC)OC)C(C)C" + } + amount { + moles { + value: 5.86e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.91e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Phenylmethanamine (57.6 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. Dicyclohexyl(2\',4\',6\'-triisopropyl-3,6-dimethoxy-[1,1\'-biphenyl]-2-yl)phosphine (31.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by preparative HPLC (Waters SunFire column, 5 silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing product were evaporated to dryness to afbenzyl-N2-phenylpyridine-2,4-diamine (8.50 mg, 6.32 %) as an off white solid.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 6.32 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/23/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "696" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000977 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CN" + } + amount { + moles { + value: 0.000537 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.91e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Phenylmethanamine (57.6 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by preparative HPLC (Waters SunFire column, 5 silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing product were evaporated to dryness to affordyl-N2-phenylpyridine-2,4-diamine (72.4 mg, 53.8 %) as an off-white solid.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 53.81 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/23/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "697" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000977 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CN" + } + amount { + moles { + value: 0.000782 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.91e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Phenylmethanamine (84 mg, 0.78 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by preparative HPLC (Waters SunFire column, 5 silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing product were evaporated to dryness to afford N-N2-phenylpyridine-2,4-diamine (85 mg, 63.1 %) as an off-white solid.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 63.1 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/25/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "698" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 5.86e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CN" + } + amount { + moles { + value: 0.000537 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=C(C=CC(=C2P(C3CCCCC3)C4CCCCC4)OC)OC)C(C)C" + } + amount { + moles { + value: 5.86e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.91e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Phenylmethanamine (57.6 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. Dicyclohexyl(2\',4\',6\'-triisopropyl-3,6-dimethoxy-[1,1\'-biphenyl]-2-yl)phosphine (31.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was thermally heated to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by preparative HPLC (Waters SunFire column, 5 silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing product were evaporated to dryness to afbenzyl-N2-phenylpyridine-2,4-diamine (49.6 mg, 36.9 %) as an off white solid.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 36.87 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/30/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "699" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 5.86e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CN" + } + amount { + moles { + value: 0.000537 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=C(C=CC(=C2P(C3CCCCC3)C4CCCCC4)OC)OC)C(C)C" + } + amount { + moles { + value: 5.86e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.91e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Phenylmethanamine (57.6 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. Dicyclohexyl(2\',4\',6\'-triisopropyl-3,6-dimethoxy-[1,1\'-biphenyl]-2-yl)phosphine (31.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was thermally heated to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by preparative HPLC (Waters SunFire column, 5 silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing product were evaporated to dryness to afbenzyl-N2-phenylpyridine-2,4-diamine (56.5 mg, 42.0 %) as an off white solid.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 41.99 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/08/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "700" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 5.86e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CN" + } + amount { + moles { + value: 0.000537 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 5.86e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.91e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Phenylmethanamine (57.6 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. 2-Dicyclohexylphosphino-2\',6\'-di-i-propoxy-1,1\'-biphenyl (27.4 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 1.5 hours under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by preparative HPLC (Waters SunFire column, 5 silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness N4-benzyl-N2-ridine-2,4-diamine (6.50 mg, 4.83 %) as an off-white solid. nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 4.83 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/24/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "702" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000977 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CN" + } + amount { + moles { + value: 0.000537 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.91e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Phenylmethanamine (57.6 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol)-diacetoxypalladium (8.78 mg, 0.04 mmol), (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2.00 mL) and sealed into a microwave tube. The reaction was heated thermally to 100 C for 30 minutes and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N4-benzyl-N2-phenylpyridine-2,4-diamine (66.4 mg, 49.4 %) as an off-white solid.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 49.35 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/20/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "703" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000977 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CN" + } + amount { + moles { + value: 0.000537 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.91e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Phenylmethanamine (57.6 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture in DMA (1 mL). Nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford N4-benzyl-N2-phenylpyridine-2,4-diamine (93 mg, 69.1 %) as an off-white solid.nbsp;nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 69.12 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/24/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "704" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000977 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CN" + } + amount { + moles { + value: 0.000537 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.91e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Phenylmethanamine (57.6 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol)-diacetoxypalladium (8.78 mg, 0.04 mmol), (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2.00 mL) and sealed into a microwave tube. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N4-benzyl-N2-phenylpyridine-2,4-diamine (77 mg, 57.0 %) as an off-white solid. nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 57.01 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/20/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "705" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000977 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CN" + } + amount { + moles { + value: 0.000537 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.91e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Phenylmethanamine (57.6 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford EN06208-42-01 (98 mg, 0.356 mmol, 72.8 %) as an off-white solid.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 72.84 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/24/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "706" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00244 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.0025 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CN" + } + amount { + moles { + value: 0.00134 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.00122 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 0.00015 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 9.77e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Phenylmethanamine (144 mg, 1.34 mmol), 4-chloro-N-phenylpyridin-2-amine (250 mg, 1.22 mmol)-diacetoxypalladium (21.94 mg, 0.10 mmol), (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (81 mg, 0.15 mmol) and sodium 2-methylpropan-2-olate (235 mg, 2.44 mmol) were suspended in DMA (2.50 mL) in a partially sealed tube. The reaction was heated thermally to 80 C for 1 hour, followed by 90C overnight and cooled to RT. The reaction mixture was filtered through celite using methanol, neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N4-benzyl-N2-phenylpyridine-2,4-diamine (33.0 mg, 9.81 %) as a brown gum. n" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 9.81 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/19/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "707" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000977 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CN" + } + amount { + moles { + value: 0.000537 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 5.86e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Phenylmethanamine (57.6 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol)-diacetoxypalladium (8.78 mg, 0.04 mmol), (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2.00 mL) in a partially sealed tube. The reaction was heated thermally to 100 C for 30 minutes and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20g SCX column. The crude product was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N4-benzyl-N2-phenylpyridine-2,4-diamine (7.60 mg, 5.65 %) as an off-white solid.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 5.65 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/20/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "710" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00403 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0249 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2" + } + amount { + moles { + value: 0.00252 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC=CC=C1Br" + } + amount { + moles { + value: 0.00252 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000101 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 5.04e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 105.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.046 g, 0.05 mmol) and rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.063 g, 0.10 mmol) were mixed together and evacuated and purged with nitrogen 3 times. toluene (24.91 ml) was added and the resulting mixture heated to 50C for 10 minutes.In a second reaction vessel was mixed sodium tert-butoxide (0.387 g, 4.03 mmol), (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.500 g, 2.52 mmol), 1-bromo-2-methoxybenzene (0.314 ml, 2.52 mmol) and toluene (24.91 ml). The mixture was evacuated and purged with nitrogen 3 times. The solution of catalyst was added to the reaction mixture and the resulting mixture was heated at 105 C for 16 hours.The reaction mixture was cooled to RT and filtered through celite and evaporated.The crude product was purified by flash silica chromatography, elution gradient 100% DCM. Pure fractions were evaporated to dryness to afford (1S,4S)-tert-butyl 5-(2-methoxyphenyl)-2,5-diazabic.1]heptane-2-carboxylate (0.529 g, 68.9 %) as a yellow gum. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C3=CC=CC=C3OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 68.91 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/02/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "711" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00225 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CCNCC1" + } + amount { + moles { + value: 0.00225 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C=C1C(=O)O)Cl)Br" + } + amount { + moles { + value: 0.0015 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "4-bromo-3-chlorobenzoic acid (0.353 g, 1.5 mmol), piperidine (0.234 mL, 2.25 mmol), and sodium tert-butoxide (0.216 g, 2.25 mmol) were stirred together under N2 and heated to 80 C. Pd2(dba)3 (0.014 g, 0.015 mmol), and BINAP (0.031 g, 0.05 mmol) were mixed in toluene (2 mL) and then added to the mixture and stirred at 110 C overnight. LCMS showed a very small amount of desired product (~2%). The reaction mixture was degassed with N2 for 30 minutes, then addtional Pd Binap was added. The reaction was again heated to 110 C. LCMS showed a small amount of desired product (~10%) but mostly still starting material. The desired product was not isolated from this reacti" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CCN(CC1)C2=C(C=C(C=C2)C(=O)O)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/10/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "712" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "[Li+].C[Si](C)(C)[N-][Si](C)(C)C" + } + amount { + moles { + value: 0.015 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1CCOC1" + } + amount { + volume { + value: 0.015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CCNC1" + } + amount { + moles { + value: 0.00734 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC2=C(C=C1Br)NN=C2" + } + amount { + moles { + value: 0.00609 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 0.000122 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4.C1=CC=C([C-]=C1)CCN.[Cl-].[Pd+2]" + } + amount { + moles { + value: 0.00012 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 60.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "uThis reaction is done in triplicateu:6-bromo-1H-indazole (1.2 g, 6.09 mmol, 1 eq each), chloro(2-dicyclohexylphosphino-2\',6\'-di-i-propoxy-1,1\'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (RuPhos-PreCatalyst) (89 mg, 0.12 mmol, 0.02 eq each), 2-Dicyclohexylphosphino-2\',6\'-di-i-propoxy-1,1\'-biphenyl (RuPhos ligand) (57 mg, 0.12 mmol, 0.02 eq, each) were taken a stoppered bottle, flush with N2, pyrrolidine (0.60 ml, 522 mg. 7.34 mmol, 1.2 eq, each) and lithium bis(trimethylsilyl)amide (1M soln in THF, 15 ml, 15 mmol, 2.46 eq, each) were added in succession, flushed with N2, stoppered the bottle and stirred at 60 C. LC-MS, after 2 hrs, showed that all the starting material is consumed. Cooled to r.t, queched the reaction with 2M HCl (9 ml, each), combined the reaction mixture and then extracted with EtOAc (250 ml) and saturated NaHCO3 (aq) soln. The organics was collected and the aq. layer was further extracted with EtOAc (250 ml). The combined organics was fer washed with brine (250 ml). The organics was collected, dried (Na2SO4), filtered and evaporated to a brown solid (4.01 g, combined crude yield). The residue was chroamtographed (SiO2 - 100 g, Biotage-Pre-packed colum, heptane-EtOAC 5:1 to 2:1 gradiant. The appropriate fractions were combined and evaporated to a light brown solids (TLC: Rf = 15 mm63 mm, heptane-EtOAc 1:1, ucompound in TLC plate beome grey colored upon standing for few minutesu) corresponds to the required product (P1) (Starting material comes at 28 mm63 mm in the same solvent system).uEN07765-42-01 (SN1050263564; AZ13824296-001u): 3.207 g (total yield, so each batch should be 1.069 g, 94%, ca 96% pure).1H NMR (500 MHz, DMSO) d 1.94 - 2 (m, 4H), 3.27 (t, 4H), 6.34 (s, 1H), 6.56 (dd, 1H), 7.50 (d, 1H), 7.78 (s, 1H), 12.35 (s, 1H).Expected Number of Hs: 13. Assigned Hs: 13.LC-MS: ESI-MS mz: [M+H]+ 188.2. Rf = 1.59 min4 min and 1.48 min4 min in acidic (pH3) and basic (pH10) system repectively.TLC: Rf = 15 mm64 mm (SiO2-glas plate, heptane-EtOAc 1:1 vv, spots were detected by UV254 (uspot became grey colored upon standing the plate at r.tu.)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CCN(C1)C2=CC3=C(C=C2)C=NN3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 93.74 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/17/2015" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "722" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00118 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.008 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCNCC1" + } + amount { + moles { + value: 0.000619 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C(=NC(=N1)Br)Br" + } + amount { + moles { + value: 0.000589 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000177 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 8.84e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of 3,5-dibromo-1-methyl-1H-1,2,4-triazole (142 mg, 0.59 mmol), 1-methylpiperazine (62.0 mg, 0.62 mmol), tris(dibenzylideneacetone)dipalladium(0) (81 mg, 0.09 mmol), BINAP (110 mg, 0.18 mmol) and sodium tert-butoxide (113 mg, 1.18 mmol) in toluene (8 ml) was stirred at 100 C for 1.5hrs. LCMS indicated no desired product formation. Discarded." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CCN(CC1)C2=NC(=NN2C)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/04/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "723" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00362 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.008 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CC(C1)N" + } + amount { + moles { + value: 0.00249 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(N=C1)Br)Cl" + } + amount { + moles { + value: 0.00208 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 3.12e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.58e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 115.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Pd2(dba)3 (0.014 g, 0.02 mmol), 2,2\'-bis(diphenylphosphanyl)-1,1\'-binaphthalene (BINAP) (0.019 g, 0.03 mmol) and toluene (8 mL) was added to a flask. 2-bromo-3-chloropyridine (0.4 g, 2.08 mmol), cyclobutanamine (0.177 g, 2.49 mmol) and sodium 2-methylpropan-2-olate (0.348 g, 3.62 mmol) was added, the mixture bubbled with N2 for 5 min, then the reaction was heated to 115 C in an oil-bath under nitrogen. LC-MS 1h: 33% product, 21% sm left.The reaction was cooled to rt and the solvent was evaporated.The residue was purified by automated flash chromatography on a 50g column. A gradient from 0% to 50% of EtOAc in heptane over 15CV was used as mobile phase. The product was collected using the wavelength 245 and 311 nm, relevant fractions pooled and evaporated to give 95 mg clear oil.1H-NMR: OK, some extra small peaks in aromatic region (sm or dba?).1H NMR (400 MHz, CDCl3) d 1.65 - 2.01 (m, 4H), 2.45 (dtd, 2H), 4.54 (h, 1H), 6.49 (dd, 1H), 7.41 (dd, 1H), 8.01 (dd, 1H)Expected Number of Hs: 11Assigned Hs: 10, NH not assigned.LC-MS: OK, 86% product. M+1=183 found." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CC(C1)NC2=C(C=CC=N2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 25.02 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/30/2016" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "724" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "[Li+].C[Si](C)(C)[N-][Si](C)(C)C" + } + amount { + moles { + value: 0.0139 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1CCOC1" + } + amount { + volume { + value: 0.001 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCC1O" + } + amount { + moles { + value: 0.0076 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=CC=C1Br" + } + amount { + moles { + value: 0.00633 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C1=CC=CC=C1C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 0.000633 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000633 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 65.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;In a 50 ml round bottomed flask THF (1 mL) was added to a mixture of 4-bromopyridine (1 g, 6.33 mmol), pyrrolidin-3-ol (0.662 g, 7.60 mmol),2-(dimethylamino)-2\'-(dicyclohexylphosphino)biphenyl (0.249 g, 0.63 mmol)nbsp;and Pd2(dba)3 (0.580 g, 0.63 mmol). To the slurry lithium bis(trimethylsilyl)amide (13.92 mL, 13.92 mmol) was added dropwise at 0 C and the solution was refluxed at 65 C overnight for 20 hrs. The reaction mixture was passed through celite, concentrated and column purified (0-20%MeOHDCM) to obtain 0.447 mg of produ" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CN(CC1O)C2=CC=NC=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 43.01 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/22/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "725" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0013 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C=O" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1C(CN1)(F)F.Cl" + } + amount { + moles { + value: 0.000478 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)CC1=NC=CC(=C1)Br" + } + amount { + moles { + value: 0.000435 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 4.35e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 6.95e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "palladium acetate (1.561 mg, 6.95 mol) and BINAP (2.71 mg, 4.35 mol) were added to methyl 2-(4-bromopyridin-2-yl)acetate (100 mg, 0.43 mmol), 3,3 difluoroazetidine hydrochloride (61.9 mg, 0.48 mmol) and cesium carbonate (425 mg, 1.30 mmol) in DMF (5 mL) at 21Cnbsp;under nitrogen. The resulting mixture was stirred at 120 C for 2.5 hours. - lcms looks ok. Cooled to room temp.The reaction mixture was diluted with EtOAc (150 mL), and washed sequentially with water (75 mL), water (75 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness - 200mg yellow oil. Contained Pd impurities.The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 1M NH3MeOH and pure fractions were evaporated to dryness to afford methyl 2-(zetidin-1-yl)pyridin-2-yl)acetate (42.0 mg, 39.9 %) as a yellow gum. maybe better to avoid aq wu and just purify by SCX column." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC(=O)CC1=NC=CC(=C1)N2CC(C2)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 39.89 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/15/2014" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "726" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0121 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00904 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)C1=CC=C(C=C1)Br" + } + amount { + moles { + value: 0.00603 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000603 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000603 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a CEM MW vial, p-Bromoacetophenone (729 ml, 6.03 mmol),tert-Butyl 1-piperazinecarboxylate (1.684 g, 9.04 mmol),racemic-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.375 g, 0.60 mmol),Palladium (II) acetate (0.135 g, 0.60 mmol),Cesium carbonate (3.93 g, 12.06 mmol) was taken in toluene (10 ml).The RM was jected to MW power of 300W,temp 120C for 45 minutes. The LCMS was checked showed the formation of required mass.Work-up:The RM was passed through hyflow bed and filtrate was evaporated and chrmatographed using Ethyl acetate hexane to obtain tert-butyl 4-(4-acetylphenyl)piperazine-1-carboxylate (0.963 g, 52.5 %)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)C1=CC=C(C=C1)N2CCN(CC2)C(=O)OC(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 52.48 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/12/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "727" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00451 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC(=C(C(=C1)C)S(=O)(=O)N[C@H](CN)C(C)C)C" + } + amount { + moles { + value: 0.00301 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC2=C(C=NN2C3=CC=C(C=C3)F)C(=C1)Br" + } + amount { + moles { + value: 0.00301 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000694 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000262 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "BINAP (0.432 g, 0.69 mmol) and Pd2(dba)3 (0.24 g, 0.26 mmol) were dissolved in toluene (10 mL) and to this (S)-N-(1-amino-3-methylbutan-2-yl)-2,4,6-trimethylbenzenesulfonamide (0.856 g, 3.01 mmol) andnbsp;4-bromo-1-(4-fluorophenyl)-1H-indazole (0.876 g, 3.01 mmol) was added followed by sodium tert-butoxide (0.434 g, 4.51 mmol). The reaction mixture was degassed and the reaction tube was filled with nitrogen before it was heated at 110C for 2h. LCMS indicated 55% product and just a small amout of starting materials remained. The reaction was partitioned between EtOAc and water. The layers were separated and the aqueous extracted twice with EtOAc. The organic extracts were combined, filtered through a fine sinter funnel to remove a grey ppte and then dried using a phase separator cartridge. The solvent was removed in vacuo and the residuenbsp;purified by silica gel column chromatography (0-20% ethyl acetate in heptane). The product 340mg was obtained as a orange foam and was 90% clean by LCMS. The maal was dissolved in DMSO and mitted to WRAP. (S)-N-(1-((1-(4-fluorophenyl)-1H-indazol-4-yl)amino)-3-methylbutan-2-yl)-2,4,6-trimethylbenzenesulfonamide (0.169 g, 11.38 %). Final form unknown. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CC(=C(C(=C1)C)S(=O)(=O)N[C@H](CNC2=C3C=NN(C3=CC=C2)C4=CC=C(C=C4)F)C(C)C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 11.38 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/22/2015" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "730" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00295 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCNCC1" + } + amount { + moles { + value: 0.00221 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=C(C2=CC(=C(C=C2N=C1)OC)Br)NC3=C(C=C(C=C3)Cl)Cl" + } + amount { + moles { + value: 0.00148 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000148 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 7.38e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a solution of ethyl 6-bromo-4-(2,4-dichlorophenylamino)-7-methoxyquinoline-3-carboxylate (694 mg, 1.48 mmol) and 1-methylpiperazine (0.246 mL, 2.21 mmol) in dioxane (10 mL) was added cesium carbonate (962 mg, 2.95 mmol), tris(dibenzylideneacetone)dipalladium(0) (67.6 mg, 0.07 mmol) and rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (92 mg, 0.15 mmol). Reaction vessel in oil bath set to 100 C. 2.15pmon 20 hours - LCMS shows product (489) and SM (470)26 hours - ratio of product : SM looks better by MS.2 x on - small SM peak remaining in MS.Concentrated onto silica and purified on ISCO. 40g column, 4:1 H:EA, then gradient up to ~1:1 EA:MeOH.Can\'t find product by LCMS in any fractions. NMR of polar fractions may be acid from Buchwald coupling.Need to purify SM on column, repeat." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=C(C2=CC(=C(C=C2N=C1)OC)N3CCN(CC3)C)NC4=C(C=C(C=C4)Cl)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/29/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "731" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00169 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.075 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCC[C@H](C1)N" + } + amount { + moles { + value: 0.048 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(N=CC=C1)Br" + } + amount { + moles { + value: 0.0403 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00169 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000778 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 115.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Production using the conditions which were shown to work in EN07957-762016-03-0114:20; Pd2(DBA)3 (1.05 g) and BINAP (712 mg mg) was stirred in toluene (75 ml). 14:25; 2-bromo-3-methylpyridine (6.94 g), the amine (9.62 g), and sodium t-butoxide (5.43 g), was added to the mixture. 14:30; Heating at 115 C. In an attempt to degas the reaction by employing vacuum to the flask good reflux, indicating a slight exotherm, took place. HPLC after 5 minutes indicated complet reaction. The mixture was allowed to cool.2016-03-0209:00; Water (50 ml) was followowed by 0.5 M citric acid (~75 ml) to give pH 3. The aqueous phase was extracted with another 25 ml toluene and the combined extracts were washed with water. Removal of the solvent in vacuo followed by evaporation of the solvent gave a reddish brown residue, 13.3 g. The mixture was dissolved in toluene and purified on a 100 g silica column, 25-100% ethyl acetate over 6 columns, collecting at 300 nm. This h was repeated on a 340 g silica column to give 6.24 g oil with a clear orange color.nbsp;About 4 g more impure material was also isolated. It was realized that preparative HPLC was required for purifiaction of the material. The impurity was mainly the diphosphine oxide originating from the BINAP. All material was purifed by preparative HPLC, 15-65% ACN in TFA 0.1%. The eluents were neutralized with ammonia and the acetonitrile was removed in vacuo. Extraction with DCM, drying (magnesium sulfate) and removal of the solvent in vacuo (over the weekend) gave 8.21 g semicrystalline material.The 1H-NMR and 13C NMR looks slightly dubious (too many protons and a13C shift at 3.8 ppm) but probably good enough for further synthesis. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(N=CC=C1)N[C@@H]2CCCN(C2)C(=O)OC(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 69.75 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/01/2016" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "732" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 3.05e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0025 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCC[C@H](C1)N" + } + amount { + moles { + value: 0.00263 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(N=CC=C1)Br" + } + amount { + moles { + value: 0.002 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 3.05e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.53e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 115.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Test reaction using the conditions which were shown to work in EN07957-762016-02-2614:30; Pd2(DBA)3 (14 mg) and BINAP (19 mg) was stirred in toluene (2.5 ml). 14:35; 2-bromo-3-methylpyridine (344 mg), sodium t-butoxide (334 mg), and the amine (526 mg) was added to the mixture. 14:40; Heating at 115 C. 15:10; 81% product. 15:40; 81% product, No further progress was observed, probably because of lack of amine15:50; Another 0.4 ml amine was added to the mixture. 16:15; No further progress by HPLC, reaction terminated. 50 microlitres of the mixture was evaporated and the residue was dissolved in methanol-d4 and 1H NMR was recorded. By 1H NMR the starting pyridine was consumed completely, as opposed to the HPLC-MS which indicated 16% starting material. 2016-02-2910:35; Purification using 25-100% ethyl acetate in heptane over 6 column lengths on a 50 g column, detection at 300 nm and collection on threshold 50 mAU. Evaporation he fractions gave 480 mg oil. ee measurement showed 99.9% ee " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(N=CC=C1)N[C@@H]2CCCN(C2)C(=O)OC(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 82.37 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/26/2016" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "733" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00341 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCNCC1" + } + amount { + moles { + value: 0.00171 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C2C=CC(=CC2=C1NC3=C(C=C(C=C3)F)F)Br.Cl" + } + amount { + moles { + value: 0.00114 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000114 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 5.69e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a solution of ethyl 6-bromo-4-(2,4-difluorophenylamino)quinoline-3-carboxylate hydrochloride (505 mg, 1.14 mmol) and 1-methylpiperazine (0.189 mL, 1.71 mmol) in dioxane (10 mL) was added cesium carbonate (1113 mg, 3.41 mmol), tris(dibenzylideneacetone)dipalladium(0) (52.1 mg, 0.06 mmol) and rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (70.9 mg, 0.11 mmol). Reaction vessel in oil bath set to 100 C. 3pmon - 20 hours, LCMS shows mostly SM (408), trace of product (427). Heating stopped after 24 hours.8608 - Additional portions of Pd cat, BINAP and Me piperazine added, and reaction returned to oil bath at 105C.on - Reaction more advanced, but still mostly SM. From past experience, Buchwald coupling may be more successful if SM is purified on silica column first.Discarded" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C2C=CC(=CC2=C1NC3=C(C=C(C=C3)F)F)N4CCN(CC4)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/31/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "734" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00242 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00161 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC2=C(C(=C1)Br)NC=C2" + } + amount { + moles { + value: 0.00161 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 0.000161 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 8.05e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-Dicyclohexylphosphino-2\',6\'-di-i-propoxy-1,1\'-biphenyl (75 mg, 0.16 mmol) and palladium (II) acetate (18.08 mg, 0.08 mmol) were dissoved in toluene (2 mL) at ambient temperature. The mixture was degassed and purged with nitrogen and warmed to 50C for 20 mins.In a separate vessel, were mixed tert-butyl piperazine-1-carboxylate (300 mg, 1.61 mmol), 7-bromo-1H-indole (316 mg, 1.61 mmol) and sodium-t-butoxide (296 mL, 2.42 mmol) in toluene (3 mL). The mixture was degasssed and purged with nitrogen and warmed to 50C.The catalyst solution was added to the reaction vessel and the resulting mixture was degassed and purged with nitrogen and heated at 100C for overnight. UPLC analysis showed virtually no reaction (only 7% conversion to product).Reaction ab" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC=CC3=C2NC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/13/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "735" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00513 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00321 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC=CC=C1Br" + } + amount { + moles { + value: 0.00321 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000128 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 6.42e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.059 g, 0.06 mmol) and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.080 g, 0.13 mmol) were mixed innbsp;toluene (10 mL) and degessed at 90 C for 10 mins. The mixture was then cooled andnbsp;1-bromo-2-methoxybenzene (0.400 mL, 3.21 mmol), sodium 2-methylpropan-2-olate (0.493 g, 5.13 mmol) and tert-butyl piperazine-1-carboxylate (0.597 g, 3.21 mmol) were added. The resulting mixture was stirred at 100 C for 16 hours under nitrogen. The reaction mixture was filtered through celite and the filtrate concentrated. The crude product was purified by flash silica chromatography, elution gradient 20 to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(2-methoxyphenyl)piperazine-1-carboxylate (0.585 g, 62.4 %) as a yellow oil which crystallised on standi" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC=CC=C2OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 62.37 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/05/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "736" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.7 [N-arylation with Ar-X] Chloro N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0129 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H](C1)C(=O)N" + } + amount { + moles { + value: 0.00429 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1(CCN2C(=C(C=N2)C3=CC(=NC=C3F)Cl)C1)C" + } + amount { + moles { + value: 0.00429 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000858 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.[Pd]" + } + amount { + moles { + value: 0.000429 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Tetrakis(triphenylphosphine)palladium(0) (0.496 g, 0.43 mmol) was added to 3-(2-chloro-5-fluoropyridin-4-yl)-5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (1.2g, 4.29 mmol), tert-butyl ((1R,3S)-3-carbamoylcyclohexyl)carbamate (1.039 g, 4.29 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.496 g, 0.86 mmol) and Cesium carbonate (4.19 g, 12.87 mmol) innbsp;1,4-dioxane (10 mL)Degassed for 5 mins under nitrogen and the resulting suspension was stirred at 120 C for 17 hours in the microwave reactor. The reaction mixture was partitioned between water (20ml) and ethyl acetate (100ml) filtered and separated. The organics were absorbed onto silica and purified by flash silica chromatography, elution gradient 1:1 EtOAc in heptane. Pure fractions were evaporated to dryness to afford tert-butyl ((1R,3S)-3-((4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexyl)carbamate (1.100 g, 52.8 %) as a white solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1(CCN2C(=C(C=N2)C3=CC(=NC=C3F)NC(=O)[C@H]4CCC[C@H](C4)NC(=O)OC(C)(C)C)C1)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 52.81 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/06/2015" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "737" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000117 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CS(=O)(=O)CC1=CC(=CC(=C1)F)N" + } + amount { + moles { + value: 0.000468 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=CC(=C1)F)C2=NC(=NC=C2F)Cl" + } + amount { + moles { + value: 0.000468 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000117 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 9.35e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine (0.12 g, 0.47 mmol), 3-fluoro-5-((methylsulfonyl)methyl)aniline (0.095 g, 0.47 mmol), cesium carbonate (0.609 g, 1.87 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.068 g, 0.12 mmol)and Pd2(dba)3 (0.086 g, 0.09 mmol) were suspended in degassed 1,4-dioxane (3 mL) at ambient temperature. The resulting mixture was degassed, purged with nitrogen and heated at 100 C for 3 hours after which time reaction was shown to be complete by LC-MS. The mixture was allowed to cool overnight. The reaction mixture was diluted with water (250 mL), and extracted with DCM (250 mL).nbsp;The organic was dried over MgSO4, filtered and evaporated to afford crude product.nbsp;The crude product was purified by flash silica chromatography, elution 50% ethyl acetate in Heptane. Fractions were evaporated to dryness to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 50 mm diam0 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-(3-fluoro-5-((methylsulfonyl)methyl)phenyl)pyrimidin-2-amine (0.120 g, 60.6 %) as a white solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=C(C=CC(=C1)F)C2=NC(=NC=C2F)NC3=CC(=CC(=C3)CS(=O)(=O)C)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 60.61 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/10/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "739" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.7 [N-arylation with Ar-X] Chloro N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00147 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H](C1)C(=O)N" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1(CC2=C(C=NN2C1)C3=CC(=NC=C3F)Cl)C" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 9.78e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.[Pd]" + } + amount { + moles { + value: 4.89e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Tetrakis(triphenylphosphine)palladium(0) (56.5 mg, 0.05 mmol) was added to 3-(2-chloro-5-fluoropyridin-4-yl)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (130 mg, 0.49 mmol), tert-butyl ((1R,3S)-3-carbamoylcyclohexyl)carbamate (119 mg, 0.49 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (56.6 mg, 0.10 mmol) and Cesium carbonate (478 mg, 1.47 mmol) in 1,4-dioxane (5.98 ml).nbsp;Degassed for 5 mins under nitrogen and the resulting suspension was stirred at 120 C for 2 hours in the microwave reactor. The reaction mixture was partitioned between water (20ml) and DCM (40ml) and separated using a phase separation cartridge.nbsp;The organics were absorbed onto silica and purified by flash silica chromatography, elution gradient 0 to 60% EtOAc in heptane. Pure fractions were evaporated to dryness to afford tert-butyl ((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexyl)carbamate (81 mg, 35.1 %) as a pale yellow solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1(CC2=C(C=NN2C1)C3=CC(=NC=C3F)NC(=O)[C@H]4CCC[C@H](C4)NC(=O)OC(C)(C)C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 35.11 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/18/2015" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "740" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.7 [N-arylation with Ar-X] Chloro N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00413 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H](C1)C(=O)N" + } + amount { + moles { + value: 0.00138 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1(CC2=C(C=NN2C1)C3=CC(=NC=C3F)Cl)C" + } + amount { + moles { + value: 0.00138 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000275 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.[Pd]" + } + amount { + moles { + value: 0.000138 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Tetrakis(triphenylphosphine)palladium(0) (159 mg, 0.14 mmol) was added to 3-(2-chloro-5-fluoropyridin-4-yl)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (365.4 mg, 1.38 mmol), tert-butyl ((1R,3S)-3-carbamoylcyclohexyl)carbamate (333 mg, 1.38 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos)nbsp;(159 mg, 0.28 mmol)and Cesium carbonate (1344 mg, 4.13 mmol) in 1,4-dioxane (15 mL). The resulting suspension was degassed for 10 minutes under nitrogen and then stirred at 120 C for 8 hours overnight in the microwave reactor. The reaction mixture was partioned between water (30 mL) and DCM (15 mL) and seperated.iLCMS analysis showed product in the aqueous extract. iThe aqueous layer was extracted with DCM (2 X 20 mL). LCMS analysis showed some product still within in the aqueous extract. iThe aqueous layer was extracted again with DCM (2 X 25 mL).nbsp;iThe organic extracts were combined, dried over MgSO4, filtered and evaporato afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 60% EtOAc in heptane. Pure fractions were evaporated to dryness to afford tert-butyl ((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexyl)carbamate (348 mg, 53.6 %) as a white solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1(CC2=C(C=NN2C1)C3=CC(=NC=C3F)NC(=O)[C@H]4CCC[C@H](C4)NC(=O)OC(C)(C)C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 53.6 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/06/2015" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "741" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00171 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CCNC(C1)C2=CC=CC=C2" + } + amount { + moles { + value: 0.000682 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)Br" + } + amount { + moles { + value: 0.000568 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 2.84e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.42e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Caesium carbonate (556 mg, 1.71 mmol) was added to bromobenzene (0.060 mL, 0.57 mmol) and 2-phenylpiperidine (110 mg, 0.68 mmol) in 1,4-dioxane (2 mL). The reaction was degassed and Tris(dibenzylideneacetone)?dipalladium(0) (13.01 mg, 0.01 mmol) and dicyclohexyl(2\',6\'-diisopropoxy-[1,1\'-biphenyl]-2-yl)phosphine (RuPhos) (13.26 mg, 0.03 mmol) were added.nbsp;The resulting solution was stirred at 100 C for 16 hours. LCMS showed The reaction mixture was diluted with EtOAc, and washed with water. The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 15% MeOH in DCM. Pure fractions were evaporated to dryness to afford 1,2-diphenylpiperidine (21.00 mg, 15.56 %) as a yellow oil. f0 = 19 mg bromobenzenef1 = 21 mg productThe reaction was abandonned." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CCN(C(C1)C2=CC=CC=C2)C3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 15.56 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/23/2015" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "742" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00478 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.025 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00341 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=CC(=C1)Br)OCC2=CC=CC=C2" + } + amount { + moles { + value: 0.00341 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000136 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000102 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Tonbsp;tert-butyl piperazine-1-carboxylate (0.635 g, 3.41 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.094 g, 0.10 mmol) and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.085 g, 0.14 mmol) andnbsp;Sodium tert-butoxide (0.459 g, 4.78 mmol) was added a solution of 1-(benzyloxy)-4-bromo-2-methoxybenzene (1 g, 3.41 mmol) in Toluene (25 mL).nbsp;The resulting solution was stirred at reflux for18 hours. The reaction was allowed to cool to room temperature and diluted with dcm (50 ml). This was washed with water (2 x 50 ml), dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The crude product was dissolved in hydrochloric acid solution in methanol (4N, 20 ml) and stirred at room temprature overnight. The solvent was removed under reduced pressure.The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness to afford 1-(4-(benzyloxy)-3-methoxyphenyl)piperazine (0.614 g, 60.3 %) as a yellow gum. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=C(C=CC(=C1)N2CCNCC2)OCC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 60.33 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/11/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "743" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0505 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.28 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)N" + } + amount { + moles { + value: 0.0433 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=CC=C1Br" + } + amount { + moles { + value: 0.0361 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00216 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000722 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "ANILINE (3.94 mL, 43.29 mmol) was added to 4-bromopyridine (5.7 g, 36.08 mmol), PALLADIUM(II) ACETATE (0.162 g, 0.72 mmol), XANTPHOS (1.252 g, 2.16 mmol) and SODIUM TERT-BUTOXIDE (4.85 g, 50.51 mmol) in toluene (280 mL) under nitrogen. The resulting mixture was stirred at 100 C for 4 hours. The reaction mixture was evaporated to dryness and redissolved in EtOAc (200 mL), and washed sequentially with water (2 x 100 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and preadsorbed onto silica. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to afford N-phenylpyridin-4-amine (1.528 g, 24.88 %) as a pink solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=CC=NC=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 24.88 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/03/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "744" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0222 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.125 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)N" + } + amount { + moles { + value: 0.019 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=CC=C1Br" + } + amount { + moles { + value: 0.0158 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000949 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000316 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "ANILINE (1.730 mL, 18.99 mmol) was added to 4-bromopyridine (2.5 g, 15.82 mmol), PALLADIUM(II) ACETATE (0.071 g, 0.32 mmol), XANTPHOS (0.549 g, 0.95 mmol) and SODIUM TERT-BUTOXIDE (2.129 g, 22.15 mmol) in toluene (125 mL) under nitrogen. The resulting mixture was stirred at 100 C for 4 hours. The reaction mixture was evaporated to dryness and redissolved in EtOAc (100 mL), and washed sequentially with water (2 x 100 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and preadsorbed onto silica. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to afford N-phenylpyridin-4-amine (1.102 g, 40.9 %) as a white solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=CC=NC=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 40.92 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/28/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "745" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0877 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.5 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)N" + } + amount { + moles { + value: 0.0752 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=CC=C1Br" + } + amount { + moles { + value: 0.0627 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00376 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00125 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "ANILINE (6.85 mL, 75.19 mmol) was added to 4-bromopyridine (9.9 g, 62.66 mmol), PALLADIUM(II) ACETATE (0.281 g, 1.25 mmol), XANTPHOS (2.175 g, 3.76 mmol) and SODIUM TERT-BUTOXIDE (8.43 g, 87.72 mmol) in toluene (500 mL) under nitrogen. The resulting mixture was stirred at 100 C for 4 hours. The reaction mixture was evaporated to dryness and redissolved in EtOAc (200 mL), and washed sequentially with water (2 x 100 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and preadsorbed onto silica. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to afford N-phenylpyridin-4-amine (2.160 g, 20.25 %) as a pale tan solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=CC=NC=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 20.25 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/06/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "746" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00253 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.006 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00169 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1C=CC2=C1C(=CC=C2)Br" + } + amount { + moles { + value: 0.00169 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 0.000338 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000169 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium (II) acetate (37.9 mg, 0.17 mmol) and 2-dicyclohexylphosphino-2\',6\'-di-i-propoxy-1,1\'-biphenyl (158 mg, 0.34 mmol) were dissolved in toluene (3 mL) and the resulting solution degassed and purged with nitrogen. The mixture was warmed to 50C for 15 mins.In a separate vessel, were mixed tert-butyl piperazine-1-carboxylate (314 mg, 1.69 mmol), tert-butyl 7-bromo-1H-indole-1-carboxylate (500 mg, 1.69 mmol) and sodium-t-butoxide (243 mg, 2.53 mmol) in toluene at ambient temperature. The mixture was degassed and purged with nitrogen. The catalyst solution was added and the resulting mixture heated at 100C under nitrogen overnight.The main product of the reaction is 7-bromoindole. Boc has been lost (high temp, base). Only small trace desired product visible in UPLC.Reaction abandoned. Try lower temps, different b" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC=CC3=C2N(C=C3)C(=O)OC(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/18/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "747" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000506 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.000338 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1C=CC2=C1C(=CC=C2)Br" + } + amount { + moles { + value: 0.000338 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 6.75e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.38e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 95.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "uTrial reactionuPalladium (II) acetate (7.58 mg, 0.03 mmol) and 2-Dicyclohexylphosphino-2\',6\'-di-i-propoxy-1,1\'-biphenyl (31.5 mg, 0.07 mmol) were suspended in 1,4-dioxane (1 mL) at ambient temperature. The mixture was degassed and purged with nitrogen and warmed to 50C for 20 mins.In a separate vessel, were mixed tert-butyl piperazine-1-carboxylate (62.9 mg, 0.34 mmol), tert-butyl 7-bromo-1H-indole-1-carboxylate (100 mg, 0.34 mmol) and cesium carbonate (165 mg, 0.51 mmol) in 1,4-dioxane (2 mL). The mixture was degassed and purged with nitrogen several times. The catalyst solution was added and the resulting mixture was heated at 95C overnight under a nitrogen atmosphere.No reaction observed by LCMS. Main component of the mixture was unreacted BOC-protected indole. No loss of BOC, but still no reacti" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC=CC3=C2N(C=C3)C(=O)OC(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/20/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "748" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0014 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=COC(=N1)N" + } + amount { + moles { + value: 0.0012 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=NC(=C1)Cl" + } + amount { + moles { + value: 0.001 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium(II) acetate (4.49 mg, 0.02 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.017 g, 0.03 mmol) were mixed together in a reaction vessel and evacuated and purged with nitrogen 3 times. Dioxane (1 mL) was added and the resulting mixture was heated to to 50C for 30 minutes.oxazol-2-amine (0.101 g, 1.20 mmol) together with 2-chloropyridine (0.094 mL, 1.00 mmol) and cesium carbonate (0.456 g, 1.40 mmol) were placed in a second vessel, evacuated and purged with nitrogen 3nbsp;times and dioxane (3 mL) was added. The catalyst solution was added and the resulting mixture heated at 100 C for 16 hours.bNo oxazol-2-amine present in proton NMR of crude reaction mixture. bThe starting material is decomposing under the reaction conditions, could be the route of the very low productivity in the C-N couplings using these strates. Only chloropyridine observed in the proton NMR and LCMS of the crude reaction mixture.Conclusion: Experiment abandoned, nhe desired product isolated. . " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=NC(=C1)NC2=NC=CO2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/12/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "749" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[K+].[K+]" + } + amount { + moles { + value: 0.0001 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=COC(=N1)N" + } + amount { + moles { + value: 0.002 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=NC(=C1)Cl" + } + amount { + moles { + value: 0.001 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C1=CC2=CC=CC=C2N1C3=CC=CC=C3)C(C)(C)C" + } + amount { + moles { + value: 0.0002 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: Comparison of the reactivity of 2-aminooxazole in the coupling with 2-chloropyridine using three different catalyst systems ( previously shown to be the best performers in a 96-well Process Research and Development Screen)To an oven-dried microwave vial was added TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.046 g, 0.05 mmol) and 2-(di-tert-butylphosphino)-1-phenyl-1H-indole (0.067 g, 0.2 mmol) and the vial was purged with nitrogen. dioxane (2 mL) (degassed) was added and the reaction mixture was heated to 50 C for 40 min followed by heating to 90 C for a further 15 min (Solution 1).nbsp;To an oven dried microwave vial was added 2-chloropyridine (0.095 mL, 1 mmol), oxazol-2-amine (0.187 g, 2.00 mmol), potassium carbonate (0.207 g, 1.50 mmol) and 4,4\'-di-tert-butylbiphenyl (0.027 g, 0.1 mmol). The vial was then capped and purged with nitrogen. To this was added the activated catalyst solution (Solution 1) . The reaction mixture was then heated to 90 C for n inert atmosphere. LCMS of the crude reaction mixture under basic conditions showed a peak which had the mass of the desired product, however, the chloropyridine starting material co-elutes under these conditions. Under acidic conditions none of the desired product mass was observed at Rt= 0.25 min (whereas for EN05378-80 and EN05378-81, the product mass was observed at this retention time). A product of mass corresponding to homo-coupled product was observed under basic conditions. Reaction not progressed.Conclusion: The \'t-Butyl Beller ligand\' was not efficent for the coupling of these strates under the above conditions." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=NC(=C1)NC2=NC=CO2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "12/20/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "750" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[K+].[K+]" + } + amount { + moles { + value: 0.0001 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=COC(=N1)N" + } + amount { + moles { + value: 0.002 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=NC(=C1)Cl" + } + amount { + moles { + value: 0.001 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=C(C=CC(=C2P(C3CCCCC3)C4CCCCC4)OC)OC)C(C)C" + } + amount { + moles { + value: 0.0002 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: Comparison of the reactivity of 2-aminooxazole in the coupling with 2-chloropyridine using three different catalyst systems ( previously shown to be the best performers in a 96-well Process Research and Development Screen)To an oven-dried microwave vial was added TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.046 g, 0.05 mmol) and dicyclohexyl(2\',4\',6\'-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.107 g, 0.2 mmol) and the vial was capped and purged with nitrogen. dioxane (2 mL) (degassed) was added and the reaction [Reactants]mixture was heated to 50 C for 40 min followed by heating to 90 C for a further 15 min (Solution 1).To an oven dried microwave vial was added 2-chloropyridine (0.095 mL, 1 mmol), oxazol-2-amine (0.187 g, 2.00 mmol), potassium carbonate (0.207 g, 1.50 mmol) and 4,4\'-di-tert-butylbiphenyl (0.027 g, 0.1 mmol). The vial was then capped and purged with nitrogen. To this was added the activated catalyst solution (Solution 1). The reaction mixture wheated to 90 C for 16 h under an inert atmosphere.LCMS of the crude reaction mixture (Base) showed the mass peak for the desired product, however, this peak co-elutes with the Cl-pyridine starting material. LCMS of the crude reaction mixture using an acidic method showed no peak in the UV which had a mass corresponding to that of the product, however, the desired mass was observed in the MS at Rt= 0.27 min. A peak in the UV of a mass corresponding to the homocoupled bipyridine product was observed under both acidic and basic methods. Dichloromethane was added to the crude reaction mixture together with silica (2 g). The solvent was removed under reduced pressure and the resulting residue was placed in a dry-load tube prior to chromatography. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% methanolic ammonia (7 M) in DCM. 2-aminooxazole (103 mg) was recovered. The fraction containing the mass of the desired product produced 33 mg of impure materiale attached proton NMR, the desired product bumayub be present (but it\'s hard to say). If this sample was to be pure it would correspond to an isolated yield of ~ 20% of the desired product, due to the fact that this is a really impure sample the real value is probably less than 10%.Conclusion: Reaction not progressed. nbsp;nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=NC(=C1)NC2=NC=CO2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "12/20/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "752" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.1 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.2 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.1 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CNC2=NC=C(C=C21)Br" + } + amount { + moles { + value: 0.0502 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 0.00251 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00502 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (9.9 g, 50.25 mmol), morpholine (7.96 mL, 100.49 mmol), sodium 2-methylpropan-2-olate (19.32 g, 200.98 mmol),dicyclohexyl(2\',6\'-diisopropoxy-[1,1\'-biphenyl]-2-yl)phosphine (1.172 g, 2.51 mmol) in degassed dioxane (200 mL) was added diacetoxypalladium (1.128 g, 5.02 mmol) and the reaction mixture was heated under nitrogen at 90 C for 17 hours, then evaporated and partitioned between DCM (150 ml) and saturated aqueous sodium bicarbonate solution (150 mL). The aqueous phase was extracted further with DCM (70 ml) and the combined organics were evaporated, redissolved in a mixture of methanol and DCM and purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-(1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine (8.54 g, 84 %) as a yellow solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1COCCN1C2=CN=C3C(=C2)C=CN3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 83.63 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/11/2014" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "754" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0518 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.1 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.0518 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CNC2=NC=C(C=C21)Br" + } + amount { + moles { + value: 0.0259 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 0.00129 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00259 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (5.1 g, 25.88 mmol), morpholine (4.10 mL, 51.77 mmol), sodium 2-methylpropan-2-olate (9.95 g, 103.54 mmol),dicyclohexyl(2\',6\'-diisopropoxy-[1,1\'-biphenyl]-2-yl)phosphine (0.604 g, 1.29 mmol) in degassed dioxane (100 mL) was added diacetoxypalladium (0.581 g, 2.59 mmol) and the reaction mixture was heated under nitrogen at 90 C for 17 hours, then evaporated and partitioned between DCM (80ml) and saturated aqueous sodium bicarbonate solution (80ml). The aqueous phase was extracted further with DCM (50ml) and the combined organics were evaporated, redissolved in a mixture of methanol and DCM and purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-(1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine (3.40 g, 64.6 %) as a yellow solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1COCCN1C2=CN=C3C(=C2)C=CN3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 64.63 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/27/2014" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "755" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.1 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.2 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.1 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CNC2=NC=C(C=C21)Br" + } + amount { + moles { + value: 0.0502 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 0.00502 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00251 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (9.9 g, 50.25 mmol), morpholine (7.96 mL, 100.49 mmol), sodium 2-methylpropan-2-olate (19.32 g, 200.98 mmol),dicyclohexyl(2\',6\'-diisopropoxy-[1,1\'-biphenyl]-2-yl)phosphine (2.345 g, 5.02 mmol) in degassed dioxane (200 mL) was added diacetoxypalladium (0.564 g, 2.51 mmol) and the reaction mixture was heated under nitrogen at 90 C for 17 hours, then evaporated and partitioned between DCM (150 mL) and saturated aqueous sodium bicarbonate solution (150 mL). The aqueous phase was extracted further with DCM (70 mL) and the combined organics were concentrated. The crude material was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-(1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine (9.28 g, 91 %) as a yellow solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1COCCN1C2=CN=C3C(=C2)C=CN3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 90.87 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/18/2014" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "756" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00178 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.1 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[Si](C)(C)OCCN" + } + amount { + moles { + value: 0.0178 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" + } + amount { + moles { + value: 0.0178 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.00178 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00178 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "PdOAc2 (0.399 g, 1.78 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.848 g, 1.78 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (5.00 g, 17.79 mmol), 2-(tert-butyldimethylsilyloxy)ethanamine (4.16 g, 17.79 mmol) and cesium carbonate (8.69 g, 26.68 mmol) in toluene (100 mL) at 20C in a microwave vial. The microwave vial was sealed and the reaction was heated to 120 C for 10 hours in the microwave reactor and cooled to RT.b bnbsp;uSplit into 5 x 20 ml mw vials such as in each was:uPdOAc2 (0.080 g, 0.36 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.170 g, 0.36 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (1.000 g, 3.56 mmol), 2-(tert-butyldimethylsilyloxy)ethanamine (0.832 g, 3.56 mmol) and cesium carbonate (1.739 g, 5.34 mmol) in toluene (20 mL) at 20C in a microwave vial. The microwave vial was sealed and thes heated to 120 C for 10 hours in the microwave reactor and cooled to RT.b bThe reaction mixtures were combined and diluted with EtOAc (150 mL), and washed sequentially with water (200 mL) and saturated brine (200 mL). The organic layer was filtered and dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was evaporated and was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)ethyl)-3-fluoroaniline (3.62 g, 54.2 %) as a yellow oil. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)[Si](C)(C)OCCNC1=CC(=C(C=C1)OCC2=CC=CC=C2)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 54.2 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/21/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "757" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000189 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[Si](C)(C)OCCN" + } + amount { + moles { + value: 0.00189 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" + } + amount { + moles { + value: 0.00189 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.000189 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000189 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "PdOAc2 (42.3 mg, 0.19 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (90 mg, 0.19 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (530 mg, 1.89 mmol), 2-(tert-butyldimethylsilyloxy)ethanamine (441 mg, 1.89 mmol) and cesium carbonate (921 mg, 2.83 mmol) in toluene (15 mL) at 20C in a microwave vial. The microwave vial was sealed and the reaction was heated to 120 C for 12 hours in the microwave reactor and cooled to RT. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was filtered and dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)ethyl)-3-fluoroaniline (312 mg, 44.1 %) as a yellow o" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)[Si](C)(C)OCCNC1=CC(=C(C=C1)OCC2=CC=CC=C2)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 44.07 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/13/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "759" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00324 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.016 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC1=CC=C(C=C1)F" + } + amount { + moles { + value: 0.00278 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC(=NC=C1)Br" + } + amount { + moles { + value: 0.00231 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 0.000347 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000116 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 105.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 100 mL round-bottomed flask (t=g) was methyl 2-bromoisonicotinate (.5 g, 2.31 mmol), 4-fluoro-N-methylaniline (0.348 g, 2.78 mmol), and CS2CO3 (1.056 g, 3.24 mmol) in toluene (16 mL) to give a yellow suspension. Pd2dba3 (0.106 g, 0.12 mmol) and biphenyl-2-yldicyclohexylphosphine (0.122 g, 0.35 mmol) were added. Reaction was allowed to stir overnight. LCMS in the morning revealed little product had formed. Something with mass 272 dominated.Reaction was discarded." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(C1=CC=C(C=C1)F)C2=NC=CC(=C2)C(=O)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/09/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "763" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000648 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CNC1=CC=C(C=C1)F" + } + amount { + moles { + value: 0.000555 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC(=NC=C1)Br" + } + amount { + moles { + value: 0.000463 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 6.94e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.31e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 85.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 100 mL round-bottomed flask (t=g) was biphenyl-2-yldicyclohexylphosphine (0.024 g, 0.07 mmol), methyl 2-bromoisonicotinate (.1 g, 0.46 mmol), and 4-fluoro-N-methylaniline (0.070 g, 0.56 mmol) in toluene (3 mL) to give a purple suspension. Pd2dba3 (0.021 g, 0.02 mmol) and CS2CO3 (0.211 g, 0.65 mmol) were added. Flask was placed in an oil bath at 85 C.LCMS taken at 1, 2 and 4 hours indicated reaction was not progressing. Reaction was discarded." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(C1=CC=C(C=C1)F)C2=NC=CC(=C2)C(=O)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/10/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "764" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00119 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC1=NC(=NC=C1Br)N" + } + amount { + moles { + value: 0.00099 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)I)C(F)(F)F" + } + amount { + moles { + value: 0.00119 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 4.95e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.95e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "repeat of uEN06995-58\\Reactionu but using XantphosbuAim:-u prepare target for further use.b1-iodo-3-(trifluoromethyl)benzene (0.171 ml, 1.19 mmol), 5-bromo-4-methoxypyrimidin-2-amine (0.202 g, 0.99 mmol), PALLADIUM(II) ACETATE (0.011 g, 0.05 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) - Xantphos (0.029 g, 0.05 mmol) and cesium carbonate (0.387 g, 1.19 mmol)nbsp;were mixed in toluene (5ml), purged with nitrogen and stirred in a sealed tube at 90 C overnight.nbsp;LCMS: pH = 3, 2 minute run time, shows sign of product at Rt = 1.41 minThe reaction mixture was diluted with EtOAc (20 ml), filtered through a celite pad and concentrated to give 477 mg yellow solid.TLC (1:1 - EtOAc : n-heptane) see diagram UV onlyThis was disolved in DCM, absorbed onto a samplet and purified on a 10 g Biotage SNAP column (approx column volume = 7 ml), eluting with a step-wise gradient from 0 : 10 to 4 : 6 EtOAc : n-heptane using a Thomson pcollecting 12 ml fractions. F1 - y = 149 mg - GCMS (Steep_10 min), Rt = 7.88 min (100%) mz: 3468.LCMS of F2 did not show anything of interest!buConclusion:u- bSeems like xanphos works but could be better - used in EN06995-68" + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=NC(=NC=C1Br)NC2=CC=CC(=C2)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 43.23 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/07/2014" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "765" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.009 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C(=CC=N1)N" + } + amount { + moles { + value: 0.00099 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN=C(N=C1C2=CN3C[C@H](N(C(=O)C3=N2)CC4=CC(=C(C=C4)F)F)COC)Cl" + } + amount { + moles { + value: 0.00119 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.0003 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.0003 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "18-mar-2014 17:15:52 +0100, blandar allt, add toluen, N2 flushar - rr 110 gCnN2. Nsta em kl 16, ftt svalna - LCMS ser bra ut, 17:49:27 - nu hydrolysrt, klart efter 90 min ca, slr p 600 uL HoAc, evap. Till SSL, 24-mar-2014 190 mg ter frn SSL. Jonbyt ( 1 g CBA prekond MeOH, lser inbsp;ngra ml ACN, eluerar mha 2.5 verkolonn vol, spder med avjonat " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)CN(C1=CC(=C(N=C1)C(=O)[C@H]2C[C@@H]2C(=O)O)OC)C3=C(C=CC(=C3)C(F)(F)F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 15.7 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/18/2014" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "766" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0003 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.03 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)CNC1=C(C=CC(=C1)C(F)(F)F)F" + } + amount { + moles { + value: 0.006 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1CC1C(=O)C2=C(C=C(C=N2)Br)OC" + } + amount { + moles { + value: 0.006 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.0003 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.0003 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "P vanligt stt (allt satsas i Toluen, N2 bubblar) start 09-jun-2014 19:51:32 +0200. LCMS-1 1600 nsta em ser bra ut, hittar inga SM, fr svalna - bryter. Spder med 30 ml etoac, filtrerar genom SiO plugg, evap. evap tv gnger ur 30 ml THF, LCMS-2 visar P10-jun-2014 19:15:25 +0200 lser i 20 ml THF, 10 ml MeOH, adderar LiOH(758 mg lst i 20 ml aq) - lsning, rr rt. Kl 1951 kr LCMS-3, ser riktigt bra ut, inga SM kvar ser det ut som. Ser ingen stitution F mot MeO. Kl 20.20 quench med 2 ml HOAc, evap hrt, m=5.0 g - till SSL.16-jun-2014 11:32:38 +0200 nu ftt ter 1.4 g dygt frn SSL samt ven dess enantiomer. Tar det via pulvret och kr HNMR (3.5 mg i DMSO). Visar rester frn upprening, stter kl 12.07 p indunstaren med fullt vakuum 60 grC badT samt kolsyreisaceton kylning f frlaget. Gr fram till 1335, sedan rt 10 min.Gr ver till PARD med hela batchen.en R.R isomeren i betydlig mngd frn SSL, anvndes frst fr att trna krist med 9010nbsp;aqetoh enligt Hkans recept, ser ok ut men mycket skumning. Dag senare slr p ngra ml iPrOH ser svrlsligt ut, add aning aq uppskattningsvis 80 iPrOH 20 aq, ser lite dimmigt utvrmer 70 gRC olja under omrn 5 min, mindre dimma?, str ngot litet faller ut sanbbt men kommer ej lngre evap, faller vits - kristallin? Vrmer 60 grC med CO2 aceton frlag 1 h.Fr ihop 128 mg ser bra ut (krist). Fr Jonas Bergare fr mrkning oc" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)CN(C1=CC(=C(N=C1)C(=O)[C@H]2C[C@@H]2C(=O)O)OC)C3=C(C=CC(=C3)C(F)(F)F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 29.09 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/09/2014" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "767" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0101 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1CCCO1" + } + amount { + volume { + value: 1.3 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1C(=CC=N1)N" + } + amount { + moles { + value: 0.00761 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN=C(N=C1C2=CN3C[C@H](N(C(=O)C3=N2)CC4=CC(=C(C=C4)F)F)COC)Cl" + } + amount { + moles { + value: 0.00507 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C1=CC=CC=C1C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 0.000406 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000203 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2016-05-18btimenbsp;tempnbsp;commentb114:20nbsp;21nbsp;(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one (2.2 g, 5.07 mmol), 1-methyl-1H-pyrazol-5-amine (0.754 g, 7.61 mmol) and cesium carbonate (3.30 g, 10.14 mmol) was charged to a 100mL reactor. 2-methyl tetrahydrofuran (1.2 L) and water (0.120 L) was charged. Degassed (6x vacN2)14:25nbsp;21nbsp;2\'-(dicyclohexylphosphanyl)-N,N-dimethyl-[1,1\'-biphenyl]-2-amine (dave phos) (0.160 g, 0.41 mmol) and Pd2dba3 (0.186 g, 0.20 mmol)nbsp;was added. degassed (6x vacN2).14:25nbsp;21nbsp;heated to 80 magnetic stirrer under nitrogen.nbsp;nbsp;nbsp;IPC1 (1,5h) SFC-MS indicates 9.5% conversion.2016-05-1908:00nbsp;reflux nbsp;IPC2 (18h) SFC-MS indicates 66% conversion. 14.00nbsp;refluxnbsp;IPC3 (23h) SFC-MS indicates 72% conversion.The reaction mixture was cooled to 40C and 1 eq. of catalysd ligand was added, 0.17g Pd and 0.15g Davefos. degassed 6 times. Jacket to 80C , stirred over night.2016-05-2007:45nbsp;reflux nbsp;IPC4 42h complete conversion.1.19 g of silicycle was added and the temperature was set to ambient..10:18:07nbsp;rtnbsp;the mixture was filtered through a celite filter (25). the filter cake was washed with EtOAc (2x 10 ml).10:30:44nbsp;rtnbsp;the filtrate was transfered to a sep funnel and washed with aq citric acid (0,5M, 15 ml) and water (5 ml). Unfortunately when washing with water some diluted HCl was used, so the reaction mixture was basified with bicarbonate solution prior to the final water wash. The organic layer was evaporated to a solid, 2.7g Material sent to SSL for separation 2016-05-23.Yield after chromatography: 1" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN=C(N=C1C2=CN3C[C@H](N(C(=O)C3=N2)CC4=CC(=C(C=C4)F)F)COC)NC5=CC=NN5C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 55.03 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/18/2016" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "769" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "[Li+].C[Si](C)(C)[N-][Si](C)(C)C" + } + amount { + moles { + value: 0.00119 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1CCOC1" + } + amount { + volume { + value: 0.001 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C(CN)C(=O)N.Cl" + } + amount { + moles { + value: 0.000622 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1C(=O)O)Br" + } + amount { + moles { + value: 0.000497 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 50.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium (II) acetate (0.011 g, 0.05 mmol) was added to(R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (0.027 g, 0.05 mmol) in THF (1 mL) in a reaction vessel evacuated and purged with nitrogen. The resulting catalyst mixture was stirred and under nitrogen at 50 C for 30 minutes. 04-Dec-2013 10:52:28 AM -0500LiHMDS (1.194 mL, 1.19 mmol), 3-aminopropanamide, HCl (0.077 g, 0.62 mmol) and 4-bromobenzoic acid (0.1 g, 0.50 mmol) was added to a second reaction vessel and purged with nitrogen. were added at 20 C.nbsp;The catalyst solution was added to the reaction mixture and the resulting mixture was stirred at 120 C for 16 hours. nbsp;LCMS showed starting material only. Desired product not isolated from this re" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1C(=O)O)NCCC(=O)N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "12/04/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "770" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0056 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.012 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1C2=CN=C(C=C2)N" + } + amount { + moles { + value: 0.00269 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN2C=C(C=C(C2=N1)Br)Cl" + } + amount { + moles { + value: 0.00224 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000448 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000336 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 105.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of 8-bromo-6-chloroimidazo[1,2-a]pyridine, HCl (600mg, 2.24 mmol),nbsp;5-morpholinopyridin-2-amine (482 mg, 2.69 mmol), BINAP (279 mg, 0.45 mmol),nbsp;cesium carbonate (1824 mg, 5.60 mmol)nbsp;in Toluene (12 mL) was spargednbsp;with nitrogen while stirring for 10 minutes. palladium(II) acetate (87 mg, 0.39 mmol) was then added and the reaction stirred at 105 Cnbsp;for overnight.nbsp;At ths stage LCMS indicated that formation of the product. After this time, the reaction was cooled to room temperature, dilutednbsp;with mixture of 1:1 methanolDCM ( 100 mL) and filtered through celite. The filtrated concentrated under reduced pressure and the resulting residue purified by flash chromatography (silicagel,nbsp;0-10%nbsp;DCMMethanol, 25 minutes) to afford 6-chloro-N-(5-morpholinopyridin-2-yl)imidazo[1,2-a]pyridin-8-amine (482 mg, 65.3 %)nbsp;as a solid. LCMS (2 minute, Acid _CV10.olp methodnbsp;330 (M + 1), 0.66 minutes.1H NMR (400 MHz, DMSO-idi6) d ppm 9.16 (sH) 8.30 - 8.34 (m, 1 H) 8.25 - 8.29 (m, 1 H) 7.98 - 8.03 (m, 1 H) 7.88 - 7.92 (m, 1 H) 7.54 - 7.57(m, 1 H) 7.36 - 7.47 (m, 2 H) 3.72 - 3.79 (m, 4 H) 3.05 - 3.12 (m, 4 H)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1COCCN1C2=CN=C(C=C2)NC3=CC(=CN4C3=NC=C4)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 65.27 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/12/2014" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "771" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00181 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1C[C@H](C(=O)NC1)N" + } + amount { + moles { + value: 0.00104 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(N=C1)Br)Cl" + } + amount { + moles { + value: 0.00104 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 1.56e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 7.9e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 115.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 5 ml MW vial,nbsp;Pd2((dba)3 (7.23 mg, 7.90 mol), 2,2\'-bis(diphenylphosphanyl)-1,1\'-binaphthalene (BINAP) (9.71 mg, 0.02 mmol),nbsp;sodium 2-methylpropan-2-olate (174 mg, 1.81 mmol), (R)-3-aminopiperidin-2-one (119 mg, 1.04 mmol) and 2-bromo-3-chloropyridine (200 mg, 1.04 mmol) mixed in toluene (2 mL) to give a brown suspension. The mixture was degassed with N2 bubbling for 5 min, then the vial was capped and the reaction stirred at 115C in an oil-bath over night.The reaction was cooled to rt, DCM and aq NaHCO3 were added, the mixture stirred, filtered through a phase separator and evaporated.LC-MS crude: Traces of product, mainly starting bromide left.Reaction discar" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1C[C@H](C(=O)NC1)NC2=C(C=CC=N2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/10/2016" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "772" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000977 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C(=C1)F)CN)F" + } + amount { + moles { + value: 0.000537 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.91e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(2,6-difluorophenyl)methanamine (77 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford N4-(2,6-difluorobenzyl)-N2-phenylpyridine-2,4-diamine (93 mg, 61.1 %) as a purple gum.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)NCC3=C(C=CC=C3F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 61.13 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/04/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "773" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000977 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C(=C1)F)CN)F" + } + amount { + moles { + value: 0.000635 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.91e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol), (2,6-difluorophenyl)methanamine (91 mg, 0.64 mmol),nbsp;(R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol),sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were suspended in DME (2.0 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 20 minutes in the microwave reactor and cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH andnbsp;fractions were evaporated to dryness to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N4-(2,6-difluorobenzyl)-N2-phenylpyridiiamine (32.0 mg, 21.04 %) as a yellow gum. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)NCC3=C(C=CC=C3F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 21.04 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/17/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "774" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00222 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000887 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C[C@@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.000739 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 7.39e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 7.39e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.213 g, 0.89 mmol), Palladium(II) acetate (0.017 g, 0.07 mmol), 2-(Dicyclohexylphosphino)biphenyl (0.026 g, 0.07 mmol) and Cesium carbonate (0.722 g, 2.22 mmol) were put in a 20 mL microwave vial and sealed. The vial was flushed with argon. (S)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.203 g, 0.74 mmol) in DME (5 mL) was added and additional 5 mL was added to the vial. The reaction mixture was run in the microwave at 100C for 80 minutes. Reaction still not complete. Additional palladium(II)acetate (0.1 eq) and 2-(dicyclohexylphosphino)biphenyl (0.1 eq) were added and the reaction was run again in the microwave for 60 minutes. Have about 14% oxazepine left. Heated for additional 45 minutes. 10% oxazepine left. Added 0.1 eq palladium(II)acetate, 0.1 eq 2-(dicyclohexylphosphino)biphenyl and 0.3 eq of 3-methoxy-4-(4-methyl-1Himidazol-1-yl)aniline andnbsp;let the reaction run in the microwave for additional 60 minutes. Thection mixture was filtrated through celite, concentrated and purified first by silica flash chromatography using methanol in dichlorometane (0 to 4%). The productcontaining fractions were pooled and purified further by preparative chromatography. The productcontaining fractions were pooled, concentrated and partitioned between sat. NaHCO3 (aq) and dichloromethane. The organic layer was washed with brine, dried (MgSO4) and concentrated giving 0.091 g of the product." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(CN(C[C@@H](O4)C5=CC=CC=C5)C)C=C3)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 27.89 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/20/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "775" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000101 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" + } + amount { + moles { + value: 6.73e-05 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=C(C=C1F)Br)F" + } + amount { + moles { + value: 7.4e-05 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.37e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)[PH+](C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5[PH+](C6=CC=CC=C6)C7=CC=CC=C7)C.C1=[C-]C=C(C=C1F)F.Br[Pd+]" + } + amount { + moles { + value: 3.37e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Pd complexe (2.96 mg, 3.37 mol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (25 mg, 0.07 mmol), 1-bromo-3,5-difluorobenzene (8.53 l, 0.07 mmol) and cesium carbonate (32.9 mg, 0.10 mmol) dissolved in 1,4-dioxane (0.5 ml) under argon. The resulting suspension was degased with argon and then stirred at 80 C for 3.5 hours.Lcms showed complete reaction.The reaction mixture was allowed to cool to room temperature, filtered and concentrated.The crude product was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (11.00 mg, 33.8 %) as a pale beige foam.LCMS and NM" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 33.8 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/04/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "776" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000216 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCNCC1" + } + amount { + moles { + value: 0.000324 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)C2=NC=CN2)NC(=O)C3=CC=C(C=C3)OCC4=C(C=CC=N4)Br" + } + amount { + moles { + value: 0.000108 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 4.32e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.16e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of N-(5-(1H-imidazol-2-yl)-2-methylphenyl)-4-((3-bromopyridin-2-yl)methoxy)benzamide (50 mg, 0.11 mmol), 1-methylpiperazine (32.4 mg, 0.32 mmol), Pd2(dba)3 (19.76 mg, 0.02 mmol) and BINAP (26.9 mg, 0.04 mmol), CS2CO3 (70.3 mg, 0.22 mmol) in DMA (5 mL) was stirred at 100 C for overnight. LCMS didn\'t mornitor the desired product." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)C2=NC=CN2)NC(=O)C3=CC=C(C=C3)OCC4=C(C=CC=N4)N5CCN(CC5)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/06/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "777" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.7 [N-arylation with Ar-X] Chloro N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00238 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H](C1)C(=O)N" + } + amount { + moles { + value: 0.000954 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CCN2C(=C(C=N2)C3=CC(=NC=C3F)Cl)C1" + } + amount { + moles { + value: 0.000795 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000159 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.[Pd]" + } + amount { + moles { + value: 7.95e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Tetrakis(triphenylphosphine)palladium(0) (0.092 g, 0.08 mmol) was added to 3-(2-chloro-5-fluoropyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (0.200 g, 0.79 mmol), tert-butyl ((1R,3S)-3-carbamoylcyclohexyl)carbamate (0.231 g, 0.95 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.092 g, 0.16 mmol) and Cesium carbonate (0.777 g, 2.38 mmol) in 1,4-dioxane (5.98 ml).nbsp;Degassed for 5 mins under nitrogen and the resulting suspension was stirred at 120 C for 2 hours in the microwave reactor. The reaction mixture was partitioned between water (20ml) and DCM (40ml) and separated using a phase separation cartridge.nbsp;The organics were absorbed onto silica and purified by flash silica chromatography, elution gradient 0 to 60% EtOAc in heptane. Still impure but telescoped through to next stage without further purification. (136mg)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H](C1)C(=O)NC2=NC=C(C(=C2)C3=C4CCCCN4N=C3)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 37.41 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/18/2015" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "779" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00497 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.00473 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C1=NC=C(C=N1)F)N.Cl" + } + amount { + moles { + value: 0.00142 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(N=C1)NC2=C3C=CN(C3=NC(=N2)Cl)C4CC4" + } + amount { + moles { + value: 0.00071 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 0.00011 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 7e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of 1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (252 mg, 1.42 mmol), 2-chloro-7-cyclopropyl-N-(1-methyl-1H-imidazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (205 mg, 0.71 mmol), palladium(II) acetate (15.94 mg, 0.07 mmol) and palladium(II) acetate (15.94 mg, 0.07 mmol) (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (62.1 mg, 0.11 mmol) and CS2CO3 (1619 mg, 4.97 mmol)nbsp;in 1,4-dioxane (4733 l) was heatd to 150 oC for 20 min with well-stirring. Reaction was diluted with DCMMeOh (10%) the organic layer was washed with water. And concntraction provided product. Reaction is clean and 70% contaminated with hydroxy product (P3). Reaction was purified on gilsen (5 to 45%) provide product 40 mg. Compound was mitted to chiral purification. Chiral sepreation:En02021-65-2 (P2, E1) : EN02021-65-3 (P3, E2) = 4:96There is no racemization observed in reaction." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C1=NC=C(C=N1)F)NC2=NC(=C3C=CN(C3=N2)C4CC4)NC5=CN(C=N5)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 37.23 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "12/04/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "780" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000977 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC=CC(=C1)CN" + } + amount { + moles { + value: 0.000537 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(3-methoxyphenyl)methanamine (73.7 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford N4-(3-methoxybenzyl)-N2-phenylpyridine-2,4-diamine (80 mg, 53.6 %) as an off-white gum.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=CC=CC(=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 53.61 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/02/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "781" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.7 [N-arylation with Ar-X] Chloro N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0101 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.007 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCC[C@H](C1)N" + } + amount { + moles { + value: 0.00605 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=NC(=C1)Cl" + } + amount { + moles { + value: 0.00504 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 3.78e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.92e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Vial 1)Pd2(dba)3 (0.018 g, 0.02 mmol) and BINAP (0.024 g, 0.04 mmol) were mixed in toluene (1mL) under N2 and stirred at rt for 5min. Vial 2)sodium tert-butoxide (0.999 g, 10.08 mmol), tert-butyl (R)-3-aminopiperidine-1-carboxylate (1.249 g, 6.05 mmol) and 2-chloropyridine (0.477 mL, 5.04 mmol) were mixed in toluene (6mL) under N2. Added the catalyst solution from vial 1. The mixture was heated at 110C in an oil-bath.LCMS (3h): product, no SM left.The reaction was cooled to rt and the solvent was evaporated. Added EtOAc, washed with water.Purified by column chromatography (using SP4 TM HPFC system, KP-Sil (50g) column, A=heptane, B=EtOAc2M NH3 in MeOH (91), 27mLfr, (0% B 2CV, 0-30% B 10CV, 30% B 2CV)) to yield tert-butyl (R)-3-(pyridin-2-ylamino)piperidine-1-carboxylate (1.306 g, 93 %) as yellow solid.[M+H]+ 278.1H NMR (400 MHz, CDCl3) d 1.42 (s, 9H), 1.51 - 1.64 (m, 2H), 1.68 - 1.8 (m, 1H), 1.93 - 2.0, 1H), 2.81 - 3.36 (m, 2H), 3.45 - 4.16 (m, 3H), 4.50 (d, 1H), 6.42 (d, 1H), 6.5 - 6.62 (m, 1H), 7.36 - 7.45 (m, 1H), 8.02 - 8.13 (m, 1H).nbsp;br Expected Number of Hs: 23nbsp;br Assigned Hs: 23." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCC[C@H](C1)NC2=CC=CC=N2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 93.42 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/26/2016" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "782" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000977 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=CC=C1CN" + } + amount { + moles { + value: 0.000537 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.91e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Pyridin-4-ylmethanamine (58.1 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by preparative HPLC (Waters SunFire column, 5 silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated ts N2-phenyl-N4-(pyridin-4-ylmethyl)pyridine-2,4-diamine (39.8 mg, 29.5 %) as an off white gum.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)NCC3=CC=NC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 29.48 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/23/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "783" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000977 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=CC=C1CN" + } + amount { + moles { + value: 0.000537 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.91e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Pyridin-4-ylmethanamine (58.1 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford impure product. Impure product was purified by flash silica chromatography, elution gradient 3 to 8% MeOH in. Fractions containing product were evaporated to dryness to afford impure product. Impure product was purified by preparative HPLC (Waters SunFire column, 5 silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to drynessnbsp;N2-phenyl-N4-(pyridin-4-ylmethyl)pyridine-2,4-diamine (31.2 mg, 23.11 %) as an off white solid.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)NCC3=CC=NC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 23.11 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/05/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "784" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0124 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0198 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC1CCNCC1" + } + amount { + moles { + value: 0.00743 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)Br)[N+](=O)[O-]" + } + amount { + moles { + value: 0.00495 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000495 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000248 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 95.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 100 mL round bottom flask was charged with a magnetic stir bar, 1-bromo-3-nitrobenzene (1.000 g, 4.95 mmol), [Reactants], Pd2dba3 (0.227 g, 0.25 mmol), BINAP (0.308 g, 0.50 mmol), Cs2CO3 (4.03 g, 12.38 mmol), and toluene (19.80 ml).nbsp;The vessel was capped with a septum, placed under an atmosphere of argon, and placed in an oil bath heated to 95 C.nbsp;The reaction was allowed to stir at this temperature for 16 h before being allowed to cool to rt.nbsp;The reaction mixture was poured into a separatory funnel containing water (~100 mL) and extracted with ethyl acetate ( 2 x 100 mL).nbsp;The combined organic extract was dried with MgSO4, filtered, and conc.i in vacuoi to yield the crude product which was purified via silica gel chromatography (80 g) using ethyl acetatehexanes (1:5) as eluent to provide pure tert-butyl 1-(3-nitrophenyl)piperidin-4-ylcarbamate (0.901 g, 56.6 %) as a light yellow solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC1CCN(CC1)C2=CC(=CC=C2)[N+](=O)[O-]" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 56.63 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "12/13/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "785" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000643 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@@H]1CNCCN1" + } + amount { + moles { + value: 0.000643 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)OCC1=C2C(=CC=C1)C(=O)C=C(O2)C3=CC=C(C=C3)Br" + } + amount { + moles { + value: 0.000536 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 4.02e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (6.02 mg, 0.03 mmol) was added to a degassed mixture ofnbsp;(2-(4-bromophenyl)-4-oxo-4H-chromen-8-yl)methyl acetate (200 mg, 0.54 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthalene (25.03 mg, 0.04 mmol) and cesium carbonate (244 mg, 0.75 mmol) in toluene (5 mL). The resulting suspension was stirred at 110 C for 3 hours under nitrogen (see note 1).nbsp;More diacetoxypalladium (6.02 mg, 0.03 mmol) was added and the reaction mixture was heated to 110C for 1 hour and again could see no product.nbsp;TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (4.91 mg, 5.36 mol) and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthalene (25.03 mg, 0.04 mmol) were added and the reaction mixture was heated to 110C for 1 hour and again could see no product.nbsp;sodium 2-methylpropan-2-olate (61.8 mg, 0.64 mmol) was added and the reaction mixture was heated to 110C for 1 hour where a small amount of product could be detected by LCMS and significant dehalogenation.nbsp;The reaction mixtuol to room temperature The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and fractions were evaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% 7N NH3MeOH in DCM.nbsp;Fractions were evaporated to dryness to afford product that was not pure.nbsp;The sample was dissolved in DMF (4ml) and the crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (R)-8-(hydroxymethyl)-2-(4-(3-methylpiperazin-1-yl)phenyl)-4H-chromen-4-one (25.00 mg, 13.31 %) as a yellow solid. nbsp;br " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@@H]1CN(CCN1)C2=CC=C(C=C2)C3=CC(=O)C4=CC=CC(=C4O3)CO" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 13.31 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/15/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "789" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00257 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.008 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC(=C(C=C1NC(=O)C)N)F" + } + amount { + moles { + value: 0.000899 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.000856 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C(C)(C)C)C(C)(C)C)C(C)C" + } + amount { + moles { + value: 8.56e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 4.28e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In 20 ml microwave vial were addednbsp;5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (200 mg, 0.86 mmol), N-(5-amino-4-fluoro-2-methylphenyl)acetamide (164 mg, 0.90 mmol), Pd2dba3 (39.2 mg, 0.04 mmol), di-tert-butyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (37.5 mg, 0.09 mmol) and Cs2CO3 (837 mg, 2.57 mmol). The vessel was fitted with septum, gas inlet and dioxane (8 mL) was added via syringe. The resulting suspension was stirred for 5 min. under N2. The septum and gas inlet quickly replaced with microwave vial cap and the mixture was heated to 150oC under microwave irradiation for 30 min.The reaction mixture filtered through celite, filtrate concentrated, combined with EN02368-53 experiment and purified by ISCO column (0-5% MeOH-CH2Cl2). The obtained compound triturated with CH3CN, filtered and dried to give light brown color solid.Conclusion: product isolated" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CC(=C(C=C1NC(=O)C)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 20.63 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/29/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "790" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00131 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.00048 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC(=CC=C1)Br" + } + amount { + moles { + value: 0.000437 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 8.73e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.18e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of ethyl 3-bromobenzoate (0.070 mL, 0.44 mmol), cesium carbonate (427 mg, 1.31 mmol), diacetoxypalladium (4.90 mg, 0.02 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (5.44 mg, 8.73 mol) and morpholine (0.042 mL, 0.48 mmol) in toluene (2 mL) was refluxed for 1h. The reaction mixture was cooled and filtered through celite. The celite was washed with EtOAc. The solvent was removed under reduced pressure. The residue was purified by automated flash chromatography on a SNAP 25 gnbsp;column. A gradient from 0% to 50% of EtOAc in Heptane over 10CV was used as mobile phase. The product was collected using the wavelength 254 nm." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CC(=CC=C1)N2CCOCC2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 79.84 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/14/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "792" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00483 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0114 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00322 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CN=C1)Br" + } + amount { + moles { + value: 0.00322 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 0.000644 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000322 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "diacetoxypalladium (0.072 g, 0.32 mmol) and RuPhos (0.301 g, 0.64 mmol) were stirred in 1,4-dioxane (11.36 ml) for 10 mins at 50 C.tert-butyl piperazine-1-carboxylate (0.6 g, 3.22 mmol), 3-bromopyridine (0.310 ml, 3.22 mmol) and sodium tert-butoxide (0.464 g, 4.83 mmol) were added and the reaction mixture was stirred at 100 C for 64 h. The reaction mixture was filtered through celite. The crude product was purified by flash silica chromatography, elution gradient 20 to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(pyridin-3-yl)piperazine-1-carboxylate (0.322 g, 38.0 %) as a yellow oil which crystallised on standing. This was then combined with EN06111-39-01.n" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CN=CC=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 37.96 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/10/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "793" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00484 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0316 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00322 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CN=C1)Br" + } + amount { + moles { + value: 0.00322 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000129 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 6.44e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 85.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.059 g, 0.06 mmol) and rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.080 g, 0.13 mmol) were mixed together and evacuated and purged with nitrogen 3 times. toluene (31.6 ml) was added and the resulting mixture heated to 90C for 10 minutes then cooled to room temperature. sodium tert-butoxide (0.465 g, 4.84 mmol), 3-bromopyridine (0.310 ml, 3.22 mmol) and tert-butyl piperazine-1-carboxylate (0.6 g, 3.22 mmol) were added and the resulting mixture was heated at 85 C for 64 hours. The reaction mixture was cooled to RT and filtered through celite and concentrated to give an orange solid. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(pyridin-3-yl)piperazine-1-carboxylate (0.248 g, 29.2 %) as a yellow oil which crystallised on standi" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CN=CC=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 29.23 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/03/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "794" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0065 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1CCOC1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)N)CO" + } + amount { + moles { + value: 0.00325 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)Br" + } + amount { + moles { + value: 0.0039 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000487 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000195 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 65.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A solution of Tris(dibenzylideneacetone)dipalladium(0) (0.178 g, 0.19 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.282 g, 0.49 mmol) in THF (20 mL) (degassed) was heated to 50 C under a nitrogen atmosphere for 30 min. (3-(phenylamino)phenyl)methanol (0.072 g, 11.13 %) (0.4 g, 3.25 mmol) and cesium carbonate (2.117 g, 6.50 mmol) were added followed by bromobenzene (0.409 mL, 3.90 mmol) and the mixture stirred at 65 C over two days. The reaction mixture was cooled to room temperature then diluted with DCM and filtered. stirred with SiliCycle SiliMet-SH (1 g) for 3 h at 60 C. The mixture was filtered through an acrodisc glassfiber filter, 25 mm, 1.0 m. The filtrate (clear) wasnbsp;concentrated to give crude product (1,00 g). The crude was dissolved in DMSO and the product was purified by prep-HPLC on a Kromasil C8 column (10 m 250x50 ID mm) using a gradient of 5-65% acetonitrile in H2OACNHOAc 9550.2 buffer over 30 minutes with a flow of 100 s were collected on UV at 303 nm, threshold 1000. The product containing fractions were pooled and concentrated on the rotavapor. Toluene was added and evaporated to get rid of residue of water to give the product (3-(phenylamino)phenyl)methanol (0.072 g, 11.13 %) as a transparent oil." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=CC=CC(=C2)CO" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 11.13 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/26/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "795" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00149 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC1=NC(=NC=C1Br)N" + } + amount { + moles { + value: 0.00124 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)I)C(F)(F)F" + } + amount { + moles { + value: 0.00149 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 8.71e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 6.22e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "cfnbsp;uEN06995-11\\Reactionu and many othersbuAim:-u prepare target for further use.b1-iodo-3-(trifluoromethyl)benzene (0.215 ml, 1.49 mmol), 5-bromo-4-methoxypyrimidin-2-amine (0.254 g, 1.24 mmol), PALLADIUM(II) ACETATE (0.014 g, 0.06 mmol), rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthalene (0.054 g, 0.09 mmol) and cesium carbonate (0.487 g, 1.49 mmol)nbsp;were mixed in toluene (5ml), purged with nitrogen and stirred in a sealed tube at 80 C overnight.nbsp;LCMS: pH = 3, 2 minute run time, Rt = 0.66 min (32% by UV),nbsp;mz: 204 (MH+)nbsp;- 316 (M-H-) - ?; Rt = 1.10 min (15% by UV),nbsp;mz: 257, 306 (MH+) - 316nbsp;(M-H-) - ?; Rt = 1.28 min (25% by UV),nbsp;mz: 350,nbsp;(MH+) product ?.The reaction mixture was diluted with EtOAc (20 ml), filtered through a celite pad and concentrated to give 902 mg yellow oil.TLC (1:1 - EtOAc : n-heptane) see diagram UV onlyThis was disolin DCM, absorbed onto a samplet and purified on a 10 g Biotage SNAP column (approx column volume = 7 ml), eluting with a step-wise gradient from 0 : 10 to 4 : 6 EtOAc : n-heptane using a Thomson pump collecting 12 ml fractions.nbsp;F1 - y = 38 mg - GCMS and NMR - show it to be productF2 - y = 229 mgnbsp;- GCMS and NMR - show it to be bromo SMbuConclusion:u- bAbandoned - to be repeated with xanphos" + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=NC(=NC=C1Br)NC2=CC=CC(=C2)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 8.77 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "12/04/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "796" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000818 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.00625 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CCNCC1" + } + amount { + moles { + value: 0.000273 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1CCN(CC1)C2=C3CN(CCC3=C(C=C2)OC)C(=O)CC4=CC=C(C=C4)Br" + } + amount { + moles { + value: 0.000273 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 1.64e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.64e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-(4-bromophenyl)-1-(5-methoxy-8-(4-methylpiperazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (125 mg, 0.27 mmol),[Reactants],piperidine (23.22 mg, 0.27 mmol) was taken in a mixture of DME (5 mL):water (1.250 mL) under N2.The reaction mixture was purged under N2 for 10 min.Tris(dibenzylideneacetone)dipalladium (0) (14.98 mg, 0.02 mmol) was added to the above reaction.The resulting reaction was stirred for 3 hrs at reflux tempt.LCMS profile showed formation of required product.Reaction was cooled to rt,solvents was evapourated to dryness.Crude was diluted with DCM and water (min) and organic layer separated and concentrated .Purification was done on RP systme to get product 1-(5-methoxy-8-(4-methylpiperazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-(4-(piperidin-1-yl)phenyl)ethanone as a solid.but the product was not mitted due to very less ammount." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CCN(CC1)C2=C3CN(CCC3=C(C=C2)OC)C(=O)CC4=CC=C(C=C4)N5CCCCC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/16/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "797" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00547 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C2C(=C1)C(=CN=N2)Cl" + } + amount { + moles { + value: 0.00182 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C(=C(C=N1)C(=O)N2CCC(CC2)N)Cl" + } + amount { + moles { + value: 0.00182 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000182 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000182 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 140.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(4-aminopiperidin-1-yl)(5-chloro-1-methyl-1H-pyrazol-4-yl)methanone (442 mg, 1.82 mmol) was taken in a microwave tube. Added racemic-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (113 mg, 0.18 mmol) followed by the addition of Palladium (II) acetate (40.9 mg, 0.18 mmol), racemic-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (113 mg, 0.18 mmol), Cesium carbonate (1782 mg, 5.47 mmol) and diisopropylethyl amine(1ml). toluene (10 mL) was added and stirred at 140 C for 8h.After the completon of the reaction adsorbed the reaction mass on silica gel and purified by silica gel column." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1C(=C(C=N1)C(=O)N2CCC(CC2)NC3=CN=NC4=CC=CC=C43)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 8.14 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/18/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "798" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000203 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CC(OC2=C(C1=O)C=CC(=N2)Cl)C3=CC=CC=C3" + } + amount { + moles { + value: 0.000203 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC.Cl" + } + amount { + moles { + value: 0.000304 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 2.03e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.03e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: " were placed in a microwave vial equipped with a stirring bar. The vial was capped and flushed with argon. DME (2 mL) and Et3N (0.028 mL, 0.20 mmol) were added via a syringe and the mixture was stirred at room temperature for 30 min and then heated to 100C in a microwave apparatus for 1h. The reaction mixture was diluted with dichloromethane and ethyl acetate, fitered and concentrated. The residue was purified by reversed phase HPLC to give 37 mg of the product as a solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(C=C3)C(=O)N(CC(O4)C5=CC=CC=C5)C)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 40.02 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/19/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "800" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0154 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)NC1=C(C=CC(=C1)N)N(C)CCN(C)C" + } + amount { + moles { + value: 0.00565 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.00514 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C(C)(C)C)C(C)(C)C)C(C)C" + } + amount { + moles { + value: 0.000514 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000257 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Two reactions setup, each 600 mg scale.A 20 mL microwave reactor vial was charged with 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (1.2 g, 5.14 mmol), N-(5-amino-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acetamide (1.414 g, 5.65 mmol), 2-Di-t-butylphosphino-2\',4\',6\'-tri-i-propyl-1,1\'-biphenyl (0.218 g, 0.51 mmol), Pd2dba3 (0.235 g, 0.26 mmol) and CS2CO3 (5.02 g, 15.41 mmol). The vessel was fitted with a septum and gas inlet andnbsp;dioxane (20 mL) was added via syringe. The resulting suspension was stirred for 5 min under nitrogen. The septum and gas inlet was quickly replaced with a microwave vial cap and the mixture was heated at 150 degrees under microwave irradiation for 1h. Two reactions combined and filtered through celite. The filtrate concentrated and mitted for purification (report attached). bReceived a 3 different set up fractions:bFirst set up fractions (EN02868-04-1), LC-MS looks clean but 1H NMR shows acetate peak, couldn\'t getrid of it even longer time on lyohillizer.Second setup fractions combined, lyophllized, purified by ISCO column (0 - 20% MeOH-CH2Cl2 + 0.05% TEA). The obtained compound is a gum. It was triturated with 2 ml of EtOAc, formed a nice solid, it was filtered, washed with Et2O and dried to give 230 mg of white solid. 1H NMR showed slight shift of couple of peaks, it may be due to the protonation. 63 mg of this compound registered and mitted (EN02868-04-2). Third setup fractions showed no required product peaks, was discarded.EN02868-04-1, the remaining material after mission (EN02868-04-2), the filtrate of EN02868-04-2 combined, concentrated, treated with 3 g of MP-carbonate in THF (30 ml). After 1 h stirring, it was filtered washed with THF, concentrated, triturated with CH3CN, filtered and dried to give white color solid (EN02868-04-3). Conclusion: Product isolated" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)NC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)N(C)CCN(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 15.62 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/31/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "801" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00455 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0151 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.00565 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC2=NC=CN2C=C1Br" + } + amount { + moles { + value: 0.00152 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 7.59e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "Cl[Pd+].C1=CC=C(C=C1)C2=CC=CC=C2N" + } + amount { + moles { + value: 8e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "6-bromoimidazo[1,2-a]pyridine (299 mg, 1.52 mmol), dicyclohexyl(2\',6\'-diisopropoxy-[1,1\'-biphenyl]-2-yl)phosphine (35.4 mg, 0.08 mmol), RuPhos 2nd generation (58.9 mg, 0.08 mmol), morpholine (0.159 ml, 1.82 mmol) and cesium carbonate (1483 mg, 4.55 mmol) were dissolved in degassed 1,4-dioxane (15.100 ml).nbsp;Reaction mixture was purged with nitrogen for 2-3 minutes before heating to 90 C and stirred under nitrogen overnight. The reaction was incomplete, therefore additional morpholine (0.159 ml, 1.82 mmol), RuPhos 2nd generation (58.9 mg, 0.08 mmol) and dicyclohexyl(2\',6\'-diisopropoxy-[1,1\'-biphenyl]-2-yl)phosphine (35.4 mg, 0.08 mmol) were added and the reaction mixture washeated for a further 6.5 hours at 105C.nbsp;The reaction was still only ~20% complete therefore additional morpholine (0.318 ml), RuPhos 2nd generation (117.8 mg) and dicyclohexyl(2\',6\'-diisopropoxy-[1,1\'-biphenyl]-2-yl)phosphine (70.8 mg) were added and the reaction heated for a further 24 hours at 105C and then all to RT. The residue partitioned between EtOAc and water, the organic phase was separated and the aq. rextracted with more EtOAc.nbsp;The combined organic extracts were washed with brine, dried over magnesium sulfate filtered and evaporated.nbsp;The crude material was purified by flash silica (12g, grace) chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-(imidazo[1,2-a]pyridin-6-yl)morpholine (98 mg, 31.8 %) as a white solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1COCCN1C2=CN3C=CN=C3C=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 31.84 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/20/2014" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "802" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0253 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0165 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)N" + } + amount { + moles { + value: 0.0145 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(N=CC=C1)Br" + } + amount { + moles { + value: 0.0145 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000218 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.00011 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 115.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Ref: EN07957-77nbsp;BIS(DIBENZYLIDENEACETONE)PALLADIUM(Pd2((dba)3) (0.101 g, 0.11 mmol) and 2,2\'-bis(diphenylphosphanyl)-1,1\'-binaphthalene (BINAP) (0.136 g, 0.22 mmol) was was stirred in toluene (16.5 mL) under N2. Then 2-bromo-3-methylpyridine (1.619 mL, 14.53 mmol), cyclohexanamine (1.662 mL, 14.53 mmol) and sodium 2-methylpropan-2-olate (2.430 g, 25.29 mmol) was added to the above reaction mixture under N2.The reaction mixture was degasssed by reapeated 3 times with N2 and vaccum before the reaction mixture was heated at 115 C for 1.5h LCMS indicated no SM left.nbsp;The reaction mixture was cooled to rt, and then diluted with EtOAcnbsp;and H2O. and neutralized by citric acid to PH ca 5. The aqoeus phase was extracted with EtOAc (4 x). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified automated flash chromatography on 100 g column. A gradient from 0 %nbsp;tonbsp;30 % of EtOAc in heptane over 1800 mL was used as mobile phase. product was collected using the wavelength 249 nm.Collect:F10, 0.231 g, light yellowish solid. LCMS ok, NMR okF11-13: 1.398 g, light yellowish solid, LCMS ok, NMR okF14-16, 79 mg, light yellowish solid, LCMS ok, NMR okNMR of F11-131H NMR (500 MHz, DMSO) d 1.09 - 1.2 (m, 1H), 1.2 - 1.37 (m, 4H), 1.61 (d, 1H), 1.71 (d, 2H), 1.90 (d, 2H), 2.01 (s, 3H), 3.86 (ddd, 1H), 5.28 (d, 1H), 6.39 (dd, 1H), 7.09 - 7.22 (m, 1H), 7.83 (dd, 1H).Expected Number of Hs: 18Assigned Hs: 18.[M + H]+ 191.2" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(N=CC=C1)NC2CCCCC2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 61.83 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/01/2016" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "803" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 2.83e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CC(NC1)C2=CC=CC=C2" + } + amount { + moles { + value: 0.000679 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)Br" + } + amount { + moles { + value: 0.000566 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 2.83e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.42e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Caesium carbonate (553 mg, 1.70 mmol) was added to bromobenzene (0.059 mL, 0.57 mmol) and 2-phenylpyrrolidine (100 mg, 0.68 mmol) in 1,4-dioxane (2 mL). The reaction was degassed and Tris(dibenzylideneacetone)?dipalladium(0) (12.96 mg, 0.01 mmol) and dicyclohexyl(2\',6\'-diisopropoxy-[1,1\'-biphenyl]-2-yl)phosphine (RuPhos) (13.21 mg, 0.03 mmol) were added.nbsp;The resulting solution was stirred at 100 C for 16 hours. LCMS showed the formation of the product.The reaction mixture was diluted with EtOAc, and washed with water. The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. NMR confirmed the presence of the product.The crude product was purified by flash silica chromatography, elution gradient 0 to 15% DCM in MeOH. Pure fractions were evaporated to dryness to afford 1,2-diphenylpyrrolidine (114 mg, 90 %) as a brown oil. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CC(N(C1)C2=CC=CC=C2)C3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 90.18 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/19/2015" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "805" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00187 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CN" + } + amount { + moles { + value: 0.000933 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CSC(=N1)Cl" + } + amount { + moles { + value: 0.000933 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 0.00011 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00011 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "phenylmethanamine (100 mg, 0.93 mmol), 2-chloro-4-methylthiazole (125 mg, 0.93 mmol) and sodium 2-methylpropan-2-olate (179 mg, 1.87 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (62.1 mg, 0.11 mmol) and diacetoxypalladium (16.76 mg, 0.07 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. No reaction. abandoned." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CSC(=N1)NCC2=CC=CC=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/18/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "808" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.002 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)N" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=NC=C1C(F)(F)F)Cl" + } + amount { + moles { + value: 0.000999 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 160.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Objective: Test of scope in the coupling of ester stituted aminooxazoleTo an oven-dried microwave vial was added ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol), 2-chloro-5-(trifluoromethyl)pyridine (181 mg, 1.00 mmol), cesium carbonate (651 mg, 2.00 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.87 mg, 0.02 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (43.4 mg, 0.075 mmol) and the vial was capped and purged with nitrogen. dioxane (4 mL) (degassed) was added and the reaction mixture was heated to 160 C for 1 h under microwave irradiation.LCMS of the crude reaction mixture indicated that the desired product had been formed with very small amounts of side products apparent.DCM (20 mL) was added to the crude reaction mixture together with silica (2 g) and the solvent was removed from the reaction mixture under reduced pressure. The resulting residue was then placed in a dry-load tube prior to chromatography. The crude product was purified by h silica chromatography, elution gradient 0 to 5% methanolic ammonia in DCM. Pure fractions were evaporated to dryness to afford the desired product in 74% yield and 92% purity by LCMS. The product was triturated with MeCN to give a solid which was collected by filtration and dried under vacuum to give ethyl 2-(5-(trifluoromethyl)pyridin-2-ylamino)oxazole-5-carboxylate (185 mg, 61.5 %) as a cream solid. This material was shown to be gt; 95% pure based on proton NMR strength.Conclusion: The desired product was formed in moderate yield and high purity." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1=CN=C(O1)NC2=NC=C(C=C2)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 61.47 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/13/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "809" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000977 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C(=C1)CN)F" + } + amount { + moles { + value: 0.000537 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(2-fluorophenyl)methanamine (67.3 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford N4-(2-fluorobenzyl)-N2-phenylpyridine-2,4-diamine (89 mg, 62.1 %) as a white solid.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)NCC3=CC=CC=C3F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 62.09 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/01/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "810" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000947 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN(C=N1)C2=C(N=C(C=C2)N)OC" + } + amount { + moles { + value: 0.000521 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN=C(S1)C2CN(CC3=C(O2)N=C(C=C3)Cl)C" + } + amount { + moles { + value: 0.000473 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 4.73e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.73e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "8-chloro-4-methyl-2-(5-methylthiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (140 mg, 0.47 mmol), 6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-amine (106 mg, 0.52 mmol), 2-(DICYCLOHEXYLPHOSPHINO)BIPHENYL (16.59 mg, 0.05 mmol), PALLADIUM(II) ACETATE (10.63 mg, 0.05 mmol) and Cs2CO3 (308 mg, 0.95 mmol) were weighed into a microwave vial, the vial was capped and DME (4 mL) was added. The vial was flushed with argon and heated to 100C in a microwave reactor for 1 h. The reaction mixture was diluted with dichloromethane and filtered and the solvents were evaporated. The residue was purified by column chromatography on Silica using gradient elution with methanol in dichloromethane (0-6 %) to give N-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methyl-2-(5-methylthiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (162 mg, 73.8 %)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN=C(S1)C2CN(CC3=C(O2)N=C(C=C3)NC4=NC(=C(C=C4)N5C=C(N=C5)C)OC)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 73.84 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/01/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "812" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.7 [N-arylation with Ar-X] Chloro N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 6.1e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)C(=O)N" + } + amount { + moles { + value: 0.00061 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(N=C1)Cl)Cl" + } + amount { + moles { + value: 0.000671 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 6.1e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.05e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 5 mL vial were added Pd(OAc)2 (6.85 mg, 0.03 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (35.3 mg, 0.06 mmol), N-(3-chloropyridin-2-yl)benzamide (15.30 mg, 10.78 %) and cesium carbonate (477 mg, 1.46 mmol) in dioxane (2 mL) to give a yellow solution. The flask was evacuated and filled with Nitrogen three times. Then, 2,3-dichloropyridine (99 mg, 0.67 mmol) was added. The reaction mixture was stirred overnight at 80C.The reaction mixture was diluted with EtOAc (3 mL) and filtered. The solid was washed with EtOAc and the collected organic layers were evaporated to dryness, to give the crude product.The compound was purified by preparative HPLC on a Kromasil C8 column (10 m 250x20 ID mm) using a gradient of 10-50% acetonitrile in H2OACNFA 9550.2 buffer, over 20 minutes with a flow of 19 mLmin. The compounds were detected by UV at 230nm. (15,3 mg pure product).The reaction was repeated at 80C, RT and 110C on microwave, overnight and a weekend: d remains very low for all conditions except for the reaction at RT (no product at all). " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)C(=O)NC2=C(C=CC=N2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 10.78 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/26/2016" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "815" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00121 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1C(F)(F)F)Cl" + } + amount { + moles { + value: 0.00121 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000101 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 5.04e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 105.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 2.0-5.0 mL microwave vial was charged with (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (200 mg, 1.01 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (62.8 mg, 0.10 mmol), Sodium tert-butoxide (116 mg, 1.21 mmol), 2-Chloro-4-(trifluoromethyl)pyridine (0.156 mL, 1.21 mmol) and a mixture of toluene (2.5 mL) and DMF (.5 mL). The reaction mixture was degassed for 10 minutes with nitrogen, and then Tris(dibenzylideneacetone)dipalladium(0) (46.2 mg, 0.05 mmol) was added. The reaction mixture was stirred at 105C in an oil bath 12h.nbsp;The solution was diluted with EtOAc and washed with saturated NaHCO3 solution, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was loaded on a 24g silica gel column and purified on a Teledyne Isco instrument, eluting with 10% to 40% ethyl acetate in heptane to provide (1S,4S)-tert-butyl 5-(4-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (254 mg, 73.3 %) as a solp1H NMR (400MHz ,CHLOROFORM-d) d 8.26 (d, J = 5.5 Hz, 1 H), 6.75 (d, J = 5.1 Hz, 1 H), 6.48 (s, 1 H), 4.99 - 4.83 (m, 1 H), 4.76 - 4.52 (m, 1 H), 3.56 (t, J = 8.4 Hz, 1 H), 3.49 - 3.32 (m, 3 H), 2.04 - 1.91 (m, 2 H), 1.45 (d, J = 18.0 Hz, 9 H); MS mz 344.2 [M+H]+ (ESI)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C3=NC=CC(=C3)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 73.34 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/29/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "816" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000908 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2" + } + amount { + moles { + value: 0.000757 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1C(F)(F)F)Cl" + } + amount { + moles { + value: 0.000908 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 7.57e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 3.78e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 2.0-5.0 mL microwave vial was charged with (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (150 mg, 0.76 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (47.1 mg, 0.08 mmol), Sodium tert-butoxide (87 mg, 0.91 mmol), 2-Chloro-4-(trifluoromethyl)pyridine (0.117 mL, 0.91 mmol) and and mixture of toluene (2.5 mL) and DMF (.5 mL). The reaction mixture was degassed for 10 minutes with nitrogen, and then Tris(dibenzylideneacetone)dipalladium(0) (34.6 mg, 0.04 mmol) was added. The reaction mixture was stirred at 120C under microwave irradiation for 30 minutes. The solution was then irradiated for another 30 min at 120C.nbsp;The solution was diluted with EtOAc and washed with saturated NaHCO3 solution, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was loaded on a 24g silica gel column and purified on a Teledyne Isco instrument, eluting with 10% to 40% ethyl acetate in heptane to provide (1S,4S)-tert-butyl 5-(4-(trifluorpyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (88 mg, 33.9 %) as a solid.MS mz 344.2 [M+H]+ (ESI)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C3=NC=CC(=C3)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 33.88 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/22/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "817" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00271 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CC(CCC1=O)N" + } + amount { + moles { + value: 0.00156 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(N=C1)Br)Cl" + } + amount { + moles { + value: 0.00156 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 2.34e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.18e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 115.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 10 ml MW vial,nbsp;Pd2((dba)3 (10.85 mg, 0.01 mmol), 2,2\'-bis(diphenylphosphanyl)-1,1\'-binaphthalene (BINAP) (14.56 mg, 0.02 mmol),nbsp;sodium 2-methylpropan-2-olate (261 mg, 2.71 mmol), 5-amino-1-methylpiperidin-2-one (200 mg, 1.56 mmol) and 2-bromo-3-chloropyridine (300 mg, 1.56 mmol) mixed in toluene (3 mL) to give a brown suspension. The mixture was degassed with N2 bubbling for 5 min, then the vial was capped and the reaction stirred at 115C in an oil-bath for 1h then to rt for 2h.LC-MS 1h: 15% product.LC-MS on: 19% product.The reaction was cooled to rt and the solvent was evaporated.The residue was purified by automated flash chromatography on a 50g column. A gradient from 20% to 100% of EtOAc in heptane over 20CV was used as mobile phase. The product was collected using the wavelength 307 and 241 nm.Product was not found in any of the fractions, reaction discarded." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CC(CCC1=O)NC2=C(C=CC=N2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/21/2016" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "819" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.012 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1C(CO1)N.Cl" + } + amount { + moles { + value: 0.004 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)[N+](=O)[O-])Br" + } + amount { + moles { + value: 0.004 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 4e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.0004 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2-bromo-1-methyl-4-nitrobenzene (864 mg, 4mmol), oxetan-3-amine hydrochloride (438 mg, 4 mmol), CS2CO3 (3910 mg, 12.00 mmol), palladium(II) acetate (44.9 mg, 0.20 mmol), (R)-(-)-1-[(S)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (224 mg, 0.40 mmol) in 1,4-doxane was degased, inflated with Ar and heated at 90 oC for 5h. LCMS showed some product peak. Silica gel 2g was added to the mixture, evaporated all solvents in GeneVac. The sample was dry loaded for purification by ISCO (HexaneEtOAc=10010-10050)N-(2-methyl-5-nitrophenyl)oxetan-3-amine (240 mg, 28.8 %)1H NMR (400 MHz, CD2Cl2) d: 7.47 (dd, 1H),nbsp;7.14 (d, 1H), 6.98 (s, 1H), 4.99 (t, 2H),nbsp;4.63 (m, 1H), 4.46 (t, 2H),nbsp;4.20(m, 1H), 2.18 (s, 3H).nbsp;LCMS: 209 [M+H]+." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)[N+](=O)[O-])NC2COC2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 28.82 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/14/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "820" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000898 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CN" + } + amount { + moles { + value: 0.000494 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1NC2=NC=CC(=C2)Cl)F" + } + amount { + moles { + value: 0.000449 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Phenylmethanamine (52.9 mg, 0.49 mmol), 4-chloro-N-(4-fluorophenyl)pyridin-2-amine (100 mg, 0.45 mmol) and sodium 2-methylpropan-2-olate (86 mg, 0.90 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (29.9 mg, 0.05 mmol) and diacetoxypalladium (8.07 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford N4-benzyl-N2-(4-fluorophenyl)pyridine-2,4-diamine (98 mg, 74.4 %) as an off-white solid.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=C(C=C3)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 74.38 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/01/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "821" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000905 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=CC(=C1)N2CCN(CC2)CCO)N" + } + amount { + moles { + value: 0.000754 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC2=C(C=NN2C=C1)C3=NC(=NC=C3Cl)Cl" + } + amount { + moles { + value: 0.000754 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 8e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 8e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 140.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "3-(2,5-dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (200 mg, 0.75 mmol), 2-(4-(4-amino-3-methoxyphenyl)piperazin-1-yl)ethanol (190 mg, 0.75 mmol), cesium carbonate (295 mg, 0.91 mmol), diacetoxypalladium (13.55 mg, 0.06 mmol)nbsp;and (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (41.8 mg, 0.08 mmol) were suspended in DME (5 mL) and sealed into a microwave tube. The reaction was degased, purged with nitrogen and heated to 140 C over a period of 30 minutes in the microwave reactor. The reaction mixture was filtratet and the fitrate was evaporated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 5% methanol in dichloromethane. The solvent was evaporated to dryness to afford 2-(4-(4-(5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-ylamino)-3-methoxyphenyl)piperazin-1-yl)ethanol (60mg) 1H NMR 01570-55-03 as anbsp;red gum.The gum was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microilica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford 2-(4-(4-(5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-ylamino)-3-methoxyphenyl)piperazin-1-yl)ethanol (40.0 mg, 11.05 %) as a yellow foam.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=C(C=CC(=C1)N2CCN(CC2)CCO)NC3=NC=C(C(=N3)C4=C5C=CC=CN5N=C4)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 11.05 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/11/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "822" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00824 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1CCOC1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00275 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1C#N)Br" + } + amount { + moles { + value: 0.00275 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.000275 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000275 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To 4-bromobenzonitrile (.5 g, 2.75 mmol)nbsp;dissolved in dry THF (10nbsp;mL) was added tert-butyl piperazine-1-carboxylate (0.512 g, 2.75 mmol), Sodium-t-butoxide (0.792 g, 8.24 mmol) and purged with N2 gas for 10 min followed by the addition of 2-(Dicyclohexylphosphino)-2\',4\',6\'-tri-i-propyl-1,1\'-biphenyl (0.131 g, 0.27 mmol)and Palladium II acetate (0.062 g, 0.27 mmol).nbsp;The contents were further purged with N2 gas for further 10 min and heated at 85 C for 2 h. The reaction mass was concentrated and the reside diluted with water and extracted with ethyl acetate . The combined organic extracts were washed with brine solution and dried over anhydrous sodium sulphate.nbsp;The organic layer was evaporated under reduced pressure to obtain the crude product which was purified by 60-120 mesh silica gel column chromatography usingnbsp;25% Ethyl acetate : Hexanes mixture to obtain tert-butyl 4-(4-cyanophenyl)piperazine-1-carboxylate (0.650 g, 82 %) as a white solid.nbsp;z (ES+), M+ = 288.4" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC=C(C=C2)C#N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 82.34 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/03/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "823" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.001 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCNCC1" + } + amount { + moles { + value: 0.0015 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC(=CC(=C1)[N+](=O)[O-])Br" + } + amount { + moles { + value: 0.0005 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "1-bromo-3-methoxy-5-nitrobenzene (116 mg, 0.5 mmol), 1-methylpiperazine (167 l, 1.50 mmol), Palladium(II) acetatenbsp;(11.23 mg, 0.05 mmol), BINAP (31.1 mg, 0.05 mmol), Cs2CO3 (326 mg, 1.00 mmol) and PhCH3 (10 mL) were added to a 100ml rb flask and heated at 150 C for 1h.LCMS showed rxn done with desired product formed.Rxn was filtered and concentrated. The residue was purified by Gilson (CH3CNWater 0-50% + 0.1%TFA) to get the desired product 1-(3-methoxy-5-nitrophenyl)-4-methylpiperazine (130 mg, 71.2" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CCN(CC1)C2=CC(=CC(=C2)OC)[N+](=O)[O-]" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 71.17 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/10/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "824" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0023 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1C(CO1)N" + } + amount { + moles { + value: 0.00192 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=CC(=C1)I)Br" + } + amount { + moles { + value: 0.00192 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000192 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 4.79e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A solution of 1-bromo-4-iodo-2-methoxybenzene (0.60 g, 1.92 mmol) dissolved in toluene (15 mL) was treated with oxetan-3-amine (0.140 g, 1.92 mmol), SODIUM TERT-BUTOXIDE (0.221 g, 2.30 mmol), XANTPHOS (0.111 g, 0.19 mmol)nbsp;and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.044 g, 0.05 mmol)nbsp;under nitrogen. The resulting mixture was stirred at 80 C in a sealed tube for 2 hours. The reaction mixture was diluted with water (10 mL), and extracted with ethyl acetate (3x 20 mL).nbsp;The organic was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution 0-30% EtOAc in Heptane. Pure fractions were evaporated to dryness to afford N-(4-bromo-3-methoxyphenyl)oxetan-3-amine (0.177 g, 35.8 %) as a beige solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=C(C=CC(=C1)NC2COC2)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 35.77 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/17/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "825" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CCC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000495 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCNC1=CC=CC=C1" + } + amount { + moles { + value: 0.000248 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=NC(=NC=C1Br)I" + } + amount { + moles { + value: 0.000272 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 1.24e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.24e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "5-bromo-2-iodo-4-methoxypyrimidine (0.086 g, 0.27 mmol), diacetoxypalladium (2.78 mg, 0.01 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) - XantPhos (7.16 mg, 0.01 mmol) and sodium 2-methylbutan-2-olate (0.055 g, 0.50 mmol) andnbsp;di((3S,5S,7S)-adamantan-1-yl)(butyl)phosphine (8.88 mg, 0.02 mmol) were added to a micro vial. Then N-ethylaniline (0.031 mL, 0.25 mmol) innbsp;toluene (1.5 mL) was added to the reaction mixture. The vial was sealed and evacuated and flushed with nitrogen and then stirred at 100C on. LCMS showed product formation. The reaction mixture was cooled to rt and then filtered over celite. The crude product was diluted with 25 ml of DCM and then washed with sat. NaHCO3 followed by brine. The organic phase was dried over a phase separator and then concentrated to dryness.bNo LCMS data due to database failure over three months and was only saved locally on LCMS computer and pdf-files seems to be deleted on machine. Not used in further reactions.b" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCN(C1=CC=CC=C1)C2=NC=C(C(=N2)OC)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 70.78 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/17/2014" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "826" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CCC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000297 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCNC1=CC=CC=C1" + } + amount { + moles { + value: 0.000248 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=NC(=NC=C1Br)I" + } + amount { + moles { + value: 0.000272 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CCCCP(C12CC3CC(C1)CC(C3)C2)C45CC6CC(C4)CC(C6)C5" + } + amount { + moles { + value: 2.48e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.24e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 60.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "5-bromo-2-iodo-4-methoxypyrimidine (0.086 g, 0.27 mmol), diacetoxypalladium (2.78 mg, 0.01 mmol), di((3S,5S,7S)-adamantan-1-yl)(butyl)phosphine (8.88 mg, 0.02 mmol) and sodium 2-methylbutan-2-olate (0.033 g, 0.30 mmol) were added to a micro vial. Then N-ethylaniline (0.031 mL, 0.25 mmol) in toluene (1.5 mL) was added to the reaction mixture. The vial was sealed and evacuated and flushed with nitrogen and then stirred at 60C on. LCMS showed product formation. The reaction mixture was cooled to rt and then filtered over celite. The crude product was diluted with 25 ml of DCM and then washed with sat. NaHCO3 followed by brine. The organic phase was dried over a phase separator and then concentrated to dryness.bNo LCMS data due to database failure over three months and was only saved locally on LCMS computer and pdf-files seems to be deleted on machine. Not used in further reactions.b" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCN(C1=CC=CC=C1)C2=NC=C(C(=N2)OC)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 53.74 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/20/2014" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "827" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00489 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCCN1" + } + amount { + moles { + value: 0.0321 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC1=C(C=CC(=C1)Br)Cl" + } + amount { + moles { + value: 0.00391 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000391 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "palladium(II) acetate (0.110 g, 0.49 mmol), BINAP (0.244 g, 0.39 mmol) and CS2CO3 (1.594 g, 4.89 mmol) were added to a mixture of [Reactants] and piperazine (2.76 g, 32.10 mmol) innbsp;toluene (10 mL), The suspension were heated to 110 C for 16 hours, LCMS showed product mass [M+1]:312.0 at retention time RT=1.69 min (polar short purity method). Workup reaction by additional of water (10mL), extracted with EtOAc (3x20 mL), washed with brine, dried with Na2SO4, evaporated off solvent to give a residue, which was purified by isco chromatographer, eluting with 0-10% MeOH in DCM to give as a yellow solid. LCMS confirmed the target compound." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC1=C(C=CC(=C1)N2CCNCC2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 57.11 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/29/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "828" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00436 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.035 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CN=C1)C2=NC(=NC=C2)N" + } + amount { + moles { + value: 0.00291 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=N1)[N+](=O)[O-])Br" + } + amount { + moles { + value: 0.0032 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000581 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000291 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium(II) acetate (65.3 mg, 0.29 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (336 mg, 0.58 mmol) were mixed together in a reaction vessel and evacuated and purged with nitrogen 3 times. Toluene (35 ml) was added and the resulting mixture was heated to to 50C for 45 minutes.To this mixture was added 3-bromo-2-methyl-5-nitropyridine (694 mg, 3.20 mmol), then 4-(pyridin-3-yl)pyrimidin-2-amine (500 mg, 2.91 mmol) and cesium carbonate (1421 mg, 4.36 mmol), andthe resulting mixture heated at 90 Cnbsp;for 16 hours.The reaction mixture was cooled to RT, 50ml EtOAc was added and the mixture was filtered. The filtrate was concentrated, diluted with EtOAc (200 mL), and washed sequentially with water (150 mL) and saturated brine (150 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product, ~2g brown wet solid.The crude product was purified by flash silica chromatography, elution gradient 0 to 4% MeOH in DCM. Pure fractiing at 3% were evaporated to dryness to afford N-(2-methyl-5-nitropyridin-3-yl)-4-(pyridin-3-yl)pyrimidin-2-amine (169 mg, 18.86 %) as a colourless solid. . " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=N1)[N+](=O)[O-])NC2=NC=CC(=N2)C3=CN=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 18.86 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/27/2014" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "829" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0131 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0871 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CN=C1)C2=NC(=NC=C2)N" + } + amount { + moles { + value: 0.00871 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=N1)[N+](=O)[O-])Br" + } + amount { + moles { + value: 0.00828 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00174 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000871 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium(II) acetate (65.3 mg, 0.29 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (336 mg, 0.58 mmol) were mixed together in a reaction vessel and evacuated and purged with nitrogen 3 times. Toluene (35 ml) was added and the resulting mixture was heated to to 50C for 45 minutes, then cooled to r.t.To this mixture at r.t was added 3-bromo-2-methyl-5-nitropyridine (694 mg, 3.20 mmol), then 4-(pyridin-3-yl)pyrimidin-2-amine (500 mg, 2.91 mmol) and cesium carbonate (1421 mg, 4.36 mmol), and the resulting mixture heated at 90 Cnbsp;for 16 hours under N2.The reaction mixture was cooled to RT, 150ml EtOAc was added and the mixture was filtered. The filtrate was concentrated, diluted with EtOAc (500 mL), and washed sequentially with water (300 mL) and saturated brine (150 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product, ~2g brown wet solid.The crude product was purified by flash silica chromatography, elution gradient 0 OH in DCM. Pure fractions eluting at 3% were evaporated to dryness to afford N-(2-methyl-5-nitropyridin-3-yl)-4-(pyridin-3-yl)pyrimidin-2-amine (169 mg, 18.86 %) as a cream solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=N1)[N+](=O)[O-])NC2=NC=CC(=N2)C3=CN=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 21.22 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/27/2014" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "830" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[K+].[K+]" + } + amount { + moles { + value: 0.00422 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0075 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)N" + } + amount { + moles { + value: 0.00187 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=NC(=C1)Cl)Cl" + } + amount { + moles { + value: 0.00154 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 3.05e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 2.67e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 160.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "2,6-dichloropyridine (228 mg, 1.54 mmol) was dissolved in toluene (7.5 ml) and diacetoxypalladium (6 mg, 0.03 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthalene (19 mg, 0.03 mmol),nbsp;aniline (0.170 ml, 1.87 mmol) and potassium carbonate (583 mg, 4.22 mmol) were added added. The reaction mixture was sparged with notrogen for 3-4 minutes before being sealed into a microwave tube and heated to 160 C over ~3 minutes, before holding at that temperature for 30 minutes.nbsp;After cooling to ambient temperature the reaction mixture was diluted to ~40 mL with ethyl acetate and insoluble material removed by filtration. The filtrate was evaporated and purification attempted by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. Product containing fractions were evaporated to dryness to afford 6-chloro-N-phenylpyridin-2-amine (167 mg, 53.0 %) as a waxy pale yellow solid" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC(=CC=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 52.97 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/05/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "831" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00244 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=C2C(=CC(=C1F)F)NC(=O)C=C2Cl" + } + amount { + moles { + value: 0.000812 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C[C@H]1C[C@@H](CCN1C(=O)C2=C(N(N=C2)C)Cl)N" + } + amount { + moles { + value: 0.000812 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 8.12e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 8.12e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 140.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 25ml Biotage microwave vial, 4-chloro-6,7-difluoroquinolin-2(1H)-one (0.175 g, 0.81 mmol), ((2S,4R)-4-amino-2-methylpiperidin-1-yl)(5-chloro-1-methyl-1H-pyrazol-4-yl)methanone (0.208 g, 0.81 mmol) ,racemic-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.051 g, 0.08 mmol), Cesium carbonate (0.793 g, 2.44 mmol), Palladium (II) acetate (0.018 g, 0.08 mmol)nbsp;were taken were taken in toluene (10 mL) to give brown suspension. The reaction mass was jected to microwave irradiation at 140 oC for 1 hour. The reaction ws monitored by LCMS, indicated required product formation.Workup: The reaction mixture was concentrated to dryness and purified by silica gel column chromatography using 0 to 20% Methanol in DCM and then purified by reverse phase chromatography to obtain 4-(((2S,4R)-1-(5-chloro-1-methyl-1H-pyrazole-4-carbonyl)-2-methylpiperidin-4-yl)amino)-6,7-difluoroquinolin-2(1H)-one (0.030 g, 8.48 %) as white solid.The compound was mitted for biological testing." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@H]1C[C@@H](CCN1C(=O)C2=C(N(N=C2)C)Cl)NC3=CC(=O)NC4=CC(=C(C=C43)F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 8.48 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/23/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "832" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00181 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1(COC1)CN" + } + amount { + moles { + value: 0.00125 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(N=C1)Br)Cl" + } + amount { + moles { + value: 0.00104 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 1.56e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 7.9e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 115.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 5 MW vial,nbsp;Pd2((dba)3 (7.23 mg, 7.90 mol), 2,2\'-bis(diphenylphosphanyl)-1,1\'-binaphthalene (BINAP) (9.71 mg, 0.02 mmol),nbsp;sodium 2-methylpropan-2-olate (174 mg, 1.81 mmol), (3-methyloxetan-3-yl)methanamine (126 mg, 1.25 mmol) and 2-bromo-3-chloropyridine (200 mg, 1.04 mmol) mixed in toluene (2 mL) to give a brown suspension. The mixture was degassed with N2 bubbling for 5 min, then the vial was capped and the reaction stirred at 115C in an oil-bath for 1h then to rt for 2h.LC-MS: 61% product, 28% sm left.The reaction was cooled to rt and the solvent was evaporated.The residue was purified by automated flash chromatography on a 25g column. A gradient from 5% to 50% of EtOAc in heptane over 15CV was used as mobile phase. The product was collected using the wavelength 315 nm, relevant fractions pooled and evaporated to give 27 mg suryp.LC-MS: M+1=213 found.1H-NMR: OK, traces of sm and solvents left.1H NMR (400 MHz, CDCl3) d 1.37 (s, 3H)d, 2H), 4.42 (d, 2H), 4.58 (d, 2H), 5.25 (s, 1H), 6.53 (dd, 1H), 7.44 (dd, 1H), 8.00 (dd, 1H).Expected Number of Hs: 13Assigned Hs: 13." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1(COC1)CNC2=C(C=CC=N2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 12.22 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/26/2016" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "834" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00484 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0297 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2" + } + amount { + moles { + value: 0.00303 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CN=C1)Br" + } + amount { + moles { + value: 0.00333 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00012 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 85.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.055 g, 0.06 mmol) and rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.075 g, 0.12 mmol) were mixed together and evacuated and purged with nitrogen 3 times. toluene (29.7 ml) was added and the resulting mixture heated to 90C for 10 minutes then cooled to room temperature.In a second reaction vessel was mixed sodium tert-butoxide (0.465 g, 4.84 mmol), 3-bromopyridine (0.321 ml, 3.33 mmol) and (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.601 g, 3.03 mmol) and toluene (29.7 ml). The mixture was evacuated and purged with nitrogen 3 times. The solution of catalyst was added to the reaction mixture and the resulting mixture was heated at 85 C for 64 hours.The reaction mixture was cooled to RT and filtered through celite and concentrated to give an orange solid.The crude product was purified by flash silica chromatography, elution gradient 30 to 50% EtOAc in heptane. Then 100% MeOH.nbsp;Pure fractions porated to dryness to afford (1S,4S)-tert-butyl 5-(pyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.823 g, 99 %) as a pale yellow dry film. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C3=CN=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 98.65 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/29/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "835" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00014 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.000103 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C(=CC=C1)C)C(=O)NC(C2=CC(=CC=C2)Br)C34CCC(N3C)CC4" + } + amount { + moles { + value: 9.36e-05 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 9.36e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.68e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a suspension of N-((3-bromophenyl)(7-methyl-7-azabicyclo[2.2.1]heptan-1-yl)methyl)-2,6-dimethylbenzamide (0.040 g, 0.09 mmol), MORPHOLINE (8.97 L, 0.10 mmol), BINAP (5.83 mg, 9.36 mol), and sodium tert-butoxide (0.013 g, 0.14 mmol) in toluene (2 mL) was added palladium(II) acetate (1.051 mg, 4.68 mol).nbsp;Nitrogen was passed through the solution for 15 min prior to being heated at 80 C overnight.nbsp;Crude LC shows starting material still present.nbsp;Heated to 110oC for 2 days.nbsp;Reaqction no longer progressing.Reaction mixture was concentrated in vacuo.nbsp;Material was diluted with ethyl acetate, filtered thru celite and concentrated in vacuo.Submitted to purification group (52 mg in 1.6 mL DMSO).nbsp;Received back dried-down fractions.nbsp;Diluted with DCM, combined and concentrated to afford 2,6-dimethyl-N-((7-methyl-7-azabicyclo[2.2.1]heptan-1-yl)(3-morpholinophenyl)methyl)benzamide (7.30 mg, 17.99 %)Submitted 4.5 mgVial # 26243972 545 g" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C(=CC=C1)C)C(=O)NC(C2=CC(=CC=C2)N3CCOCC3)C45CCC(N4C)CC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 17.99 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/13/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "836" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000977 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC=C(C=C1)CN" + } + amount { + moles { + value: 0.000537 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(4-methoxyphenyl)methanamine (73.7 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford N4-(4-methoxybenzyl)-N2-phenylpyridine-2,4-diamine (101 mg, 67.7 %) as a white solid.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 67.69 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/01/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "837" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000498 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0493 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1C2=CC=CC=C2CN1" + } + amount { + moles { + value: 0.00498 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1Br)I" + } + amount { + moles { + value: 0.00498 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000498 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000498 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "palladium(II) acetate (0.112 g, 0.50 mmol) and XANTPHOS (0.288 g, 0.50 mmol) were added to a degassed solution of isoindoline (0.566 ml, 4.98 mmol), 1-bromo-4-iodobenzene (1.41 g, 4.98 mmol) and SODIUM TERT-BUTOXIDE (1.197 g, 12.46 mmol) in toluene (49.3 ml) under nitrogen. The resulting solution was stirred at 100 C for 18 hours. The reaction mixture was allowed to cool to RT and was partitioned between EtOAc and H2O, filtered and the organic layer separated and dried over MgSO4, filtered and evaporated to dryness to give crude product.nbsp;The crude product preabsorbed onto SiO2 and was purified by flash silica (40g, grace) chromatography, elution gradient 0 to 10% DCM in heptane. Pure fractions were evaporated to dryness to afford 2-(4-bromophenyl)isoindoline (0.660 g, 48.3 %) as an orange solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1C2=CC=CC=C2CN1C3=CC=C(C=C3)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 48.3 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/14/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "838" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0065 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CC(C1)N.Cl" + } + amount { + moles { + value: 0.00338 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(N=C1)Br)Cl" + } + amount { + moles { + value: 0.0026 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 3.9e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.97e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 115.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Pd2(dba)3 (0.018 g, 0.02 mmol), 2,2\'-bis(diphenylphosphanyl)-1,1\'-binaphthalene (BINAP) (0.024 g, 0.04 mmol) and toluene (4 mL) was added to a flask. 2-bromo-3-chloropyridine (0.5 g, 2.60 mmol), 1-methylazetidin-3-amine hydrochloride (0.414 g, 3.38 mmol) and sodium 2-methylpropan-2-olate (0.624 g, 6.50 mmol) was added, the mixture bubbled with N2 for 5 min, then the reaction was heated to 115 C in an oil-bath under nitrogen for 2h, then to rt over night.The reaction was cooled to rt and the solvent was evaporated.The residue was purified by automated flash chromatography on a 100g column. A gradient from 10% to 100% of EtOAc (with 2% TEA) in heptane over 25CV was used as mobile phase. The product was collected using the wavelength 243 and 308 nm.No product found in any fractions.Reaction discarded." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CC(C1)NC2=C(C=CC=N2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/31/2016" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "840" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0193 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1CCOC1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00644 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC(=CC(=C1)Br)F" + } + amount { + moles { + value: 0.00644 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.000644 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000644 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To methyl 3-bromo-5-fluorobenzoate (1.5 g, 6.44 mmol)nbsp;dissolved in dry THF (20nbsp;mL) was added tert-butyl piperazine-1-carboxylate (1.199 g, 6.44 mmol), Sodium-t-butoxide (1.856 g, 19.31 mmol) and purged with N2 gas for 10 min followed by the addition of2-(Dicyclohexylphosphino)-2\',4\',6\'-tri-i-propyl-1,1\'-biphenyl (0.307 g, 0.64 mmol), Palladium II acetate (0.145 g, 0.64 mmol) .nbsp;The contents were further purged with N2 gas for further 10 min and heated at 85 C for overnight. The reaction mass was concentrated and the reside diluted with water and extracted with ethyl acetate . The combined organic extracts were washed with brine solution and dried over anhydrous sodium sulphate.nbsp;The organic layer was evaporated under reduced pressure to obtain the crude product which was purified by 60-120 mesh silica gel column chromatography usingnbsp;25% Ethyl acetate ; hexanes mixture to obtain 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-fluorobenzoic acid (1.500 g, 71.8 % oil. mz (ES-), M- = 323" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC(=CC(=C2)C(=O)O)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 71.85 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/12/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "841" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.7 [N-arylation with Ar-X] Chloro N-arylation" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00243 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.0072 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N[C@@H]1CCC[C@H](C1)C(=O)N" + } + amount { + moles { + value: 0.000971 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1(CC2=C(C=NN2C1)C3=CC(=NC=C3F)Cl)C" + } + amount { + moles { + value: 0.000809 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000162 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.[Pd]" + } + amount { + moles { + value: 8.09e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Tetrakis(triphenylphosphine)palladium(0) (0.094 g, 0.08 mmol) was added to Racemic tert-butyl ((1R,3R)-3-carbamoylcyclohexyl)carbamate (0.235 g, 0.97 mmol),3-(2-chloro-5-fluoropyridin-4-yl)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (0.215 g, 0.81 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (0.094 g, 0.16 mmol) and cesium carbonate (0.791 g, 2.43 mmol) in 1,4-dioxane (6 mL) and water (1.200 mL).nbsp;The resulting suspension was degassed for 10 minutes under nitrogen and then stirred at 100 C for 48 hours. LCMS is complete, it needs this long. The mixture was cooled, diluted with water (40 ml), and extracted with EtOAc (3 x 20 ml). The combined organics were evaporated to crude material. The crude product was purified by flash silica chromatography, elution gradient 0 to 60% EtOAc in heptane. Pure fractions were evaporated to dryness to afford Racemic tert-butyl ((1R,3R)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexarbamate (0.322 g, 84 %) as a white foam. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1(CC2=C(C=NN2C1)C3=CC(=NC=C3F)NC(=O)[C@@H]4CCC[C@H](C4)NC(=O)OC(C)(C)C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 84.39 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/09/2015" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "842" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00127 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0127 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00127 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC1=C(C=C(C=C1)Br)Cl" + } + amount { + moles { + value: 0.00127 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000127 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 6.37e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 50 mL round-bottomed flask, PALLADIUM ACETATE (0.014 g, 0.06 mmol) was treated with BINAP (0.079 g, 0.13 mmol) under nitrogen in degassed Toluene (12.74 ml). The reaction was heated to 80 C and was stirred for 10 min. To the flask was then added tert-butyl piperazine-1-carboxylate (0.237 g, 1.27 mmol), cesium carbonate (0.208 g, 0.64 mmol), potassium carbonate (0.176 g, 1.27 mmol), and 18-CROWN-6 (0.034 g, 0.13 mmol). The reaction was then treated with 4-bromo-2-chloro-1-ethoxybenzene (0.300 g, 1.27 mmol) and was allowed to stir at 80C 5 h.bLCMS High pH:bNo reaction obse" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC1=C(C=C(C=C1)N2CCN(CC2)C(=O)OC(C)(C)C)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/25/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "843" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00242 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0157 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN(C)CCN" + } + amount { + moles { + value: 0.00201 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=CC(=C1)I)Br" + } + amount { + moles { + value: 0.00201 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000201 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 5.03e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A solution of 1-bromo-4-iodo-2-methoxybenzene (0.63 g, 2.01 mmol) dissolved in toluene (15.73 ml) was treated with N1,N1-dimethylethane-1,2-diamine (0.177 g, 2.01 mmol), SODIUM TERT-BUTOXIDE (0.232 g, 2.42 mmol), XANTPHOS (0.116 g, 0.20 mmol)nbsp;and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.046 g, 0.05 mmol)nbsp;under nitrogen. The resulting mixture was stirred at 80 C in a sealed tube for 2 hours. The reaction mixture was diluted with water (200 mL), and extracted with ethyl acetate (200 mL).nbsp;The organic was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution 0-10% methanol in dcm. Pure fractions were evaporated to dryness to afford N1-(4-bromo-3-methoxyphenyl)-N2,N2-dimethylethane-1,2-diamine (0.251 g, 45.6 %) as a brown oil. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN(C)CCNC1=CC(=C(C=C1)Br)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 45.64 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/13/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "844" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0102 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.03 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)N" + } + amount { + moles { + value: 0.00732 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC(=NC(=C1)Cl)Cl" + } + amount { + moles { + value: 0.00732 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000219 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 7.32e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "SODIUM TERT-BUTOXIDE (0.984 g, 10.24 mmol) was added to 2,6-dichloro-N-methylisonicotinamide (1.5 g, 7.32 mmol), ANILINE (0.667 mL, 7.32 mmol), PALLADIUM(II) ACETATE (0.016 g, 0.07 mmol) and XANTPHOS (0.127 g, 0.22 mmol) in toluene (30 mL) under nitrogen. The resulting mixture was stirred at 80 C for 4 hours. The reaction mixture was evaporated to dryness and redissolved in EtOAc (100 mL), and washed sequentially with water (2 x 50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and preadsorbed onto silica. The crude product was purified by flash silica chromatography, elution gradient 30 to 80% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 2-chloro-N-methyl-6-(phenylamino)isonicotinamide (1.012 g, 52.9 %) as a cream solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CNC(=O)C1=CC(=NC(=C1)Cl)NC2=CC=CC=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 52.86 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/23/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "845" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000977 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)F)CN" + } + amount { + moles { + value: 0.000537 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" + } + amount { + moles { + value: 0.000489 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(3-fluorophenyl)methanamine (67.3 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford N4-(3-fluorobenzyl)-N2-phenylpyridine-2,4-diamine (84 mg, 58.6 %) as an off-white solid.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)NCC3=CC(=CC=C3)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 58.6 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/02/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "846" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000353 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CCN(CC1)C2CCNCC2" + } + amount { + moles { + value: 0.00353 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1Br)I" + } + amount { + moles { + value: 0.00353 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000353 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000177 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.162 g, 0.18 mmol) was added to 1,4\'-bipiperidine (0.595 g, 3.53 mmol), 1-bromo-4-iodobenzene (1.000 g, 3.53 mmol),nbsp;(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.205 g, 0.35 mmol) and sodium 2-methylpropan-2-olate (0.408 g, 4.24 mmol) in toluene (10 mL). The resulting mixture was degassed again and was stirred at 80 C for 18 hours under nitrogen. The reaction mixture was cooled to room temperature and filtered then the filtrate was diluted with EtOAc (50 mL), and washed sequentially with water (50 mL), water (50 mL), and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 1\'-(4-bromophenyl)-1,4\'-bipiperidine (0.736 g, 64.4 %) as a pale brown oil. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CCN(CC1)C2CCN(CC2)C3=CC=C(C=C3)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 64.41 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/13/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "847" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00649 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@@H]1CNCCN1C(=O)OC(C)(C)C" + } + amount { + moles { + value: 0.00433 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CCOC1=C(C=C(C=C1)Br)OC" + } + amount { + moles { + value: 0.00433 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000173 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000216 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium(II) acetate (0.049 g, 0.22 mmol)and (R)-(+)-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.108 g, 0.17 mmol) were added to 4-bromo-1-ethoxy-2-methoxybenzene (1 g, 4.33 mmol),(R)-1-N-Boc-2-methyl piperazine (0.867 g, 4.33 mmol)nbsp;and Sodium tert-butoxide (0.624 g, 6.49 mmol) in anhydrous Toluene (20 mL) under argon. The resulting solution was stirred at reflux for18 hours. The reaction was allowed to cool to room temperature and diluted with dcm (50 ml). This was washed with water (2 x 50 ml), dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The crude product was dissolved in hydrochloric acid solution in methanol (4N, 20 ml) and stirred at room temprature overnight. The solvent was removed under reduced pressure.The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness to afford (R)-1-(4-ethoxy-3-methoxyphenyl)-3-methylpiperazine (0.550 g, 50.8 %) as a yellow gum. nbsp;nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC1=C(C=C(C=C1)N2CCN[C@@H](C2)C)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 50.77 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/11/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "848" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0045 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.003 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C1=CC=CC=C1Br" + } + amount { + moles { + value: 0.003 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 0.0006 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.0003 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium (II) acetate (67.3 mg, 0.30 mmol) and 2-dicyclohexylphosphino-2\',6\'-di-i-propoxy-1,1\'-biphenyl (280 mg, 0.60 mmol) were dissolved in toluene (7 mL) and purged with nitrogen. The mixture was warmed to 50C for 15 mins.In a separate vessel, were mixed 2-bromo-N,N-dimethylaniline (600 mg, 3.00 mmol), tert-butyl piperazine-1-carboxylate (559 mg, 3.00 mmol) and sodium-t-butoxide (432 mg, 4.50 mmol) in toluene (8 mL). The mixture was degassed and purged with nitrogen. The catalyst solution was added and the resulting mixture heated at 100C overnight. The reaction mixture was filtered through celite, washing with MeOHEtOAc. The filtrate was concentrated and purified by flash silica chromatography, elution gradient 0 to 70% EtOAc in heptane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(2-(dimethylamino)phenyl)piperazine-1-carboxylate (293 mg, 32.0 %) as a colourless gum.Difficult column; three spots with same Rf, but clearly different retention timuct present, but purity low. Carry through and de-BOC. See if can purify at that stage." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC=CC=C2N(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 31.99 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/17/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "849" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00105 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.000701 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC=CC=C1Cl" + } + amount { + moles { + value: 0.000701 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 7.01e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 7.01e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "RuPhos (32.7 mg, 0.07 mmol) and palladium (II) acetate (15.75 mg, 0.07 mmol) were suspended in toluene (1 mL) at ambient temperature. The mixture was degassed and purged with nitrogen several times and warmed to 50C for 20 mins.In a separate vessel were mixed 1-chloro-2-methoxybenzene (100 mg, 0.70 mmol), tert-butyl piperazine-1-carboxylate (131 mg, 0.70 mmol), sodium tertbutoxide (101 mg, 1.05 mmol) and toluene (2 mL). The suspension was degassed and purged with nitrogen then warmed to 50C.The solution of catalyst was added to the reaction vessel and the resulting mixture was degassed and purged with nitrogen. The reaction was heated to 110C (ext T) under nitrogen for 6 hours then allowed to cool to ambient temperature overnight.The reaction mixture was filtered and concentrated and the crude material purified by flash silica chromatography, elution gradient 20 to 60% EtOAc in heptane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(2-methoxyphene-1-carboxylate (23.00 mg, 11.22 %) as a colourless dry film. Yield not good....if this route followed maybe try different catalyst - pepsi? " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC=CC=C2OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 11.22 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/20/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "851" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00238 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.025 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@H]1CNCCN1C" + } + amount { + moles { + value: 0.00106 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC(=NC=C1C2=CC=C(C=C2)C3=NC4=C(C=CC=C4C(=O)N3)CO)Cl" + } + amount { + moles { + value: 0.000529 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 0.000106 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4.CC(C)(C)OC.C1=CC=C([C-]=C1)CCN.Cl[Pd+]" + } + amount { + moles { + value: 0.000106 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of CHLORO(2-DICYCLOHEXYLPHOSPHINO-2\',6\'-DI-I-PROPOXY-1,1\'-BIPHENYL)[2-(2-AMINOETHYLPHENYL)]PALLADIUM(II), METHYL-T-BUTYLETHER ADDUCT (Ru Phos Pd cycle) (43.2 mgs, 0.1eq), sodium tert-butoxide (229 mg, 2.38 mmol),nbsp;2-(4-(6-chloro-4-methylpyridin-3-yl)phenyl)-8-(hydroxymethyl)quinazolin-4(3H)-one (250 mg, 0.53 mmol)nbsp;, (S)-1,2-dimethylpiperazine (198 mg, 1.06 mmol) in dioxane (25ml) was stirred at 105C for 1hr, LCMS only detected a small peak as product. 2 more equivalent of sodium tert-butoxide was added to the mixture and stirred for overnight under N2,nbsp;LCMS indicated major peak as starting material; another batch of Ru phos pd cycle was added to the mixture, and the mixture was stirred at 120C for 1.5hrs. LCMS indicated the completion of reaction. The solvent was removed by concentration, taken into 2ml of DMSO, filtered, the filtrate was purified with reverse phase chromatography column (eluted with 5% to 50% 0.1%TFA in ACN0.1%TFA in water) and repurified with basic co(eluted with 5% to 95% ACN10MM ammonium acetate and 10MM ACN in water), still not pure enough for mission.Repurified again by analytical group, to yield (S)-2-(4-(6-(3,4-dimethylpiperazin-1-yl)-4-methylpyridin-3-yl)phenyl)-8-(hydroxymethyl)quinazolin-4(3H)-one (64.0 mg, 26.5 %) as a light yellow solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@H]1CN(CCN1C)C2=NC=C(C(=C2)C)C3=CC=C(C=C3)C4=NC5=C(C=CC=C5C(=O)N4)CO" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 26.54 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/10/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "852" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00254 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@H]1CNCCN1C" + } + amount { + moles { + value: 0.00106 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC(=NC=C1C2=CC=C(C=C2)C3=NC4=C(C=CC=C4C(=O)N3)CO)Cl" + } + amount { + moles { + value: 0.000423 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 0.000212 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4.CC(C)(C)OC.C1=CC=C([C-]=C1)CCN.Cl[Pd+]" + } + amount { + moles { + value: 0.000212 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 115.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of CHLORO(2-DICYCLOHEXYLPHOSPHINO-2\',6\'-DI-I-PROPOXY-1,1\'-BIPHENYL)[2-(2-AMINOETHYLPHENYL)]PALLADIUM(II), METHYL-T-BUTYLETHER ADDUCT (Ru Phos Pd cycle) (69.2 mgs, 0.2eq), sodium tert-butoxide (244 mg, 2.54 mmol) ,2-(4-(6-chloro-4-methylpyridin-3-yl)phenyl)-8-(hydroxymethyl)quinazolin-4(3H)-one (200 mg, 0.42 mmol)nbsp;, (S)-1,2-dimethylpiperazine (198 mg, 1.06 mmol) in dioxane (20ml) was stirred at 115C for 1hr,nbsp;LCMS indicated the completion of reaction. The solid was filtered off through a pad of celite, washed with DCM. The solvent of the filtrate was removed by concentration, taken into 2ml of DMSO, purified with reverse phase chromatography column (eluted with 5% to 50% 0.1%TFA in ACN0.1%TFA in water), the fractions were combined and lyphlized, to yield 117mgs of product. LCMS indicated 9% of TFA coupled side product. The solid was taken into 10ml sat. NaHCO3 aq, sonicated, until the disapearance of the side product, filtered, washed with water, dried to yield (S)-2-(4-(6--dimethylpiperazin-1-yl)-4-methylpyridin-3-yl)phenyl)-8-(hydroxymethyl)quinazolin-4(3H)-one (67.0 mg, 34.7 %) as a yellow solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@H]1CN(CCN1C)C2=NC=C(C(=C2)C)C3=CC=C(C=C3)C4=NC5=C(C=CC=C5C(=O)N4)CO" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 34.73 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/14/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "853" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.3 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00176 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.2 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCN1" + } + amount { + moles { + value: 0.0176 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=NC=C1I)Br" + } + amount { + moles { + value: 0.0176 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00176 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000616 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 20.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Pd2(dba)3 (0.564 g, 0.62 mmol) was added to 2-bromo-5-iodopyridine (5.00 g, 17.61 mmol), morpholine (1.541 mL, 17.61 mmol), sodium tert-butoxide (4.23 g, 44.03 mmol) and Xantphos (1.019 g, 1.76 mmol) in toluene (200 mL) at 20C. The resulting solution was stirred at r.t. for 3 days (as the reaction was started on a Friday). Complete.The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried with MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100%nbsp;(EtOAc:MeOH - 10:1)nbsp;in heptane. Pure fractions were evaporated to dryness LCMS indicated some di-stituted product present. Triturated in heptane:EtOAc, filtered and dried to afford 4-(6-bromopyridin-3-yl)morpholine (2.400 g, 56.1 %) as a beige solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1COCCN1C2=CN=C(C=C2)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 56.05 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/08/2015" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "855" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000415 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.006 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1N)F" + } + amount { + moles { + value: 0.000831 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=NC(=C(N2CCN1C(=O)CNC(=O)OC(C)(C)C)Br)C3=CC=C(C=C3)F)C" + } + amount { + moles { + value: 0.000415 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 4.15e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.08e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a microwave vial, cesium carbonate (135 mg, 0.42 mmol), 4-fluoroaniline (92 mg, 0.83 mmol), tris(dibenzylideneacetone)dipalladium(0) (19.02 mg, 0.02 mmol), Xantphos (24.04 mg, 0.04 mmol) and dry 1,4-dioxane (6 mL) were stirred for 5 minutes at room temperature. tert-butyl (2-(3-bromo-2-(4-fluorophenyl)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethyl)carbamate (200 mg, 0.42 mmol) was added to the reaction mixture after which the reaction mixture was degassed for 15 mins and then stirred at 120 C under N2 for 20 h. The reaction was monitored by LCMS. The profile showed formation of title product.nbsp;The reaction mixture was filtered through a pad opf celite and the filtrate was concentrated to give a residue. The residue was purified by silica gel followed by reverse phase HPLC to givenbsp;tert-butyl (2-(2-(4-fluorophenyl)-3-((4-fluorophenyl)amino)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethyl)carbamate (177 mg, 83 %) as a white solipConclusion:The product was used for the next step." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1(C2=NC(=C(N2CCN1C(=O)CNC(=O)OC(C)(C)C)NC3=CC=C(C=C3)F)C4=CC=C(C=C4)F)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 83.27 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/07/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "857" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000541 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC=CC=C1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC1=CC=CC(=C1)N" + } + amount { + moles { + value: 0.000447 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)Br)C(F)(F)F" + } + amount { + moles { + value: 0.000358 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 6.91e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.56e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 50.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "PdOAc2 (8 mg, 0.04 mmol) andnbsp;(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (40 mg, 0.07 mmol) were added to a dried vial. The vial was caped with a septa-cap and inerted with nitrogen. Degassed anisole (2 mL)was added and the catalyst mixture was heated to 50C for 30 minutes, then cooled down to rt.A dry 2ml microwave vial was charged with sodium 2-methylpropan-2-olate (52 mg, 0.54 mmol). It was caped and inerted with nitrogen.nbsp;A degassed mixture of 1-bromo-3-(trifluoromethyl)benzene (50 L, 0.36 mmol) and 3-methoxyaniline (50 L, 0.45 mmol) innbsp;anisole (2 mL) wad addednbsp;at rt. The catalyst solution was added to the reaction mixture. The nitrogen inlet was removed and the vial was inserted into an alumina block at 100C. The reaction was stirred over night.After 19h, the reaction was cooled down and filtered through celite. The filtrate was concentrated. Large amounts of anisole was present. No product was detected by LCMS.The sampl" + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=CC=CC(=C1)NC2=CC=CC(=C2)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/14/2013" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "859" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00575 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.006 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2" + } + amount { + moles { + value: 0.00144 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)Br)C(F)(F)F" + } + amount { + moles { + value: 0.00216 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000345 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000144 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 50 ml round bottom equipped with stir bar was charged with binap (0.219 g, 0.34 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.132 g, 0.14 mmol)nbsp;dissolved in dioxane (6 mL).nbsp;This was degassed and purged with nitrogen and stirred at RT for 10 mins.nbsp;1-bromo-3-(trifluoromethyl)benzene (0.301 mL, 2.16 mmol) followed by tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.3 g, 1.44 mmol) andnbsp;SODIUM TERT-BUTOXIDE (0.570 g, 5.75 mmol) were added, and the reaction was stirred at 180 C for 5 min (see notes).nbsp;The solution was filtered trough celite, diluted with EtOAc and washed with saturated NaHCO3 solution. The aqueous phase was extracted with EtOAc (3X20mL), combined, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude material was loaded on a Snap KP-SIL 25g column and purified on a Biotage SP4 instrument, eluting with 10% to 35% ethyl acetate in heptane to provide tert-butyl 5-(3-(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]hee-2-carboxylate (0.489 g, 99 %) as an oil. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CC2CC1CN2C3=CC=CC(=C3)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 99.36 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/04/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "860" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00383 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2" + } + amount { + moles { + value: 0.000958 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)Br)C(F)(F)F" + } + amount { + moles { + value: 0.00144 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00023 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 9.58e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 50 ml round bottom equipped with stir bar was charged with binap (0.146 g, 0.23 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.088 g, 0.10 mmol)nbsp;dissolved in dioxane (5 mL).nbsp;This was degassed and purged with nitrogen and stirred at RT for 10 mins.nbsp;1-bromo-3-(trifluoromethyl)benzene (0.323 g, 1.44 mmol) followed by tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.2 g, 0.96 mmol) andnbsp;SODIUM TERT-BUTOXIDE (0.380 g, 3.83 mmol) were added, and the reaction was stirred at 80 C for 2 hrs. The solution was diluted with EtOAc and washed with saturated NaHCO3 solution. The aqueous phase was extracted with EtOAc (3X20mL), combined, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude material was loaded on a Snap KP-SIL 25g column and purified on a Biotage SP4 instrument, eluting with 10% to 35% ethyl acetate in heptane to provide tert-butyl 5-(3-(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.305 g, 93 %) as an op" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CC2CC1CN2C3=CC=CC(=C3)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 92.96 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/18/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "862" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00405 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.15 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC(=NC=C1)N" + } + amount { + moles { + value: 0.0338 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.0338 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00405 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.0027 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium(II) acetate (0.607 g, 2.70 mmol) was added to 2,4-dichloropyridine (5.00 g, 33.79 mmol), 4-methylpyrimidin-2-amine (3.69 g, 33.79 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (2.346 g, 4.05 mmol) and Cesium carbonate (22.02 g, 67.57 mmol) in dioxane (150 mL) at 20C under nitrogen. The resulting suspension was stirred at 100 C for 90 minutes. Complete reaction by LCMS, cooled to room temperature. The reaction mixture was then filtered, washed with DCM and filtrate concentrated iin vacuoi to give a yellow gum. This was then dissolved in DCM (200 mL), washed with water (200 mL) and brine (200 mL). The organic layer was passed through phase separating cartridge and concentrated under reduced pressure. The crude product was suspended in DCM, isolubles filtered off and dried to give EN01580-50-1, N-(4-chloropyridin-2-yl)-4-methylpyrimidin-2-amine (2.859 g, 38.3 %), as a yellow solid. The fltrate was then purified by flash silica chromatography, elution gradient 0 to 5% MeOH io separation acheived so all fractions containing product concentrated iin vacuoi. The residue was suspended in acetonitilewater, insolubles filtered off and dried to give EN01580-50-2, N-(4-chloropyridin-2-yl)-4-methylpyrimidin-2-amine (0.934 g, 12.5 %), as a yellow solid. The filtrate was then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford EN01580-50-3, N-(4-chloropyridin-2-yl)-4-methylpyrimidin-2-amine (0.511 g, 6.85 %), as a white solid. nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=NC(=NC=C1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 57.73 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/05/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "863" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[K+]" + } + amount { + moles { + value: 0.000275 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1CCOC1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@@H]1CN(CCN1)C(=O)OC(C)(C)C" + } + amount { + moles { + value: 0.000125 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC=C1O)Br" + } + amount { + moles { + value: 0.00025 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" + } + amount { + moles { + value: 1.25e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C.[Pd]" + } + amount { + moles { + value: 1.25e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of (R)-tert-butyl 3-methylpiperazine-1-carboxylate (0.025 g, 0.12 mmol), 4-bromophenol (0.043 g, 0.25 mmol), bis(tri-t-butylphosphine)palladium(0) (6.38 mg, 0.01 mmol) and [Reactants] in THF (2 mL) was flushed with nitrogen and sealed into a microwave tube.nbsp;The reaction was heated to 100 C for 20 minutes in the microwave reactor and cooled to RT.nbsp;No trace of desired product by LCMS.The reaction was not progressed further.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@@H]1CN(CCN1C2=CC=C(C=C2)O)C(=O)OC(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/26/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "864" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0028 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.017 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC1=NC(=NC=C1Br)N" + } + amount { + moles { + value: 0.00251 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C=C1C(F)(F)F)I)F" + } + amount { + moles { + value: 0.00338 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=COC(=C1)P(C2=CC=CO2)C3=CC=CO3" + } + amount { + moles { + value: 0.000543 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000245 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a microwave vial was added a mixture of 5-bromo-4-methoxypyrimidin-2-amine (0.513 g, 2.51 mmol), diacetoxypalladium (0.055 g, 0.245 mmol), tri(furan-2-yl)phosphine (0.126 g, 0.54 mmol), 1-fluoro-2-iodo-4-(trifluoromethyl)benzene (0.98 g, 3.38 mmol) and toluene (17 mL) under inert atmosphere.The reaction mixture was sealed and heated at 90 C under 15h.The LCMS indicated no reaction ???The sample discarded." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=NC(=NC=C1Br)NC2=C(C=CC(=C2)C(F)(F)F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/20/2014" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "866" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.3 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00223 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCNCC1" + } + amount { + moles { + value: 0.00112 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=CC(=C1)Cl)I" + } + amount { + moles { + value: 0.00112 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000559 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000112 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium II acetate (25.09 mg, 0.11 mmol) was added to 4-chloro-1-iodo-2-methoxybenzene (300 mg, 1.12 mmol), 1-methylpiperazine (0.124 ml, 1.12 mmol), sodium 2-methylpropan-2-olate (215 mg, 2.23 mmol) and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (323 mg, 0.56 mmol) in toluene (4 ml) at room temperture under nitrogen. The resulting mixture was stirred at 100oC overnight. The reaction mixture was filtered through celite and then concentrated under reduced pressure. The crude product was then taken up in DCM and washed with water. The crude product was purified by chromatography in DCM:MeOH 0--gt;10% to afford 1-(4-chloro-2-methoxyphenyl)-4-methylpiperazine (171 mg, 63.6 %) as yellow oil. This was carried through to the next reaction immediately as it is a controlled stance." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CCN(CC1)C2=C(C=C(C=C2)Cl)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 63.57 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/10/2016" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "869" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 9.54e-06 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)O" + } + amount { + volume { + value: 0.0017 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C2C(=C1)C=C(C=N2)N" + } + amount { + moles { + value: 0.000668 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CN(CC2=C1C(=NC=C2)Cl)S(=O)(=O)C3=CC=CO3" + } + amount { + moles { + value: 0.000191 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 9.54e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 4.58e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "The yellow residue containing 5-chloro-2-(furan-2-ylsulfonyl)-1,2,3,4-tetrahydro-2,6-naphthyridine (0.057 g, 0.19 mmol) and quinolin-3-amine (0.096 g, 0.67 mmol) from 02910-38 was dissolved in toluene (1 mL) and tert-butanol (0.170 mL).nbsp;The resulting yellow solution was degassed (vacuum) and then tris(dibenzylideneacetone)dipalladium(0) (4.19 mg, 4.58 mol), Xantphos (5.52 mg, 9.54 mol), and sodium tert-butoxide (0.026 g, 0.27 mmol) were added.nbsp;Another 2 mL of toluene and 0.340 mL of tert-butanol were also added.nbsp;The resulting mixture was jected to microwave conditions for 30 min (300W, 110C) and then cooled.nbsp;The biphasic red-brownbrown-black mixture was poured into saturated aqueous sodium chloride and extracted with ethyl acetate.nbsp;The combined organic layers were dried over sodium sulfate, filtered, and concentrated.nbsp;The resulting residue was purified by falsh column chromatography (SiO2, 0-100% ethyl acetate in hexanes) and then preparative Lhanol in water containing ammonium carbonate, pH 10).nbsp;The resulting white solid was repurified a third time via preparative HPLC (C18, acetonitrile in water containing ammonium carbonate, pH 10)nbsp;to afford 6-(furan-2-ylsulfonyl)-N-(quinolin-3-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine (7.60 mg, 9.80 %) of 95% purity as a white solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CN(CC2=C1C(=NC=C2)NC3=CC4=CC=CC=C4N=C3)S(=O)(=O)C5=CC=CO5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 9.8 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/07/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "870" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.007 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "COCCOC" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=NC(=C1)N" + } + amount { + moles { + value: 0.006 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CN=C1)Br" + } + amount { + moles { + value: 0.005 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" + } + amount { + moles { + value: 4.86e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.86e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Stock solution: 0.01 mmol Pd and ligand were dissolved in 2 mL DME.3-bromopyridine (0.482 mL, 5.00 mmol) was dissolved in DME (10 mL). To the solution was added the stock solution, and sodium tert-butoxide (0.673 g, 7.00 mmol). To the mixture was added a solution of pyridin-2-amine (0.565 g, 6.00 mmol) in DME (10 mL). The mixture was heated at 90 C overnight. The mixture was filtered. The filtrate was concentrated, and the compound was purified by preparative HPLC on a XBridge C18 column (10 m 250x50 ID mm) using a gradient of 0-50% acetonitrile in H2OACNNH3 9550.2 buffer over 15 minutes with a flow of 100 mLmin. The compounds were detected by UV at 254nm. To the fractions (ca. 60mL) were added 5 mL of HOAc. The product was freezing-dried to give the product N-(pyridin-3-yl)pyridin-2-amine (0.190 g, 22.20" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=NC(=C1)NC2=CN=CC=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 22.2 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/30/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "871" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000395 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C1=CC2=C(C=C1)C=CN2" + } + amount { + moles { + value: 0.00036 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.00036 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.8e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In microwave tube, added 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (84mg), N-(1H-indol-6-yl)-N-methylacetamide (67 mg), Pd2(dba)3 (16 mg), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (20mg) cesium carbonate(129 mg) in anhydrous DMA (0.5mL). under microwave 150C for 30 min.the mixture was filtered. washed with MeOH. combinde organic solvent, dried to dryness. The residue solid was washed with MeOH to give about 22mg offwhite solid (product." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)N(C)C1=CC2=C(C=C1)C=CN2C3=NC4=C(C=NN4C(=C3)NC5CC5)C#N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 15.88 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/18/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "876" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000414 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.000377 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CS(=O)(=O)CC1=C(C=CC(=C1)N)Cl" + } + amount { + moles { + value: 0.000377 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.77e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.88e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 40mL vialnbsp;(t=g) was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (88 mg, 0.38 mmol), [Reactants], and cesium carbonate (135 mg, 0.41 mmol) in DMA (0.5 mL) ([VOLUME]),Pd2(dba)3 (17.24 mg, 0.02 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (21.79 mg, 0.04 mmol) were added.to give a brown suspension. The vial was filled with N2,150C microwave for 30 min. LCMS showed completion.added DMF(3 mL), filtered through celite. concentrated. The residue was washed with EtOAc and water, MeoH to give about 55mg light brown solid" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CS(=O)(=O)CC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 35.03 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/30/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "877" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00762 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CCNC1" + } + amount { + moles { + value: 0.00305 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C=C1F)C=O)Br" + } + amount { + moles { + value: 0.00305 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000152 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000152 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 95.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Tonbsp;a mixture of pyrrolidine (328 mg, 3.05 mmol), 2-bromo-4-fluorobenzaldehyde (619 mg, 3.05nbsp;mmol) in toluene (10 ml) was added Cs2CO3 (2.48g, 7.62 mmol), BINAP (95 mg ) and palladium(II) acetate (35 mg) was added. The mixture was purged with Ar for 5 min, then heated at 95 oC for 4 hrs.nbsp;After cooled to RT, EtOAc (30 mL) was added.nbsp;The organic layer was washed with water (3 x 30 mL), brine (30 mL), dried over MgSO4, filetred and concentrated. The residue was purified via combiflush (0 - 20% EtOAcHexane; 40 g column) to give the desired product as a clear reddish liquid. LCMS and H-NMR look good. 290 mgConclusion: reaction progressed to give desired productnbsp;in 49% yield." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CCN(C1)C2=C(C=C(C=C2)F)C=O" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/14/2014" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "878" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0188 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCC(=O)N1" + } + amount { + moles { + value: 0.00989 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=NC(=C1)Br)Br" + } + amount { + moles { + value: 0.0148 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00198 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000989 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "biSeptember 10 2015ibmorpholin-3-one (1g, 9.89 mmol), 2,6-dibromopyridine (3.51 g, 14.84 mmol), PdOAc2 (0.222 g, 0.99 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.145 g, 1.98 mmol) and CS2CO3 (6.12 g, 18.79 mmol) in 1,4-dioxane (20 mL) were heated at 80 C for 12 hours.biSeptember 11 2015ibLCMS showed no precursor and 37% of the desired mass MH+ 257259 @ 0.86 min along with lots of unknowns on a 2-min basic run.The reaction was cooled to RT, and filtered off the solid (Cs2CO3).nbsp;The filter was concentrated, re-dissolved in EtOAc, washed with waster, dried through MgSO4, and evaporated to give an orange gum.biSeptember 14 2015ibThe orange gum was added to a Biotage column and was eluted with 10-100%EtOAc in Heptane.nbsp;Collected fractions.The column was stuck as 37% EtOAc in Heptane.nbsp;A lot of CH2Cl2 was pushed through the column manually, and then continued the elution with 0-100% Etin DCM. Collected fractions.The product fractions were identified, combined based on LCMS and TLC, and evaporated to give a white solid as the desired product (EN07946-27-001).nbsp;Based on LCMS, it was 98% pure; based on NMR in DMSO, it was gt; 95%pure; uhowever, based on NMR in CDCl3, there were ~30% impurity in the aromatic proton region.unbsp;The product was used for next step without further purification." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1COCC(=O)N1C2=NC(=CC=C2)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 68.82 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/10/2015" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "879" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000377 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)NC1=CC=CC(=C1)N" + } + amount { + moles { + value: 0.000342 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.000342 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.42e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.71e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "in microwave tube was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (80 mg, 0.34 mmol), N-(3-aminophenyl)acetamide (51.4 mg, 0.34 mmol), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (19.81 mg, 0.03 mmol) in DMA (0.5 mL).Pd2(dba)3 (15.68 mg, 0.02 mmol) and cesium carbonate (123 mg, 0.38 mmol) were added.degassed, filled with N2.capped. then microwave 150C for 30 min.added 2 mL of MeOH, filtered through celite. concentrated. The residue was purified by ISCO (Hex to Hex:EtOAc=1:4 to 1:1 to EtOAc), collected prod fractions. concentrated to brown semi-solid" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)NC1=CC=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 67.26 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/25/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "880" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000377 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CC(C1)N2CCN(CC2)C(=O)C3CC4(C3)CCNCC4" + } + amount { + moles { + value: 0.000343 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)Br" + } + amount { + moles { + value: 0.00036 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 6.86e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.43e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "cesium carbonate (123 mg, 0.38 mmol) was added to a solution of (4-cyclobutylpiperazin-1-yl)(7-azaspiro[3.5]nonan-2-yl)methanone (100 mg, 0.34 mmol), PdOAc2 (7.70 mg, 0.03 mmol), BINAP (42.7 mg, 0.07 mmol) and bromobenzene (56.6 mg, 0.36 mmol)nbsp;in toluene (5 mL). The reaction mixture was heated to 110C for 18hrs. The room temperature cooled down mixture was filtered over celite. The solvent was concentrated. The product was purified by preparative HPLC using a low pH shallow gradient method (Mobile phase: 20-40% B; A: H2O with 0.05% TFA , B: CH3CN,nbsp;25 min. run) on Luna 15 m, C8 (2), 21.2x250 mm Phenomenex reverse phase column to provide (4-cyclobutylpiperazin-1-yl)(7-phenyl-7-azaspiro[3.5]nonan-2-yl)methanone (59.0 mg, 46.8 %) as white solid.1H NMR (400 MHz, CHLOROFORM-idi) d ppm 1.60 - 1.75 (m, 4 H) 1.75 - 1.81 (m, 2 H) 1.81 - 1.95 (m, 2 H) 1.96 - 2.10 (m, 4 H) 2.10 - 2.20 (m, 2 H) 2.21 - 2.35 (m, 4 H) 2.71 (dq, iJi=8.01, 7.75 Hz, 1 H) 3.00 - 3.11 (m,) 3.11 - 3.26 (m, 3 H) 3.31 - 3.42 (m, 2 H) 3.56 - 3.70 (m, 2 H) 6.82 (t, iJi=7.23 Hz, 1 H) 6.93 (d, iJi=7.81 Hz, 2 H) 7.18 - 7.29 (m, 2 H)HRMS imzi calcd for C23H33N3O 368.26964 [M+H]+, found 368.26981.nbsp;MS imzi 368.3 [M+H]+ (ES+)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CC(C1)N2CCN(CC2)C(=O)C3CC4(C3)CCN(CC4)C5=CC=CC=C5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 46.78 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/09/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "881" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000856 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.001 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)NC1=C(C=CC(=C1)N)N2CC[C@@H](C2)N(C)C" + } + amount { + moles { + value: 0.000471 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.000428 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 4.28e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.14e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "in microwave tube was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (100mg, 0.43 mmol), [Reactants], and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (24.76 mg, 0.04 mmol) in DMA (1.0 mL).Pd2(dba)3 (19.60 mg, 0.02 mmol) and cesium carbonate (279 mg, 0.86 mmol) were added.degassed, filled with N2.capped. then microwave 150C for 30 min.filtered, then concentrated. The crude material was purified by ISC(Hex to Hex:EtOAc=1;1 to EtOAc to EtOAc:MeOH=10:1 to EtOAc:MeOH:Et3N=10:1:0.1)) to give no very pure product.collect the product fraction, concentrated to dryness. no pure enough, tried to form solid. it failedsent to ananlytic group for purification.came back. it was OK 1TFA salt. NMR LCMS are OK" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)NC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)N5CC[C@@H](C5)N(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 36.66 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "01/29/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "882" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000476 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N" + } + amount { + moles { + value: 0.000381 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC(=CC(=N1)Cl)CO" + } + amount { + moles { + value: 0.000317 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 2.54e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 3.17e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 2.0-5.0 mL microwave vial was charged with XANTPHOS (14.66 mg, 0.03 mmol), Pd2(dba)3 (29.1 mg, 0.03 mmol), CESIUM CARBONATE (155 mg, 0.48 mmol),(2-chloro-6-methylpyridin-4-yl)methanol (50 mg, 0.32 mmol), tert-butyl carbamate (44.6 mg, 0.38 mmol)nbsp;and dioxane (3 mL). The reaction mixture was degassed for 2 minutes with nitrogen, and then the reaction mixture was stirred at 80C under microwave irradiation for 30 min. Water (5 mL) was added and the mixture was washed using EtOAc (3 x 10 mL). The organic layers were combined, dried using MgSO4, filtered and concentrated. The crude material was loaded on a 12g silica gel column and purified on a Teledyne Isco instrument, eluting with 0% to 20% EtOAc in DCM. The product that seems to be the compound was collected. Unfrtunately NMR showed that this compound is dba. The compound was not isolated." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CC(=CC(=N1)NC(=O)OC(C)(C)C)CO" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/26/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "884" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000899 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=C(C=C(C=C1)N)NC(=O)C" + } + amount { + moles { + value: 0.0003 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.0003 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 140.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 5 mL microwave reactor vial was charged with 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (0.070 g, 0.30 mmol), N-(5-amino-2-isopropylphenyl)acetamide (0.058 g, 0.30 mmol), Pd2(dba)3 (0.014 g, 0.01 mmol), Pd2(dba)3 (0.014 g, 0.01 mmol) and cesium carbonate (0.293 g, 0.90 mmol), the vessel was sealed with a microwave cap, and degassed and refilled with argon for 3 times. DMA (0.5 mL)was added via syringe. The resulting suspension heated at 140C for 30mins in microwave.nbsp;LCMS analysis showed product mass and byproduct.The reaction mixture was concentrated. 10% MeOH in DCM was added to the resulting residue to generate a brown suspension. This brown suspension was filtered to remove inorganic impurity. The filtrate was concentrated to give a brown crude product. This material was loaded on isco column (12g, DCM to 10% MeCNin DCM to 25% MeCN in DCM to 50%MeCN to 100% MeCM) and purified. Only 3mg of product was isolated.The ISCO column was saved. Some solis presented on the top of the column. This solid was recovered, washed with water and dried under high vacuum at 60C to give N-(5-(3-cyano-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)-2-isopropylphenyl)acetamide (0.012 g, 10.29 %) as an offwhite solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)C1=C(C=C(C=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)NC(=O)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 10.29 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/04/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "885" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 7.45e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CSC(=N1)N" + } + amount { + moles { + value: 0.000745 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CN(C(=O)OC1)C2=NC(=CC=C2)Br" + } + amount { + moles { + value: 0.000745 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 7.45e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" + } + amount { + moles { + value: 3.72e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "biSeptember 21 2015ib4-methylthiazol-2-amine (85 mg, 0.74 mmol), 3-(6-bromopyridin-2-yl)-1,3-oxazinan-2-one (191 mg, 0.74 mmol), 3-(6-bromopyridin-2-yl)-1,3-oxazinan-2-one (191 mg, 0.74 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (43.1 mg, 0.07 mmol) and cesium carbonate (291 mg, 0.89 mmol) in toluene (5 mL) were microwaved at 120 C under N2 for one hour.LCMS showed no precursors and 51% of the desired mass MH+291 @ 0.86 min on a 2-min basic run.The reaction mixture was diluted with EtOAc, washed with water, filtered, and evaporated to give a brown solid as the crude product.nbsp;The crude product was added to a Biotage column, and was eluted with 15-100%EtOAc in Heptane.nbsp;Collected fractions.biSeptember 22 2015ibBased on TLC and LCMS, the product fractions were combined, and evpoarated to give an yellow-brown solid (94 mg).nbsp;Based on LCMS, it was only 89% pure.Based on LCMS, it was 96% pure; based on NMt was gt; 95% pure." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CSC(=N1)NC2=NC(=CC=C2)N3CCCOC3=O" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 43.95 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/17/2015" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "886" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00315 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CSC(=N1)N" + } + amount { + moles { + value: 0.00263 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CN(C(=O)OC1)C2=NC(=CC=C2)Br" + } + amount { + moles { + value: 0.00263 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000263 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" + } + amount { + moles { + value: 0.000131 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 115.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "biSeptember 28 2015ib4-methylthiazol-2-amine (300 mg, 2.63 mmol), 3-(6-bromopyridin-2-yl)-1,3-oxazinan-2-one (676 mg, 2.63 mmol), 3-(6-bromopyridin-2-yl)-1,3-oxazinan-2-one (676 mg, 2.63 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (152 mg, 0.26 mmol) and cesium carbonate (1027 mg, 3.15 mmol) in toluene (13 mL)DMF (2.00 mL) were microwaved at 115 C under N2 for one hour.(Note: Based on the observation in EN07946-41, iDMF was added to improve the heating due to the low thremal absorbance of toluene.)iOne hour later, LCMS showed 13% of the precursor MH+257259 @ 0.84 min and 36% of the desired mass MH+291 @ 0.86 min along with some unknowns on a 2-min basic run.The reaction seemed not complete.nbsp;The reaction was microwaved at 115 C for another 45 min.One hour and 45 min later, LCMS showed 7% of the precursor MH+257259 @ 0.84 min and 37% of the desired mass MH+291 @ 0.86 min along with some unknowns on a 2-min basic r;The reaction seemed stuck, and was cooled to RT.biSeptember 29 2015ibThe reaction mixture was diluted with EtOAc, washed with water, filtered, and evaporated to give a brown solid as the crude product.nbsp;The crude product was added to a Biotage column, and was eluted with 15-100%EtOAc in Heptane.nbsp;Collected fractions.biSeptember 30 2015ibBased on TLC and LCMS, the product fractions were combined, and evpoarated to give an yellow-brown solid, which was vacuumed overnight at 40 CbiOCtober 1 2015ibBased on LCMS, it was 100% pure; based on NMR, it was 90~95% pure, and contained 0.1eq of DMF." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CSC(=N1)NC2=NC(=CC=C2)N3CCCOC3=O" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 57.15 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/28/2015" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "889" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0275 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.157 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCCN1" + } + amount { + moles { + value: 0.0495 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC(=C(C=C1)NC2=C(N=NC3=C2C=CC(=C3)Br)C#N)F" + } + amount { + moles { + value: 0.011 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.00165 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.00088 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 1L flask was charged with 7-bromo-4-(2-fluoro-4-methylphenylamino)cinnoline-3-carbonitrile (3.93 g, 11.00 mmol), Piperazine (3.88 ml, 49.51 mmol), Tris(dibenzylideneacetone)dipalladium (0) (0.806 g, 0.88 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (0.787 g, 1.65 mmol) and Sodium tert-butoxide (3.37 ml, 27.51 mmol).nbsp;The atmosphere was evacuated and replaced with N2(g) and DMA (157 ml) was added to the mixture.nbsp;The reaction mixture was stirred at 100 C for 1h.nbsp;The reaction mixture was cooled to rt, adsorbed on silica gel and flash chromatography using DCM to DCMMeOHNH4OH (10:1:0.1) provided the desired adduct as a light brown solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CC(=C(C=C1)NC2=C(N=NC3=C2C=CC(=C3)N4CCNCC4)C#N)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 50.66 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/21/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "890" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00448 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.0256 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCCN1" + } + amount { + moles { + value: 0.00806 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC(=C(C=C1)NC2=C(N=NC3=C2C=CC(=C3)Br)C#N)F" + } + amount { + moles { + value: 0.00179 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.000269 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000143 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 100 mL flask was charged with 7-bromo-4-(2-fluoro-4-methylphenylamino)cinnoline-3-carbonitrile (0.64 g, 1.79 mmol), Piperazine (0.631 ml, 8.06 mmol), Tris(dibenzylideneacetone)dipalladium (0) (0.131 g, 0.14 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (0.128 g, 0.27 mmol) and Sodium tert-butoxide (0.548 ml, 4.48 mmol).nbsp;The mixture was suspended in DMA (25.6 ml) and the reaction mixture was stirred at 100 C for 30min.nbsp;The reaction mixture was cooled to rt, diluted with DCMMeOH (10:1) and filtered over a pad of celite.nbsp;The filterate was concentrated under reduced pressure, adsorbed onto silica gel and flash chromatography using DCM to DCMMeOHNH4OH (10:1:0.1) provided the desired compound as a light orange solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CC(=C(C=C1)NC2=C(N=NC3=C2C=CC(=C3)N4CCNCC4)C#N)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 84.7 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/16/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "891" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00405 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.15 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC(=NC(=N1)C)N" + } + amount { + moles { + value: 0.0338 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.0338 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00405 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.0027 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium(II) acetate (0.607 g, 2.70 mmol) was added to 2,4-dichloropyridine (5.00 g, 33.79 mmol), 2,6-dimethylpyrimidin-4-amine (4.16 g, 33.79 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (2.346 g, 4.05 mmol) and Cesium carbonate (22.02 g, 67.57 mmol) in dioxane (150 mL) at 20C under nitrogen. The resulting suspension was stirred at 100 C for 90 minutes. Complete reaction by LCMS, cooled to room temperature. The reaction mixture was then filtered, washed with DCM and filtrate concentrated iin vacuoi to give a yellow gum. This was then dissolved in DCM (200 mL), washed with water (200 mL) and brine (200 mL). The organic layer was passed through phase separating cartridge and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford N-(4-chloropyridin-2-yl)-2,6-dimethylpyrimidin-4-amine (4.86 g, 61.2 %) as a yellow solid. n" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CC(=NC(=N1)C)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 61.24 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/09/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "892" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00221 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCCC1=O" + } + amount { + moles { + value: 0.00111 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C=C1F)Cl)Br" + } + amount { + moles { + value: 0.00122 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 5.53e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 5.53e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a round bottom flask was added palladium(II) acetate (0.012 g, 0.06 mmol), dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.026 g, 0.06 mmol), and sodium tert-butoxide (0.213 g, 2.21 mmol).nbsp;Added 5 mL toluenet-butanol mix and purged with nitrogen.nbsp;Added piperidin-4-one (0.15 g, 1.11 mmol), in 3 mL toltbuoh (slurry), followed by 1-bromo-2-chloro-4-fluorobenzene (0.255 g, 1.22 mmol), in 2 mL toltbuoh.nbsp;Flushed with additional nitrogen and then heated to 120oC overnight.Let reaction mixture cool to room temperature and filtered through Celite.nbsp;Rinsed repeatedly with EtOAc and concentrated in vacuo.Purified via ISCO 12g SiO2 column using 0-20% hexanesethyl acetate.nbsp;Fractions 19 and 20 were combined and concentrated to afford a white solid.nbsp;NMR (I200805922.42) shows a mess.nbsp;Discarded.nbsp;Will try another way." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CN(CCC1=O)C2=C(C=C(C=C2)F)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/14/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "893" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000377 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CC(C1)N2CCN(CC2)C(=O)C3CC4(C3)CCNCC4" + } + amount { + moles { + value: 0.000343 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=NC(=C1)Br" + } + amount { + moles { + value: 0.00036 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 6.86e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.43e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "cesium carbonate (123 mg, 0.38 mmol) was added to a solution of (4-cyclobutylpiperazin-1-yl)(7-azaspiro[3.5]nonan-2-yl)methanone (100 mg, 0.34 mmol), PdOAc2 (7.70 mg, 0.03 mmol), BINAP (42.7 mg, 0.07 mmol) and 2-bromopyridine (56.9 mg, 0.36 mmol) in toluene (2 mL). The reaction mixture was heated to 110C for 18hrs. The room temperature cooled down mixture was filtered over celite. The solvent was concentrated. The product was purified by preparative HPLC using a low pH shallow gradient method (Mobile phase: 20-40% B; A: H2O with 0.05% TFA , B: CH3CN,nbsp;25 min. run) on Luna 15 m, C8 (2), 21.2x250 mm Phenomenex reverse phase column to provide (4-cyclobutylpiperazin-1-yl)(7-(pyridin-2-yl)-7-azaspiro[3.5]nonan-2-yl)methanone (54.1 mg, 42.8 %) as white solid.1H NMR (400 MHz, CHLOROFORM-idi) d ppm 1.62 - 1.75 (m, 4 H) 1.75 - 1.81 (m, 2 H) 1.81 - 1.94 (m, 2 H) 1.98 - 2.10 (m, 4 H) 2.12 - 2.21 (m, 2 H) 2.23 - 2.32 (m, 4 H) 2.71 (quin, iJi=7.91 Hz, 1 H) 3.05 - 3.14 ( H) 3.14 - 3.26 (m, 3 H) 3.33 - 3.40 (m, 2 H) 3.58 - 3.68 (m, 2 H) 7.09 - 7.15 (m, 1 H) 7.16 - 7.21 (m, 1 H) 8.06 (dd, iJi=4.49, 1.37 Hz, 1 H) 8.31 (d, iJi=2.73 Hz, 1 H)HRMS imzi calcd for C22H32N4O 369.26489 [M+H]+, found 369.26461 .MS imzi 369.2 [M+H]+ (ES+)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CC(C1)N2CCN(CC2)C(=O)C3CC4(C3)CCN(CC4)C5=CC=CC=N5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 42.78 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/16/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "895" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00111 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)NC1=C(C=CC(=C1)N)N(C)CCN(C)C" + } + amount { + moles { + value: 0.000856 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.000856 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 8.56e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 4.28e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 40mL vialnbsp;(t=g) was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (200 mg, 0.86 mmol), N-(5-amino-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acetamide (214 mg, 0.86 mmol), and cesium carbonate (363 mg, 1.11 mmol) in DMA (0.5 mL) ([VOLUME]),Pd2(dba)3 (39.2 mg, 0.04 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (49.5 mg, 0.09 mmol) were added.to give a brown suspension. The vial was filled with N2,150C microwave for 30 min. LCMS showed completion.concentrated. loaded on ISCO (Hex to Hex:EtOAc To EtOAc:MeOH=10:1 to EtOAc:MeOH:Et3N=10:1:0.1) to give yellow sticky oil. tried to use EtOAc(1 mL) as solvent to make the product to form crys. finally the solid was formed and washed with EtOA (1mL) and Et2O(2mL) to give 86mg white solidNMR LCMS are OK" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)NC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)N(C)CCN(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 22.45 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/04/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "896" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000445 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)NC1=C(C=CC(=C1)N)N(C)CCN(C)C" + } + amount { + moles { + value: 0.000342 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.000342 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.42e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.71e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 40mL vialnbsp;(t=g) was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (80 mg, 0.34 mmol), [Reactants], and cesium carbonate (145 mg, 0.45 mmol) in DMA (0.5 mL) ([VOLUME]),Pd2(dba)3 (15.68 mg, 0.02 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (19.81 mg, 0.03 mmol) were added.to give a brown suspension. The vial was filled with N2,150C microwave for 30 min. LCMS showed completion.concentrated. loaded on ISCO (Hex to Hex:EtOAc To EtOAc:MeOH=10:1 to EtOAc:MeOH:Et3N=10:1:0.1) to give yellow solid.This yellow solid was washed with EtOAc(1mL) and Et2O(2mL) to give 50 mg pure compound.NMR, 1H,HPLC are OK, see attachment" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)NC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)N(C)CCN(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 29.37 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/15/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "897" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00342 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)N)NC(=O)C" + } + amount { + moles { + value: 0.00171 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.00171 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000171 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 8.56e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "in microwave tube was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (400 mg, 1.71 mmol), N-(5-amino-2-methylphenyl)acetamide (281 mg, 1.71 mmol), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (99 mg, 0.17 mmol) in DMA (0.5 mL).Pd2(dba)3 (78 mg, 0.09 mmol) and cesium carbonate (1116 mg, 3.42 mmol) were added.degassed, filled with N2.capped. then microwave 150C for 30 min.The reaction was divided by 4, run 100mg scale four time.combined all of crude mixture, filtered and washed with MeOH.the organic solvent was removed. The black residue was tried to purifed by ISCO. impurity and prod came out together too quickly.purified by glass-clumn (150g silica, Hex to EtOAc:Hex =1:1 to EtOAc), colleceted product fraction. concentrated to give offwhite solid. LCMS showed about 10% impurity.The solid was washed with hot EtOAc(5 mL), filtered.The solild was washed with water (1mL) and EtOAc(1 mL) to give about 110mg white solid.LCMS and NMR are OK, see attachment.low yield was due to hot EtOAc wash, lost some prod." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)NC(=O)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 18.09 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/16/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "898" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000377 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)N)NC(=O)C" + } + amount { + moles { + value: 0.000342 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.000342 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.42e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.71e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "in microwave tube was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (80 mg, 0.34 mmol), N-(5-amino-2-methylphenyl)acetamide (56.2 mg, 0.34 mmol), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (19.81 mg, 0.03 mmol) in DMA (0.5 mL).Pd2(dba)3 (15.68 mg, 0.02 mmol) and cesium carbonate (123 mg, 0.38 mmol) were added.degassed, filled with N2.capped. then microwave 150C for 30 min.added 2 mL of MeOH, filtered through celite. concentrated. The residue was purified by ISCO (Hex to Hex:EtOAc=1:4 to 1:1 to EtOAc), collected prod fractions. concentrated to give offwhite solid. This solid was washed with 0.5 mL of EtOAc to give pure prod" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)NC(=O)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 18.59 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/25/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "900" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00428 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.0025 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)N)NC(=O)C" + } + amount { + moles { + value: 0.00214 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.00214 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000214 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000107 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "in microwave tube was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (500 mg, 2.14 mmol), N-(5-amino-2-methylphenyl)acetamide (351 mg, 2.14 mmol), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (124 mg, 0.21 mmol) in DMA (2.5 mL).Pd2(dba)3 (98 mg, 0.11 mmol) and cesium carbonate (1394 mg, 4.28 mmol) were added.degassed, filled with N2.capped. then microwave 150C for 30 min.The reaction was divided by 5, run 100mg scale five time.combined all of crude mixture, filtered and washed with MeOH.the organic solvent was removed. The black residue was tried to purifed by ISCO.(40g cloumn, Hex to EtOAc:Hex =1:1 to EtOAc), colleceted product fraction. concentrated to give offwhite solid. LCMS showed about 10% impurity.The solid was washed with hot EtOAc(5 mL), filtered.The solild was washed withnbsp;to give about 175mg white solid.LCMS and NMR are OK, see attachment.low yield was due to hot EtOAc wash, lost some prod." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)NC(=O)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 22.63 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/10/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "901" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000257 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.0015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)N)NC(=O)C" + } + amount { + moles { + value: 0.000171 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.000171 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" + } + amount { + moles { + value: 1.71e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 8.56e-06 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 25 mL round-bottomed flask (t=g) was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (40 mg, 0.17 mmol), Pd2(dba)3 (7.84 mg, 8.56 mol), and [Reactants] in DMA (1.5 mL) ([VOLUME]) to give a black suspension.[Reactants] and N-(5-amino-2-methylphenyl)acetamide (28.1 mg, 0.17 mmol) were added.stirred at 110C for 2 days. TLC showed major is SM, small amount of product was formeddid not workupLCMS showed 349 mass ??" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)NC(=O)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/19/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "902" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[K+]" + } + amount { + moles { + value: 0.00298 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C[C@@H]1CNCCN1C(=O)OC(C)(C)C" + } + amount { + moles { + value: 0.00213 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CS(=O)(=O)C1=CC=C(C=C1)Br" + } + amount { + moles { + value: 0.00213 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" + } + amount { + moles { + value: 0.00011 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C.[Pd]" + } + amount { + moles { + value: 0.000106 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "13-May-09 10:32:28 +01001-bromo-4-(methylsulfonyl)benzene (515 mg, 2.13 mmol), (R)-tert-butyl 2-methylpiperazine-1-carboxylate (426 mg, 2.13 mmol) and BIS(TRI-T-BUTYLPHOSPHINE)PALLADIUM(0) (54.3 mg, 0.11 mmol) and potassium 2-methylpropan-2-olate (352 mg, 2.98 mmol) were suspended in dioxane (10 mL) and heated to 90C for 3 hours. LC-MS shows starting material. Reaction abandoned. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C[C@@H]1CN(CCN1C(=O)OC(C)(C)C)C2=CC=C(C=C2)S(=O)(=O)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/13/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "906" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00323 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.035 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00323 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C=C1Br)Cl)C#N" + } + amount { + moles { + value: 0.00323 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000314 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000162 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 250 mL round-bottomed dried flask , diacetoxypalladium (0.036 g, 0.16 mmol) was treated with 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.195 g, 0.31 mmol) under nitrogen in toluene (35 mL). The reaction was heated to 80 C and was stirred for 10 min. To the flask was then added tert-butyl piperazine-1-carboxylate (0.602 g, 3.23 mmol), cesium carbonate (0.527 g, 1.62 mmol),nbsp;potassium carbonate (0.447 g, 3.23 mmol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (0.085 g, 0.32 mmol). The reaction was then treated with 4-bromo-2-chlorobenzonitrile (0.7 g, 3.23 mmol) and was allowed to stir at 80C for 5 h. The mixture was then filtered over celite and celite was washed with heptanes. The mixture was condensed under reduced pressure and the crude material was purified on preparative HPLC MS using the short high pH shallow gradient method (Mobile phase: 50-70% B; A: H2O with 10 mM NH4CO3 and 0.375% NH4OH vv, B: CH3CN, 10 min run) on XBridg18 OBD, 30x50 mm, 5 mm, Waters reverse phase column, to afford tert-butyl 4-(3-chloro-4-cyanophenyl)piperazine-1-carboxylate (0.490 g, 47.1 %) as a white solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC(=C(C=C2)C#N)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 47.09 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/14/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "907" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 5.54e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.00542 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C/C=C(/C1=CC=C(C=C1)C)\\N(C2=CC=C(C=C2)OC)C(=O)NC" + } + amount { + moles { + value: 0.000554 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=NC(=CC=C1)Br" + } + amount { + moles { + value: 0.00111 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 5.54e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.77e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(Z)-1-(4-methoxyphenyl)-3-methyl-1-(1-p-tolylprop-1-enyl)urea (0.17200 g, 0.55 mmol),2-bromo-6-methylpyridine (0.126 ml, 1.11 mmol),SODIUM TERT-BUTOXIDE (0.160 g, 1.66 mmol),XANTPHOS (0.032 g, 0.06 mmol) and Pd2(dba)3 (0.025 g, 0.03 mmol) were dissolved intoluene (5.42 ml) and sparged under nitrogen for 15minutes . The resulting mixture was then heated to 110 C for 29032010 48 hours or unitil conversion was complete by TLC. NH4Cl (10 mL) was added 31-Mar-10 09:49:52 +0100 and the mixture was extracted twice (EtOAc 20 mL). The organic phases were combined, washed with brine (20 mL), dried (MgSO4) and the solvent removed under reduced pressure. The crude product was then purified by flash column chromatography to give (Z)-1-(4-methoxyphenyl)-3-methyl-3-(6-methylpyridin-2-yl)-1-(1-p-tolylprop-1-enyl)urea (0.189 g, 85 %)633-444 = 189 mg" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C/C=C(/C1=CC=C(C=C1)C)\\N(C2=CC=C(C=C2)OC)C(=O)N(C)C3=CC=CC(=N3)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 84.95 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/25/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "909" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00144 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)NC1=CC(=C(C=C1C2CC2)F)N" + } + amount { + moles { + value: 0.00048 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1C(CO1)NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.000528 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C(C)(C)C)C(C)(C)C)C(C)C" + } + amount { + moles { + value: 9.6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 4.8e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 140.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "dioxane (4 mL) was adde to the mixture of N-(5-amino-2-cyclopropyl-4-fluorophenyl)acetamide (100 mg, 0.48 mmol), 5-chloro-7-(oxetan-3-ylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (132 mg, 0.53 mmol),cesium carbonate (469 mg, 1.44 mmol), Pd2(dba)3 (44.0 mg, 0.05 mmol),nbsp;di-tert-butyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (40.8 mg, 0.10 mmol) in 5 ml microwave vial. N2 flow was bubbled through for 3 mins. Then the reaction solution was sealed with cap, degassed and refilled with argon 3 times. The resulting solution was heated at 140C for 40 mins in microwave. LCMS showed desired product as major peak. After the crude solution was concentrated, the crude residue was purified by chromatography (100% EtOAc to 3% MeOH in EtOAc). N-(5-(3-cyano-7-(oxetan-3-ylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)-2-cyclopropyl-4-fluorophenyl)acetamide (48.4 mg, 23.91 %) was obtained. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)NC1=CC(=C(C=C1C2CC2)F)NC3=NC4=C(C=NN4C(=C3)NC5COC5)C#N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 23.91 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/22/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "910" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000601 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)NC1=CC(=C(C=C1C2CC2)F)N" + } + amount { + moles { + value: 0.00026 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1C(CO1)NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.0002 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C(C)(C)C)C(C)(C)C)C(C)C" + } + amount { + moles { + value: 4.01e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 130.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "The mixture of N-(5-amino-2-cyclopropyl-4-fluorophenyl)acetamide (54.2 mg, 0.26 mmol), 5-chloro-7-(oxetan-3-ylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (50.0 mg, 0.20 mmol), cesium carbonate (196 mg, 0.60 mmol), Pd2(dba)3 (18.34 mg, 0.02 mmol) and di-tert-butyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (17.01 mg, 0.04 mmol) sealed with microwave vial was degassed and refilled with argon 3 times. Then the degassed dioxane (4 mL) was added. The resulting solution was heated at 130C for 30 mins in microwave.nbsp;After removed all the solvents, the crude residue was purified by chromatography (100% EtOAc to 3% MeOH in EtOAc). N-(5-(3-cyano-7-(oxetan-3-ylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)-2-cyclopropyl-4-fluorophenyl)acetamide (10.00 mg, 11.85 %) was obtained. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)NC1=CC(=C(C=C1C2CC2)F)NC3=NC4=C(C=NN4C(=C3)NC5COC5)C#N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 11.85 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/19/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "911" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0016 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.001 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)NC1=CC(=C(C=C1C2CC2)F)N" + } + amount { + moles { + value: 0.000801 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1C(CO1)NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.000801 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C(C)(C)C)C(C)(C)C)C(C)C" + } + amount { + moles { + value: 8.01e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 4.01e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 145.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a microwave tube, was Cs2CO3 (0.522 g, 1.60 mmol), N-(5-amino-2-cyclopropyl-4-fluorophenyl)acetamide (0.167 g, 0.80 mmol), Pd2dba3 (0.037 g, 0.04 mmol),5-chloro-7-(oxetan-3-ylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (0.200 g, 0.80 mmol),di-tert-butyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.034 g, 0.08 mmol). anhydrous DMA (1.0 mL) was added. The resulting mixture was bubbled through N2. Then the tube was capped. under microwave 145C for 25min.LCMS showed product and byproduct mass, did not showed SMThe mixture was filtered through celite. The resulting black solution was concentrated to dryness by rotavapor. The crude product was purified by ISCO (40g, Hex to EtOAc:HEx=1;2 to 1;1 to EtOAcO) to give product (offwhite solid). HPLC showed some impurity. This offwhite solid was washed with warm EtOAc (1mL) to giveN-(5-(3-cyano-7-(oxetan-3-ylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)-2-cyclopropyl-4-fluorophenyl)acetamide (0.012 g, 3.55 %)nbsp;LCMS and NMR were OK, see attachment. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)NC1=CC(=C(C=C1C2CC2)F)NC3=NC4=C(C=NN4C(=C3)NC5COC5)C#N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 3.55 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/30/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "912" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.174 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.193 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CSC(=N1)N" + } + amount { + moles { + value: 0.0579 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=NC(=C1)Br)C(=O)O" + } + amount { + moles { + value: 0.0579 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 0.00579 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.00145 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "iThe aim of this reaction is to synthesize material to check some ideas for route development and see if \'normal\' Buchwald conditions is applicable here. IPC.s were taken and the reaction was monitored either by LCMS or HNMR (a crude sample dissolved in DMSO).i1911-201514:00A dried 250 mL rb-flask under nitrogen atmosphere was charged with 4-methylthiazol-2-amine (C0033995, BT250061) (6.61 g, 57.92 mmol), 6-bromopicolinic acid (C0013377, BT249846) (11.7 g, 57.92 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0)nbsp;(C0007769, BT234652) (1.326 g, 1.45 mmol), dicyclohexyl(2\',4\',6\'-triisopropyl-[1,1\'-biphenyl]-2-yl)phosphane (C0018897, BT153355) (2.76 g, 5.79 mmol), SODIUM T-BUTOXIDEnbsp;(C0006296, BT235115) (16.70 g, 173.76 mmol), Toluene (193 ml) was added and the suspension was heated and stirred at reflux (110 C).Start heating 14:30 -IPC was taken after 18 h bIPC1 LCMSb, seems difficult to identify if any of the desired product was formed.Man aqueous wash between citric acidwater and ethyl acetate, tedious separation, analysed the two phases IPC2 LCMS but still impossible to identify any product neither in the organic phase IPC3 LCMS.bNo evidence of product formation.bThe phases were discarded and the reaction judged as failed" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CSC(=N1)NC2=CC=CC(=N2)C(=O)O" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/19/2015" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "915" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00568 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.03 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00474 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=NC(=C1)Cl)C(F)(F)F" + } + amount { + moles { + value: 0.00474 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000474 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000237 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 105.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 20 mL microwave vial was charged with 2-chloro-6-(trifluoromethyl)pyridine (860 mg, 4.74 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (295 mg, 0.47 mmol), Sodium tert-butoxide (546 mg, 5.68 mmol), tert-butyl piperazine-1-carboxylate (882 mg, 4.74 mmol) and a mixture of toluene (25 mL) and DMF (5 mL). The reaction mixture was degassed for 10 minutes with nitrogen, and then Tris(dibenzylideneacetone)dipalladium(0) (217 mg, 0.24 mmol) was added. The reaction mixture was stirred at 105C in an oil bath 12h.nbsp;The solution was diluted with EtOAc and washed with saturated NaHCO3 solution, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was loaded on a 80g silica gel column and purified on a Teledyne Isco instrument, eluting with 0% to 100% ethyl acetate in heptane to provide tert-butyl 4-(6-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (811 mg, 51.7 %) as a solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC=CC(=N2)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 51.68 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/08/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "916" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000568 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.000474 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=NC(=C1)Cl)C(F)(F)F" + } + amount { + moles { + value: 0.000474 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 4.74e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.37e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 105.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 2.0-5.0 mL microwave vial was charged with 2-chloro-6-(trifluoromethyl)pyridine (86 mg, 0.47 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (29.5 mg, 0.05 mmol), Sodium tert-butoxide (54.6 mg, 0.57 mmol), tert-butyl piperazine-1-carboxylate (88 mg, 0.47 mmol) and a mixture of toluene (2.5 mL) and DMF (.5 mL). The reaction mixture was degassed for 10 minutes with nitrogen, and then Tris(dibenzylideneacetone)dipalladium(0) (21.69 mg, 0.02 mmol) was added. The reaction mixture was stirred at 105C in an oil bath 12h.nbsp;The solution was diluted with EtOAc and washed with saturated NaHCO3 solution, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was loaded on a 24g silica gel column and purified on a Teledyne Isco instrument, eluting with 0% to 100% ethyl acetate in heptane to provide tert-butyl 4-(6-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (72.8 mg, 46.4 %) as a solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC=CC(=N2)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 46.38 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/07/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "917" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00135 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CC2CNCC2C1" + } + amount { + moles { + value: 0.000966 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=CC(=C1)Br)Cl" + } + amount { + moles { + value: 0.00106 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 4.83e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 4.83e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (205 mg, 0.97 mmol), 5-Bromo-2-chloroanisole (235 mg, 1.06 mmol), Sodium tert-butoxide (130 mg, 1.35 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (30.1 mg, 0.05 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (44.2 mg, 0.05 mmol) in toluene (10 mL) under a nitrogen atmosphere was stirred at 90 C for 12h.nbsp;The solution was washed with saturated NaHCO3 solution, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.nbsp;The crude material was loaded on a 24g silica gel column and purified on a Teledyne Isco instrument, eluting with 20% to 40% ethyl acetate in heptane to provide tert-butyl 5-(4-chloro-3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (220 mg, 64.6 %) as a solid.nbsp;Used directly for the next step.MS mz 353.3 [M+H]+ (ESI)nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CC2CN(CC2C1)C3=CC(=C(C=C3)Cl)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 64.57 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/05/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "918" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.3 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000372 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.00065 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCNCC1" + } + amount { + moles { + value: 0.000186 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=CC(=C1)Cl)I" + } + amount { + moles { + value: 0.000186 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 1.86e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.86e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "1-methylpiperazine (0.021 mL, 0.19 mmol) was added to 4-chloro-1-iodo-2-methoxybenzene (50 mg, 0.19 mmol) and sodium 2-methylpropan-2-olate (35.8 mg, 0.37 mmol) in toluene (0.650 mL) and the solution degassed. rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (11.60 mg, 0.02 mmol) and Palladium II acetate (4.18 mg, 0.02 mmol) were added to the resulting mixture and the vial stirred at 80 C for 17 hours. LCMS revelead product peak, but not great. Product not isolated. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CCN(CC1)C2=C(C=C(C=C2)Cl)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/05/2016" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "919" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0021 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CSC(=N1)N" + } + amount { + moles { + value: 0.00175 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCC(=O)N1C2=NC(=CC=C2)Br" + } + amount { + moles { + value: 0.00175 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00014 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" + } + amount { + moles { + value: 7.01e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 115.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "biSeptember 24 2015ib4-methylthiazol-2-amine (200 mg, 1.75 mmol), 4-(6-bromopyridin-2-yl)morpholin-3-one (450 mg, 1.75 mmol), 4-(6-bromopyridin-2-yl)morpholin-3-one (450 mg, 1.75 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (81 mg, 0.14 mmol) and cesium carbonate (685 mg, 2.10 mmol) in toluene (15 mL) and DMF (1)were microwaved at 115 C under N2 for one hour.i(Note: Initially, DMF was not added as co-solvent, the microwave instrument was repeatly failed to reach the temperature, and shut down ar 100 C.nbsp;It was due to the low thremal absorbance of toluene.nbsp;Therefore, DMF was added to improve this situation.)iLCMS showed no precursors and 87% of the desired mass MH+291 @ 0.87 min on a 2-min basic run.nbsp;The reaction was cooled to RT.biSeptember 25 2015ibThe reaction mixture was diluted with EtOAc, washed with water, filtered, and evaporated to give a brown solid as the crude product.nbsp;The oduct was added to a silica gel column, and was eluted with 20-100%EtOAc in Heptane.nbsp;Collected fractions.nbsp;Based on TLC and LCMS, most product fractions contained a non-MS-ionization unknown, were combined, and evpoarated to give an orange-yellow solid. The orange-yellow solid was reloaded to a silica gel column and was eluted with 20-100%EtOAc in Heptanenbsp;.nbsp;Collected fractions .biSeptember 28 2015ibBased on TLC and LCMS, the product fractions were combined, and evpoarated to give a pale-yellow solid.nbsp;Based on LCMS, it was 93% pure; based on NMR, it was 94~95% pure." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CSC(=N1)NC2=NC(=CC=C2)N3CCOCC3=O" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 80.02 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/23/2015" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "920" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000683 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CSC(=N1)N" + } + amount { + moles { + value: 0.000569 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1COCC(=O)N1C2=NC(=CC=C2)Br" + } + amount { + moles { + value: 0.000569 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 4.55e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" + } + amount { + moles { + value: 2.28e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 120.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "biSeptember 16 2015ib4-methylthiazol-2-amine (65 mg, 0.57 mmol), 4-(6-bromopyridin-2-yl)morpholin-3-one (146 mg, 0.57 mmol), 4-(6-bromopyridin-2-yl)morpholin-3-one (146 mg, 0.57 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (26.4 mg, 0.05 mmol) and cesium carbonate (223 mg, 0.68 mmol) in toluene (5 mL) were microwaved at 120 C under N2 for one hour.LCMS showed no precursors and 68% of the desired mass MH+291 @ 0.87 min on a 2-min basic run.The reaction mixture was diluted with EtOAc, washed with water, filtered, and evaporated to give a brown solid as the crude product.nbsp;biSeptembernbsp;17 2015ibThe crude product was added to a Biotage column, and was eluted with 0-10% ammoniated MeOH in DCM.nbsp;Collected fractions.Based on TLC and LCMS, the product fractions were combined, and evpoarated to give an orange-brown solid (150 mg).nbsp;Based on LCMS, it was only 89% pure.The orange-brown solid was loade a Grace column, and eluted with 20-100%EtOAc in Heptane.nbsp;Collected fractions. (Note: the solubility of the orange-brown solid was not good, and about 12 mL CH2Cl2 was used to dissolved everything)Based on TLC and LCMS, the product fractions were combined, and evpoarated to give an off-white solid (110 mg).nbsp;Based on LCMS, it was 100% pure; based on M;R, it was gt; 95% pure." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CSC(=N1)NC2=NC(=CC=C2)N3CCOCC3=O" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 66.55 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/15/2015" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "921" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0134 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.02 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N" + } + amount { + moles { + value: 0.0336 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=NN=C1Cl)Cl" + } + amount { + moles { + value: 0.00671 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00201 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "biApril 15 2016ib3,5-dichloropyridazine (1 g, 6.71 mmol),nbsp;tert-butyl carbamate (3.93 g, 33.56 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (0.583 g, 1.01 mmol), PdOAc2 (0.452 g, 2.01 mmol) and CS2CO3 (4.37 g, 13.43 mmol) in 1,4-dioxane (20 mL) was degassed through recharged with nitrogen, and was heated at 80 C overnight.biApril 18 2016ibLCMS showed 23% of the precursor @ 0.55 min (no mass ionization) left on a 2-min basic run.nbsp;GCMS showed no precursor and 94% of an unknown @ 6.90 min (whihcnbsp;might be the desired product but not ionizable) on a 10-min run.The reaction was cooled to RT.nbsp;The crude mixture was concentrated to givr a dark-brown gum. The dark-brown gum was dissolved in EtOAc, washed with water, and evaporated to give a brown solid.nbsp;The brown solid was passed through a 10 g SiO2 flash column eluting with EtOAc, collected all of the eluent, and then evaporated to give a brown solid as the crude.;The crude would be used in EN08121-59 without purification, assuming 100% yield." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)NC1=NN=CC(=C1)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/18/2016" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "922" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.0043 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.004 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C(CN)N" + } + amount { + moles { + value: 0.0215 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C(=C1)Cl)Br" + } + amount { + moles { + value: 0.0043 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=C(C=C1)P(C2=CC=C(C=C2)C)C3=CC=C(C=C3)C" + } + amount { + moles { + value: 0.000861 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00043 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 140.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Ref: R2239To a mixture of 1-bromo-2-chlorobenzene (0.824 g, 4.30 mmol), tri-p-tolylphosphine (0.262 g, 0.86 mmol), sodium 2-methylpropan-2-olate (0.414 g, 4.30 mmol), diacetoxypalladium (0.097 g, 0.43 mmol) in toluene (4 mL) was added ethane-1,2-diamine (1.293 g, 21.52 mmol). The mixture was heated with microwave at 140 C for 1 h. No product was formed." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CC=C(C(=C1)NCCN)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/09/2014" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "924" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[K+]" + } + amount { + moles { + value: 0.00295 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCCN1" + } + amount { + moles { + value: 0.00211 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC2=C(C=C1Br)OC(O2)(F)F" + } + amount { + moles { + value: 0.00211 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" + } + amount { + moles { + value: 0.00011 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C.[Pd]" + } + amount { + moles { + value: 0.000105 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "13-May-09 10:32:07 +01005-bromo-2,2-difluorobenzo[d][1,3]dioxole (0.500 g, 2.11 mmol), piperazine (0.182 g, 2.11 mmol) and BIS(TRI-T-BUTYLPHOSPHINE)PALLADIUM(0) (0.054 g, 0.11 mmol) and potassium 2-methylpropan-2-olate (0.349 g, 2.95 mmol) were suspended in dioxane (10vol) (10 mL) and heated to 90C for 1 hour. LC-MS shows no starting material 52% product and 41% dimer. The reaction mixture was combined with EN02263-54 filtered and the crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)piperazine (0.259 g, 50.7 %) as a yellow oil. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CN(CCN1)C2=CC3=C(C=C2)OC(O3)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 50.68 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/01/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "925" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000121 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0118 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C/C=C(/C1=CC=C(C=C1)Cl)\\N(C2=CC=C(C=C2)OC)C(=O)NC" + } + amount { + moles { + value: 0.00121 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=NC(=CC=C1)Br" + } + amount { + moles { + value: 0.00242 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000121 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 6.05e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(Z)-1-(1-(4-chlorophenyl)prop-1-enyl)-1-(4-methoxyphenyl)-3-methylurea (0.400 g, 1.21 mmol),2-bromo-6-methoxypyridine (0.292 ml, 2.42 mmol),SODIUM TERT-BUTOXIDE (0.349 g, 3.63 mmol),XANTPHOS (0.070 g, 0.12 mmol) and Pd2(dba)3 (0.055 g, 0.06 mmol) were dissolved intoluene (11.80 ml) and sparged under nitrogen for 1 hour. The resulting mixture was then heated to 110 C for 48 hours or unitil conversion was complete by TLC. NH4Cl (10 mL) was added and the mixture was extracted twice (EtOAc 20 mL). The organic phases were combined, washed with brine (20 mL), dried (MgSO4) and the solvent removed under reduced pressure. The crude product was then purified by flash column chromatography to give (Z)-1-(1-(4-chlorophenyl)prop-1-enyl)-1-(4-methoxyphenyl)-3-(6-methoxypyridin-2-yl)-3-methylurea (0.381 g, 72.0 %)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C/C=C(/C1=CC=C(C=C1)Cl)\\N(C2=CC=C(C=C2)OC)C(=O)N(C)C3=NC(=CC=C3)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 71.95 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/22/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "928" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00191 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C1=CC(=CC2=C1OC(=CC2=O)N3CCOCC3)C(=O)N(C)C)N" + } + amount { + moles { + value: 0.000869 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=C(C=C1F)Br)C#N" + } + amount { + moles { + value: 0.00191 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000217 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 6.51e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a mixture of 8-(1-aminoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (300 mg, 0.87 mmol), cesium carbonate (1104 mg, 3.39 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (126 mg, 0.22 mmol) and 3-bromo-5-fluorobenzonitrile (382 mg, 1.91 mmol) in degassed 1,4-dioxane (2ml), was addednbsp;TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (59.7 mg, 0.07 mmol). The suspension was heated in a sealed container up to 85-95Cnbsp;for 16hours. The reaction mixture was filtered through a short pad of dicalite, concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 0 to 5% methanol in dichloromethane. The solvent was evaporated to dryness to afford the product which still containing some impurities (see UPLC 03441-77-003). The product mixture was then re-purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml minute) and decrealy polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-(3-cyano-5-fluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (330 mg, 82 %)nbsp;as a clear white solid.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C1=CC(=CC2=C1OC(=CC2=O)N3CCOCC3)C(=O)N(C)C)NC4=CC(=CC(=C4)C#N)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 81.8 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "12/09/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "930" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00676 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(N=C1)N" + } + amount { + moles { + value: 0.00338 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.00338 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000405 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00027 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium(II) acetate (0.061 g, 0.27 mmol) was added to 2,4-dichloropyridine (0.500 g, 3.38 mmol), 2-Aminopyrimidine (0.321 g, 3.38 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (0.235 g, 0.41 mmol) and Cesium carbonate (2.202 g, 6.76 mmol) in dioxane (15 mL) at 20C under nitrogen. The resulting suspension was stirred at 100 C for 90 minutes. Complete reaction by LCMS, cooled to room temperature. The reaction mixture was then filtered, washed with DCM and filtrate concentrated iin vacuoi to give a yellow gum. This was then dissolved in DCM (200 mL), washed with water (200 mL) and brine (200 mL). The organic layer was passed through phase separating cartridge and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford N-(4-chloropyridin-2-yl)pyrimidin-2-amine (0.361 g, 51.7 %) as an off-white solid. n" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CN=C(N=C1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 51.71 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/30/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "931" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0676 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.015 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(N=C1)N" + } + amount { + moles { + value: 0.0338 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1Cl)Cl" + } + amount { + moles { + value: 0.0338 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.00405 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.0027 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Palladium(II) acetate (0.607 g, 2.70 mmol) was added to 2,4-dichloropyridine (5.00 g, 33.79 mmol), 2-Aminopyrimidine (3.21 g, 33.79 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (2.346 g, 4.05 mmol) and Cesium carbonate (22.02 g, 67.57 mmol) in dioxane (15 mL) at 20C under nitrogen. The resulting suspension was stirred at 100 C for 90 minutes. Complete reaction by LCMS, cooled to room temperature. The reaction mixture was then filtered, washed with DCM and filtrate concentrated iin vacuoi to give a yellow gum. This was then dissolved in DCM (200 mL), washed with water (200 mL) and brine (200 mL). The organic layer was passed through phase separating cartridge and concentrated under reduced pressure. The crude material was suspended in DCM, solid filtered off and dried to give EN01580-46-2 N-(4-chloropyridin-2-yl)pyrimidin-2-amine (2.975 g, 42.6 %). The filtrate was purified by silica gel chromatography, elution gradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated ts to afford EN01580-46-1, N-(4-chloropyridin-2-yl)pyrimidin-2-amine (0.889 g, 12.73 %) as a white solid. nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1=CN=C(N=C1)NC2=NC=CC(=C2)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 55.35 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/03/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "932" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000965 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.0018 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)N)NC(=O)C" + } + amount { + moles { + value: 0.000585 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(N=C1)NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.000292 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 2.92e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.46e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a microwave vial containing N-(5-amino-2-methylphenyl)acetamide (0.096 g, 0.58 mmol), 5-chloro-7-(1-methyl-1H-imidazol-4-ylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (0.08 g, 0.29 mmol), sodium tert-butoxide (0.093 g, 0.96 mmol) and 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (0.014 g, 0.03 mmol) was added DMA (1.8 ml). Vial was flushed with argon and to it was added Pd2(dba)3 (0.013 g, 0.01 mmol) and the reaction was heated in a MW reactor at 100 C for 50 min . Reaction was filtered through celite and the filterate diluted with EtOAC (5 ml) and the organic solution was washed with minimum amt ofnbsp;brine( 1X 5 ml) and organic layer dried over Na2SO4 filtered and concentrated to give crude liquid. this was purified by flash column using 5-8% MeOH: DCM (1% NH4OH) as gradient to give N-(5-(3-cyano-7-(1-methyl-1H-imidazol-4-ylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)-2-methylphenyl)acetamide (0.015 g, 12.78 %) as desired product. nmr amp; MASS AGREE WITH THE STRUCTURE." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)NC2=NC3=C(C=NN3C(=C2)NC4=CN(C=N4)C)C#N)NC(=O)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 12.78 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/20/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "933" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00121 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.0022 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)N)NC(=O)C" + } + amount { + moles { + value: 0.000731 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C=C(N=C1)NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.000365 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 3.65e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.83e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a microwave vial containingN-(5-amino-2-methylphenyl)acetamide (0.120 g, 0.73 mmol),nbsp;5-chloro-7-(1-methyl-1H-imidazol-4-ylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (0.1 g, 0.37 mmol) ,sodium 2-methylpropan-2-olate (0.116 g, 1.21 mmol) and 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (0.017 g, 0.04 mmol)was added DMA (2.2 ml). Vial was flushed with argon and to it was added Pd2(dba)3 (0.017 g, 0.02 mmol) and the reaction was heated in a MW reactor at 100 C for 60 min.Reaction was filtered, and filterate concentrated under reduced pressure to give dark red gum. This was suspended in 10% MeOH : DCM (10 ml) filtered and filterate concentrated to give crude solid. This was purified by flash column using 5-8% MeoH :DCM (1% NH4OH) to give 75 mg of pale yellow solid (EN02331-12-1). LCMS short purity indicated 90% pure. This sample was further purifiednbsp;by trituratingnbsp;the solid in 20% EtOAC: ether (10ml). The solid was filtered, dried to give pale yellow solid (EN 023312) as desired pdt. Mass spec and NMR are in agreement with the structure. (Note : The Etoac:Ether solution(filterate in the above step)nbsp;obtained after trituration was concentrated to give solid (23 mg) this was stored for future use." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)NC2=NC3=C(C=NN3C(=C2)NC4=CN(C=N4)C)C#N)NC(=O)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 29.32 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/03/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "934" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00103 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)NC1=C(C=CC(=C1)N)N(C)CCO" + } + amount { + moles { + value: 0.000514 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.000514 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 5.14e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.57e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 40mL vialnbsp;(t=g) was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (120mg, 0.51 mmol), N-(5-amino-2-((2-hydroxyethyl)(methyl)amino)phenyl)acetamide (115 mg, 0.51 mmol), and cesium carbonate (335 mg, 1.03 mmol) in DMA (3.0 mL) (),Pd2(dba)3 (23.51 mg, 0.03 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (29.7 mg, 0.05 mmol) were added.to give a brown suspension. The vial was filled with N2,150C microwave for 30 min. LCMS showed SM and product. under microwave 150C for another 2h. 15% SM remained.nbsp;MeOH (2 mL) was added to the reaction mixture.nbsp;filtered. The mother liquid solvent was removed by ratovapor to yield stick oil. The crude product was loaded on ISCO (Hex to Hex:EtOAc To EtOAc to EtOAc:MeOH=10:1) to give sticky oil.The product was not pure. added 1 mL of EtOAc, the solid was promoted to form by scratching the flask wall. The resulting suspension was heated to reflux. When it was warm, the mixture was filtered to give offwhite solid. This solid was washed with EtOAc ( 2 mL) and dried at 80C under reduced press oven to givenbsp;N-(5-(3-cyano-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)-2-((2-hydroxyethyl)(methyl)amino)phenyl)acetamide (110 mg, 50.9 %)NMR and LCMS showed desired product, see attachment" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)NC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)N(C)CCO" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 50.94 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/09/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "935" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000377 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CC(C1)N2CCN(CC2)C(=O)C3CC4(C3)CCNCC4" + } + amount { + moles { + value: 0.000343 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CN=C1)Br" + } + amount { + moles { + value: 0.00036 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 6.86e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 3.43e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "cesium carbonate (123 mg, 0.38 mmol) was added to a solution of (4-cyclobutylpiperazin-1-yl)(7-azaspiro[3.5]nonan-2-yl)methanone (100 mg, 0.34 mmol), PdOAc2 (7.70 mg, 0.03 mmol), BINAP (42.7 mg, 0.07 mmol) and 3-bromopyridine (56.9 mg, 0.36 mmol) in toluene (2 mL). The reaction mixture was heated to 110C for 18hrs. The room temperature cooled down mixture was filtered over celite. The solvent was concentrated. The product was purified by preparative HPLC using a low pH shallow gradient method (Mobile phase: 20-40% B; A: H2O with 0.05% TFA , B: CH3CN,nbsp;25 min. run) on Luna 15 m, C8 (2), 21.2x250 mm Phenomenex reverse phase column to provide (4-cyclobutylpiperazin-1-yl)(7-(pyridin-3-yl)-7-azaspiro[3.5]nonan-2-yl)methanone (10.00 mg, 7.91 %) as white solid.1H NMR (400 MHz, CHLOROFORM-idi) d ppm 1.58 (s, 3 H) 1.63 (dd, iJi=6.25, 4.69 Hz, 2 H) 1.66 - 1.79 (m, 3 H) 1.80 - 1.94 (m, 2 H) 1.97 - 2.10 (m, 3 H) 2.12 - 2.21 (m, 2 H) 2.27 (q, iJi=5.60 Hz, 3 H) 2.71in, iJi=7.91 Hz, 1 H) 3.21 (quin, iJi=8.79 Hz, 1 H) 3.32 - 3.39 (m, 2 H) 3.41 (dd, iJi=6.64, 4.69 Hz, 2 H) 3.54 (dd, iJi=6.25, 4.69 Hz, 2 H) 3.63 (t, iJi=4.88 Hz, 2 H) 6.53 - 6.60 (m, 1 H) 6.65 (d, iJi=8.59 Hz, 1 H) 7.40 - 7.48 (m, 1 H) 8.16 (td, iJi=2.34, 1.17 Hz, 1 H)HRMS imzi calcd for C22H32N4O 369.26489 [M+H]+, found 369.26533.MS imzi 369.2 [M+H]+ (ES+)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CC(C1)N2CCN(CC2)C(=O)C3CC4(C3)CCN(CC4)C5=CN=CC=C5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 7.91 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/16/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "936" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000645 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)[C@@H]1CNCCN1C(=O)OC(C)(C)C" + } + amount { + moles { + value: 0.000553 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)Br)OC" + } + amount { + moles { + value: 0.000461 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C1=CC=CC=C1C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 2.76e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.3e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "21-Apr-09 08:58:54 +0100 4-bromo-1,2-dimethoxybenzene (0.068 mL, 0.46 mmol), (R)-tert-butyl 2-isopropylpiperazine-1-carboxylate (126 mg, 0.55 mmol) and 2-Dicyclohexylphosphino-2\'-(N,N-dimethylamino)biphenyl (11.21 mg, 0.03 mmol) and Sodium tert-butoxide (63.9 mg, 0.64 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (21.09 mg, 0.02 mmol) were suspended in toluene (5 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 20 minutes in the microwave reactor and cooled to RT.nbsp;LC-MS shows 36% product and 57% SM reaction will be combined with EN02263-47" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)[C@@H]1CN(CCN1C(=O)OC(C)(C)C)C2=CC(=C(C=C2)OC)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/22/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "938" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00129 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)[C@@H]1CNCCN1C(=O)OC(C)(C)C" + } + amount { + moles { + value: 0.00111 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)Br)OC" + } + amount { + moles { + value: 0.000921 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C1=CC=CC=C1C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" + } + amount { + moles { + value: 2.76e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.3e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "21-Apr-09 08:58:54 +0100 4-bromo-1,2-dimethoxybenzene (0.135 mL, 0.92 mmol), (R)-tert-butyl 2-isopropylpiperazine-1-carboxylate (252 mg, 1.11 mmol) and 2-Dicyclohexylphosphino-2\'-(N,N-dimethylamino)biphenyl (10.88 mg, 0.03 mmol) and Sodium tert-butoxide (128 mg, 1.29 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (21.09 mg, 0.02 mmol) were suspended in toluene (5 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT. LC-MS show sproduct at 60% and SM 33% reaction mixture to be combined with EN02263-45 and worked up." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)[C@@H]1CN(CCN1C(=O)OC(C)(C)C)C2=CC(=C(C=C2)OC)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/21/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "939" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[K+]" + } + amount { + moles { + value: 0.000645 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1CCOC1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)[C@@H]1CNCCN1C(=O)OC(C)(C)C" + } + amount { + moles { + value: 0.000553 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC1=C(C=C(C=C1)Br)OC" + } + amount { + moles { + value: 0.000461 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" + } + amount { + moles { + value: 5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C.[Pd]" + } + amount { + moles { + value: 4.61e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "22-Apr-09 09:56:23 +01004-bromo-1,2-dimethoxybenzene (0.068 mL, 0.46 mmol), (R)-tert-butyl 2-isopropylpiperazine-1-carboxylate (126 mg, 0.55 mmol) and BIS(TRI-T-BUTYLPHOSPHINE)PALLADIUM(0) (23.54 mg, 0.05 mmol) and potassium 2-methylpropan-2-olate (76 mg, 0.64 mmol) were suspended in THF (5 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 10 minutes in the microwave reactor and cooled to RT. LC-MS shows no starting material. The reaction mixture was filtered and the crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl 4-(3,4-dimethoxyphenyl)-2-isopropylpiperazine-1-carboxylate (152 mg, 91 %) as a yellow gum. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)[C@@H]1CN(CCN1C(=O)OC(C)(C)C)C2=CC(=C(C=C2)OC)OC" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 90.52 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/22/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "941" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "[O-]P(=O)([O-])[O-].[K+].[K+].[K+]" + } + amount { + moles { + value: 0.00515 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N" + } + amount { + moles { + value: 0.00447 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=CC(=N1)Cl)F" + } + amount { + moles { + value: 0.00343 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000172 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 8.59e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of 6-chloro-3-fluoro-2-methylpyridine (500 mg, 3.43 mmol), tert-Butyl carbamate (523 mg, 4.47 mmol), Potassium phosphate (1094 mg, 5.15 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (99 mg, 0.17 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (79 mg, 0.09 mmol) were combined in a sealed vial which was purged with nitrogen.nbsp;Degassed toluene (5 mL) and water (5.00 mL) were added and the mixture was stirred under a nitrogen atmosphere at 90 C for 6h. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3 solution, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with mixtures of 5-50%EtOAc in heptane.nbsp;Many spots isolated, but none of them seemed to be the desired product.nbsp;Not continued. nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=CC(=N1)NC(=O)OC(C)(C)C)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/29/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "942" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000192 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.012 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CN1CCNCC1" + } + amount { + moles { + value: 0.01 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=CC(=CC(=C1)Br)[N+](=O)[O-]" + } + amount { + moles { + value: 0.00769 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000192 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000192 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To the stirred suspension ofmethyl 3-bromo-5-nitrobenzoate (2 g, 7.69 mmol) , cesium carbonate (12.53 g, 38.46 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.111 g, 0.19 mmol) in Dioxane (12 mL) (degassed with N2) was added pd (dba)3 (0.176 g, 0.19 mmol) and cesium carbonate (12.53 g, 38.46 mmol) ANDnbsp;rxn was heated at 110 C for 1 hr in microwaved. LCMS showed the m+1= 280. The crude raection mixture was filtered over celite. The filtrate was concentarted. The crude solid was diluted by 20 mL ethyl acetate, washed with 3x10 mL water, brine, collected the organic layers, concentrated. The crude solid was added to a silica gel column and was eluted with 0-10% methanol in DCM. Collected desired fractions.Obtained=1.4 gm.1H NMR (300 MHz, DICHLOROMETHANE-idi2) d ppm 2.32 (s, 3 H) 2.43 - 2.64 (m, 4 H) 3.13 - 3.40 (m, 4 H) 3.93 (s, 3 H) 7.85 (d, iJi=1.70 Hz, 2H) 8.18 (t, iJi=1.60 Hz, 1 H)Registered as AZ1345." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CN1CCN(CC1)C2=CC(=CC(=C2)C(=O)OC)[N+](=O)[O-]" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 65.18 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/05/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "943" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00289 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCCN1" + } + amount { + moles { + value: 0.0188 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)Br)[N+](=O)[O-]" + } + amount { + moles { + value: 0.00231 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000231 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000289 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "palladium(II) acetate (0.065 g, 0.29 mmol), BINAP (0.144 g, 0.23 mmol) and CS2CO3 (0.943 g, 2.89 mmol) were added to a mixture of 4-bromo-1-methyl-2-nitrobenzene (0.5 g, 2.31 mmol) and piperazine (1.623 g, 18.84 mmol) . The suspension were heated to 110 C for 24 hours, LCMS showed product mass [M+1]: 222.1 at retension time RT=1.21 min (polar short purity method). Workup reaction by additional of water (10mL), extracted with EtOAc (3x20 mL), washed with brine, dried with Na2SO4, evaporated off solvent to give a residue, which was purified by isco chromatographer, eluting with 0-10% MeOH in DCM to give 1-(4-methyl-3-nitrophenyl)piperazine (0.201 g, 39.3 %) as a yellow solid. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)N2CCNCC2)[N+](=O)[O-]" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 39.25 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/22/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "944" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0174 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.01 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCCN1" + } + amount { + moles { + value: 0.113 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)Br)[N+](=O)[O-]" + } + amount { + moles { + value: 0.0139 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00139 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.00174 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "palladium(II) acetate (0.390 g, 1.74 mmol), BINAP (0.865 g, 1.39 mmol) and CS2CO3 (5.66 g, 17.36 mmol) were added to a mixture of 4-bromo-1-methyl-2-nitrobenzene (3 g, 13.89 mmol) and piperazine (9.74 g, 113.04 mmol) innbsp;microwave. The suspension were heated to 110 C for 24 hours, LCMS showed product mass [M+1]: 222.0 at retension time RT=1.38 min (polar short purity method). Workup reaction by additional of water (10mL), extracted with EtOAc (3x20 mL), washed with brine, dried with Na2SO4, evaporated off solvent to give a residue, which was purified by isco chromatographer, eluting with 0-10% MeOH in DCM to give 1-(4-methyl-3-nitrophenyl)piperazine (1.670 g, 54.4 %) as a yellow solid. LCMS confirmed the target compound." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)N2CCNCC2)[N+](=O)[O-]" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 54.35 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/29/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "945" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000646 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC(=C(C=C1NC(=O)C)N)F" + } + amount { + moles { + value: 0.000323 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CC(C1)NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.000323 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.23e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.61e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "nbsp;5-chloro-7-(cyclobutylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (80 mg, 0.32 mmol), N-(5-amino-4-fluoro-2-methylphenyl)acetamide (58.8 mg, 0.32 mmol), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (18.69 mg, 0.03 mmol) in DMA (5 mL) were added to a microwave tube. Pd2(dba)3 (14.79 mg, 0.02 mmol) and cesium carbonate (210 mg, 0.65 mmol) were added.The solution was degassed, filled with N2, capped, then microwaved at 150C for 30 min.The organic solvent was removed. TLC showed two closely associated peaks, so product was purified via Gilson. Appropriate fractions were collected, concentrated by rotovap, and dried in the oven overnight. LCMS, HPLC, and NMR revealed desired product. See attachments. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CC(=C(C=C1NC(=O)C)NC2=NC3=C(C=NN3C(=C2)NC4CCC4)C#N)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 5.51 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/13/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "946" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00657 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.025 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00548 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(N=CC(=N1)Cl)C(F)(F)F" + } + amount { + moles { + value: 0.00548 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000548 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000274 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 105.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 20 mL microwave vial was charged with 2-chloro-5-(trifluoromethyl)pyrazine (1 g, 5.48 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.341 g, 0.55 mmol), Sodium tert-butoxide (0.632 g, 6.57 mmol), tert-butyl piperazine-1-carboxylate (1.020 g, 5.48 mmol) and a mixture of toluene (25 mL) and DMF (5 mL). The reaction mixture was degassed for 10 minutes with nitrogen, and then Tris(dibenzylideneacetone)dipalladium(0) (0.251 g, 0.27 mmol) was added. The reaction mixture was stirred at 105C in an oil bath 12h.nbsp;The solution was diluted with EtOAc and washed with saturated NaHCO3 solution, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was loaded on a 80g silica gel column and purified on a Teledyne Isco instrument, eluting with 0% to 25% ethyl acetate in heptane to provide tert-butyl 4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1-carboxylate (0.390 g, 21.41 %) as a solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=NC=C(N=C2)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 21.41 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/27/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "947" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000644 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.000537 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C2C(=C1)C=CC(=N2)Cl" + } + amount { + moles { + value: 0.000644 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 5.37e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.68e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 2.0-5.0 mL microwave vial was charged with tert-Butyl 1-piperazinecarboxylate (100 mg, 0.54 mmol), 2-Chloroquinoline (0.086 mL, 0.64 mmol), Sodium tert-butoxide (61.9 mg, 0.64 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (33.4 mg, 0.05 mmol) and toluene (3 mL). The reaction mixture was degassed for 10 minutes with nitrogen, and then Tris(dibenzylideneacetone)dipalladium(0) (24.58 mg, 0.03 mmol) was added. The reaction mixture was stirred at 100C in an oil bath for 12h.nbsp;The solution was diluted with EtOAc and washed with saturated NaHCO3,nbsp;brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.nbsp;The crude material was loaded on a 40g silica gel column and purified on a Teledyne Isco instrument, eluting with 10% to 40% ethyl acetate in heptane.nbsp;Product not pure.nbsp;Product was repurifed using a 40g Gold column with same eluent to provide tert-butyl 4-(quinolin-2-yl)piperazine-1-carboxylate (78 mg, 46.4 %) as a solid.MS mz 314.3 [M+H]+I)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=NC3=CC=CC=C3C=C2" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 46.36 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/01/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "948" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000781 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C=O" + } + amount { + volume { + value: 0.001 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CN=C(C=C1NC(=O)C)N" + } + amount { + moles { + value: 0.00026 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.000364 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C(C)(C)C)C(C)(C)C)C(C)C" + } + amount { + moles { + value: 5.21e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Ref:i Angew. Chem. Int. Ed.i b2006b, i45i, 6523-65271. To a microwave tube was added N-(2-amino-5-methylpyridin-4-yl)acetamide (43 mg, 0.26 mmol), 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (85 mg, 0.36 mmol), Cs2CO3 (254 mg, 0.78 mmol), Pd2dba3 (23.84 mg, 0.03 mmol), and di-tert-butyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (22.11 mg, 0.05 mmol). The mixture was dissolved in DMF (1 mL) and sealed. The tube was de-gassed and inflated with N2.2. The reaction was heated at 90C in oil-bath for 4 hr. LCMS showed partial formation of product. Heated overnight at 90C.3. The reaction mixture was filtered through celite pad and the filtrate was loaded onto column and run chromotography to purify (10% MeOH in DCM), semi-pure product was obtained and the sample was mitted to analytical group for further purification. 4. 10 mg pure product was obtained. 1H NMR (400 MHz, DMSO-idi6) d ppm 0.73 (d, iJi=2.78 Hz.85 (d, iJi=5.05 Hz, 2 H) 2.15 (d, iJi=12.88 Hz, 7 H) 2.62 (br. s., 1 H) 7.36 (s, 1 H)7.98 (s, 1 H) 8.09 (s, 1 H) 8.35 (s, 1 H) 8.38 (s, 1 H) 9.38 (s, 1 H) 10.11 (s, 1 H)" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CN=C(C=C1NC(=O)C)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 10.6 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/12/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "949" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0556 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.1 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCCC1O" + } + amount { + moles { + value: 0.0554 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC(=C1)Br)C(F)(F)F" + } + amount { + moles { + value: 0.0444 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000889 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000889 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of 1-bromo-3-(trifluoromethyl)benzene (6.13 mL, 44.44 mmol), piperidin-4-ol (5.608 g, 55.44 mmol), diacetoxypalladium (0.200 g, 0.89 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.553 g, 0.89 mmol) and cesium carbonate (18.10 g, 55.55 mmol) in dioxane (100 mL) was evacuated and backfilled with N2 three times and then it was heated at 100 C for 6h. The mixture was filtered through filter agent(supercell), washed with EtOAc. The combined filtrate was concentrated. The residue was purified by silica gel column(0-35% EtOAchexane) to give 1-(3-(trifluoromethyl)phenyl)piperidin-4-ol (4.70 g, 43.1 %) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) d 7.38 (t, iJi = 8.03 Hz, 1H), 7.20 (dd, iJi = 2.38, 8.41 Hz, 1H), 7.13 (s, 1H), 7.00 (d, iJi = 7.78 Hz, 1H), 4.64 - 4.72 (m, 1H), 3.53 - 3.72 (m, 3H), 2.93 (ddd, iJi = 3.01, 9.98, 12.86 Hz, 2H), 1.71 - 1.88 (m, 2H), 1.45 (dtd, iJi = 3.89, 9.44, 12.86 Hz, 2H). LCMS 246." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CN(CCC1O)C2=CC=CC(=C2)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 43.09 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/26/2011" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "951" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 4.22e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.003 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1COCCC1N" + } + amount { + moles { + value: 0.000422 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=NC(=C1)Br)Br" + } + amount { + moles { + value: 0.000422 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 4.22e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 4.22e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: nan + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "to 2,6-dibromopyridine (100 mg, 0.42 mmol), 4-Aminotetrahydropyran (42.7 mg, 0.42 mmol) in dioxane (3 mL) while bubbling N2 was added Xantphos (24.43 mg, 0.04 mmol), CS2CO3 (316 mg, 0.97 mmol) and palladium(II) acetate (9.48 mg, 0.04 mmol). This was heated in a microwave at 130 oC for 30 mins. A small peak corresponding to product was obseved. Discontinued" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1COCCC1NC2=NC(=CC=C2)Br" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/27/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "953" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0016 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.002 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)N)NC(=O)C" + } + amount { + moles { + value: 0.000801 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1C(CO1)NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.000801 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C(C)(C)C)C(C)(C)C)C(C)C" + } + amount { + moles { + value: 8.01e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 4.01e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 145.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a microwave tube, was Cs2CO3 (0.522 g, 1.60 mmol), N-(5-amino-2-methylphenyl)acetamide (0.132 g, 0.80 mmol), Pd2dba3 (0.037 g, 0.04 mmol),5-chloro-7-(oxetan-3-ylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (0.200 g, 0.80 mmol),di-tert-butyl(2\',4\',6\'-triisopropyl-[1,1\'-biphenyl]-2-yl)phosphine (0.034 g, 0.08 mmol). anhydrous DMA (2.0 mL) was added. The resulting mixture was bubbled through N2. Then the tube was capped. under microwave 145C for 30min.This reaction was repeated at 150mg again.The two batches were combined to workupThe mixture was concentrated to dryness. Water (20 mL) was added. it was extracted with 10% MeOH in EtOAc, The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness. It was purified by chromatography )Hex to 50% etAOc in Hex to EtOAc to 5% MeOH in EtOAc) to collect the pure product to give the product (86mg, 16.5% from total 350mg SM 5-chloro-7-(oxetan-3-ylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile) which was washed with EtOAc and dried under a high vacuum at 60C for 16h as an offwhite solid" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)NC2=NC3=C(C=NN3C(=C2)NC4COC4)C#N)NC(=O)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 16.54 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/10/2012" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "954" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00289 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.017 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC1=NC(=NC=C1Br)N" + } + amount { + moles { + value: 0.00255 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C=C1C(F)(F)F)I)F" + } + amount { + moles { + value: 0.00307 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000262 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000263 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a microwave vial was added a mixture of 5-bromo-4-methoxypyrimidin-2-amine (0.520 g, 2.55 mmol), diacetoxypalladium (0.059 g, 0.26 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (151.8 mg, 0.26 mmol), 1-fluoro-2-iodo-4-(trifluoromethyl)benzene (0.89 g, 3.07 mmol) and toluene (17 mL) under inert atmosphare.The reaction mixture was sealed and heated at 90 C under 16h.The LCMS indicated a complete conversion of the SM.The reaction mixture was partitioned between ethyl acetate and NH4Cl-solution.The organic layer was washed with NH4Cl-solution, brine dried over sodium sulphate, filtered and concentrated in vacuum to give a yellow gum.The oil dissolved in dichloromethane charged on silica 100g and purified by flash chromatography eluting with Ethyl acetate (0-80)% in heptane giving the product 5-bromo-N-(2-fluoro-5-(trifluoromethyl)phenyl)-4-methoxypyrimidin-2-amine (792 mg, 85 %) as a white solid.Collected at 260 nm1H NMR (500 MDMSO) d 3.93 (s, 3H), 7.49 (td, 2H), 8.29 - 8.35 (m, 1H), 8.40 (s, 1H), 9.60 (s, 1H).Expected Number of Hs: 8Assigned Hs: 8." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=NC(=NC=C1Br)NC2=C(C=CC(=C2)C(F)(F)F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 84.88 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/21/2014" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "955" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00304 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.017 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "COC1=NC(=NC=C1Br)N" + } + amount { + moles { + value: 0.00279 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C=C1C(F)(F)F)I)F" + } + amount { + moles { + value: 0.00341 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000264 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000263 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 100.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a microwave vial was added a mixture of 5-bromo-4-methoxypyrimidin-2-amine (0.570 g, 2.79 mmol), diacetoxypalladium (0.059 g, 0.26 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (152.9 mg, 0.26 mmol), 1-fluoro-2-iodo-4-(trifluoromethyl)benzene (0.99 g, 3.41 mmol) and toluene (17 mL) under inert atmosphare.The reaction mixture was sealed and heated at 100 C under 16h.The LCMS indicated a complete conversion of the SM.The reaction mixture was partitioned between ethyl acetate and aqueous NH4Cl-solution.The organic layer was washed with NH4Cl-solution, brine dried over sodium sulphate, filtered and concentrated in vacuum to give a yellow gum.The oil dissolved in dichloromethane charged on silica 100g and purified by flash chromatography eluting with Ethyl acetate (0-80)% in heptane giving the product 5-bromo-N-(2-fluoro-5-(trifluoromethyl)phenyl)-4-methoxypyrimidin-2-amine (827 mg, 81 %) as a white solid.Collected at 260 nm1H N500 MHz, DMSO) d 3.94 (d, 3H), 7.45 - 7.53 (m, 2H), 8.33 (t, 1H), 8.40 (d, 1H), 9.60 (s, 1H).Expected Number of Hs: 8Assigned Hs: 8." + } + outcomes { + products { + identifiers { + type: SMILES + value: "COC1=NC(=NC=C1Br)NC2=C(C=CC(=C2)C(F)(F)F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 80.85 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "02/27/2014" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "956" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00036 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0045 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CC(C1)N2CCN(CC2)C(=O)C3CC34CCNCC4" + } + amount { + moles { + value: 0.00036 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=NC(=C1)Br" + } + amount { + moles { + value: 0.000397 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 1.8e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 1.8e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 160.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "(4-cyclobutylpiperazin-1-yl)(6-azaspiro[2.5]octan-1-yl)methanone (100 mg, 0.36 mmol), Sodium tert-butoxide (34.6 mg, 0.36 mmol) and 2-bromopyridine (62.7 mg, 0.40 mmol) were weighted in a microwave vial. A solution of Palladium(II) acetate (4.05 mg, 0.02 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (X-Phos) (8.59 mg, 0.02 mmol) in toluene (3.75 mL) and tert-butanol (0.75 mL)was added and the mixture heated at 160 C for 10 minutes, and then 20 minutes more. The mixture was evaporated to dryness, redissolved in a minimum of methanol, filtered and purified on preparative HPLC using the long high pH (acetonitrile in water ammonium carbonate buffer, 25 min.) 20 to 40% gradient method on XBridge Prep C18 OBD, 30x150 mm, 5 mm, Waters reverse phase column, giving (4-cyclobutylpiperazin-1-yl)(6-(pyridin-2-yl)-6-azaspiro[2.5]octan-1-yl)methanone (34.0 mg, 26.6 %) as a slightly yellow solid after lyophilization.1H NMR (400 MHz, DMSO-idi6) d ppm 0.75 (dd, iJi=7.81, 3.91 H H) 1.06 (t, iJi=4.49 Hz, 1 H) 1.31 - 1.67 (m, 6 H) 1.74 (d, iJi=10.16 Hz, 2 H) 1.85 - 2.00 (m, 3 H) 2.01 - 2.36 (m, 4 H) 2.65 (quin, iJi=7.52 Hz, 1 H) 3.35 - 3.69 (m, 8 H) 6.58 (dd, iJi=6.64, 5.08 Hz, 1 H) 6.82 (d, iJi=8.59 Hz, 1 H) 7.49 (td, iJi=7.81, 1.95 Hz, 1 H) 8.08 (dd, iJi=4.88, 1.37 Hz, 1 H)HRMS imiizi calcd for C21H31N4O [M + H]+ 355.24924, found 355.24965." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CC(C1)N2CCN(CC2)C(=O)C3CC34CCN(CC4)C5=CC=CC=N5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 26.61 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "05/07/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "957" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000238 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CC(C1)N2CCN(CC2)C(=O)C3CC34CCNCC4" + } + amount { + moles { + value: 0.000216 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=NC(=C1)Br" + } + amount { + moles { + value: 0.000238 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" + } + amount { + moles { + value: 6.49e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 6.49e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 160.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Reagents were put in a sealed vial and heated in the microwave oven for 10 minutes at 160C. According to LC-MS analysis, the conversion is gt;90%. The crude mixture was transferred to a round-bottomed flask and volatiles were evaporated under vacuum. The residue was purified on preparative HPLC using the long high pH (acetonitrile in water ammonium carbonate buffer, 25 min.) 20 to 40% gradient method on XBridge Prep C18 OBD, 30x150 mm, 5 mm, Waters reverse phase column, giving (4-cyclobutylpiperazin-1-yl)(6-(pyridin-2-yl)-6-azaspiro[2.5]octan-1-yl)methanone (7.20 mg, 9.39 %). However, the compound was not pure enought for mission and there was not enough of it to attempt another purification." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CC(C1)N2CCN(CC2)C(=O)C3CC34CCN(CC4)C5=CC=CC=N5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 9.39 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/10/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "958" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000235 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=CC2=C1C=CN2)CO" + } + amount { + moles { + value: 0.000214 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.000214 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 2.14e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.07e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 40mL vialnbsp;(t=g) was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (50 mg, 0.21 mmol), [Reactants], and cesium carbonate (77 mg, 0.24 mmol) in DMA (0.5 mL) ([VOLUME]),Pd2(dba)3 (9.80 mg, 10.70 mol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (12.38 mg, 0.02 mmol) were added.to give a brown suspension. The vial was filled with N2,150C microwave for 30 min. LCMS showed completion.added MeOH (3 mL), filtered through celite. concentrated. The residue was purified by ISCO (Hexane to EtOAc:Hex=1;1 to EtOAc) to give about 34 mg offwhite solid" + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)N4C=CC5=C4C=C(C=C5)CO" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 47.5 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/26/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "960" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000445 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)NC1=C(C=CC(=C1)N)N2CCN(CC2)C" + } + amount { + moles { + value: 0.000342 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.000342 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.42e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.71e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 40mL vialnbsp;(t=g) was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (80 mg, 0.34 mmol), [Reactants], and cesium carbonate (145 mg, 0.45 mmol) in DMA (0.5 mL) ([VOLUME]),Pd2(dba)3 (15.68 mg, 0.02 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (19.81 mg, 0.03 mmol) were added.to give a brown suspension. The vial was filled with N2,150C microwave for 30 min. LCMS showed completion.concentrated. loaded on ISCO (Hex to Hex:EtOAc To EtOAc:MeOH=10:1 to EtOAc:MeOH:Et3N=10:1:0.1) to give yellow solid.This yellow solid was washed with EtOAc(1mL) to give 40mg pure compound.NMR, 1H,HPLC are OK, see attachment" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)NC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)N5CCN(CC5)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 32.78 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/14/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "963" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0016 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.016 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.0016 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "COC(=O)C1=C(C=C(C=C1)Br)Cl" + } + amount { + moles { + value: 0.0016 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00016 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 8.02e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a solution of palladium acetate (18.00 mg, 0.08 mmol) in dry toluene (16 mL) under nitrogen was added BINAP (100 mg, 0.16 mmol).nbsp;The reaction was heated to 80 C and stirred for 10 min.nbsp;To the reaction was then added tert-butyl piperazine-1-carboxylate (299 mg, 1.60 mmol), cesium carbonate (261 mg, 0.80 mmol), potassium carbonate (222 mg, 1.60 mmol), 18-crown-6 (42.4 mg, 0.16 mmol) and methyl 4-bromo-2-chlorobenzoate (400 mg, 1.60 mmol).nbsp;The reaction was stirred at 80C overnight, filtered through celite and washed with small amounts of DCM.nbsp;The filtrate was concentrated under reduced pressure and purified by flash chromatography on silica gel, eluting with mixtures of EtOAc and heptane, to afford tert-butyl 4-(3-chloro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (517 mg, 91 %) as a so" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC(=C(C=C2)C(=O)OC)Cl" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 90.88 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/09/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "964" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000961 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)NC1=C(C=CC(=C1)N)C2CC2" + } + amount { + moles { + value: 0.000352 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1C(CO1)NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.00032 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C(C)(C)C)C(C)(C)C)C(C)C" + } + amount { + moles { + value: 3.2e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 10 mL microwave reactor vial was charged with 5-chloro-7-(oxetan-3-ylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (80 mg, 0.32 mmol), N-(5-amino-2-cyclopropylphenyl)acetamide (67.1 mg, 0.35 mmol), Cs2CO3 (313 mg, 0.96 mmol), Pd2(dba)3 (14.67 mg, 0.02 mmol) and 2-Di-t-butylphosphino-2\',4\',6\'-tri-i-propyl-1,1\'-biphenyl (13.61 mg, 0.03 mmol). The suspended in DMA (.5 mL), added via syringe. The resulting brown suspension was stirred under nitrogen, then microwave vial capped and heated at 150 C under microwave irradiation for 20 min.LCMS indicated formation of product.The cooled reaction mixture was put through vacuum filtration and concentrated in rotovap. The crude material was purified by ISCO using MeOH and EtOAc (1:10). The solid was suspended in water, stirred for 12 h at rt, repurified with EtOAc, collected and dried to afford a light brown powder (9 mg, 6%) at 93% purity. LCMS, HPLC, and HNMR consistent with desired product- see attached.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)NC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4COC4)C#N)C5CC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 6.96 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "06/26/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "965" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000601 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CN(C)C=O" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)NC1=C(C=CC(=C1)N)C2CC2" + } + amount { + moles { + value: 0.0002 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1C(CO1)NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.00024 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C(C)(C)C)C(C)(C)C)C(C)C" + } + amount { + moles { + value: 4.01e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "Ref:i Angew. Chem. Int. Ed.i b2006b, i45i, 6523-65271. To a microwave tube was added N-(5-amino-2-cyclopropylphenyl)acetamide (0.038 g, 0.20 mmol), 5-chloro-7-(oxetan-3-ylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (0.060 g, 0.24 mmol), Cs2CO3 (0.196 g, 0.60 mmol), Pd2dba3 (0.018 g, 0.02 mmol), and di-tert-butyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.017 g, 0.04 mmol). The mixture was dissolved in DMF (0.5 mL) and sealed. The tube was de-gassed and inflated with N2.2. The reaction was heated at 90C in oil-bath overnight. LCMS showed SM and byproducts and small amount of product mass.did not workup" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)NC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4COC4)C#N)C5CC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/29/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "966" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0016 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.001 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)NC1=C(C=CC(=C1)N)C2CC2" + } + amount { + moles { + value: 0.000801 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1C(CO1)NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.000801 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C(C)(C)C)C(C)(C)C)C(C)C" + } + amount { + moles { + value: 8.01e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 4.01e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 145.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a microwave tube, was Cs2CO3 (0.522 g, 1.60 mmol), N-(5-amino-2-cyclopropylphenyl)acetamide (0.152 g, 0.80 mmol), Pd2dba3 (0.037 g, 0.04 mmol),5-chloro-7-(oxetan-3-ylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (0.200 g, 0.80 mmol),di-tert-butyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.034 g, 0.08 mmol). anhydrous DMA (1.0 mL) was added. The resulting mixture was bubbled through N2. Then the tube was capped. under microwave 145C for 25min.LCMS showed product and byproduct mass, did not showed SMThe mixture was filtered through celite. The resulting black solution was concentrated to dryness by rotavapor. The crude product was purified by ISCO (40g, Hex to EtOAc:HEx=1;2 to 1;1 to EtOAcO) to give product (offwhite solid). HPLC showed some impurity. This offwhite solid was washed with warm EtOAc (1mL) to give N-(5-(3-cyano-7-(oxetan-3-ylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)-2-cyclopropylphenyl)acetamide (0.028 g, 8.66 %).LCMS and NMR were OKlt; see attachment. " + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)NC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4COC4)C#N)C5CC5" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 8.66 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "07/29/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "971" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00103 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)NC1=C(C=CC(=C1)N)N2CCC[C@H](C2)N(C)C" + } + amount { + moles { + value: 0.000514 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.000514 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 5.14e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 2.57e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 40mL vialnbsp;(t=g) was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (120mg, 0.51 mmol), (R)-N-(5-amino-2-(3-(dimethylamino)piperidin-1-yl)phenyl)acetamide (142 mg, 0.51 mmol), and cesium carbonate (335 mg, 1.03 mmol) in DMA (0.5 mL) (),Pd2(dba)3 (23.51 mg, 0.03 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (29.7 mg, 0.05 mmol) were added.to give a brown suspension. The vial was filled with N2,150C microwave for 30 min. LCMS showed completion. added MeOH (2 mL), filtered. The solvent was removed by ratovapor to yield stick oil. The crude product was loaded on ISCO (Hex to Hex:EtOAc To EtOAc to EtOAc:MeOH:Et3N=10:1:0.1) to give sticky oil.The product was not pure. It was purifed by Gilson to give (R)-N-(5-(3-cyano-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)-2-(3-(dimethylamino)piperidin-1-yl)phenyl)acetamide (22.00 mg, 7.29 %) as anbsp;light brown solid (TFA salt).the solid was dried under high vacuum under 60C for 2h.LCMS and NMR were OK, see the attachment" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)NC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)N5CCC[C@H](C5)N(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 7.29 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/31/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "972" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000253 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.00225 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C1=CC(=CC2=C1OC(=CC2=O)N3CCOCC3)C(=O)N(C)C)N" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=C(C(=C1F)F)Br)F" + } + amount { + moles { + value: 0.00223 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000253 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 7.6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a mixture of 8-(1-aminoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (350 mg, 1.01 mmol), cesium carbonate (1288 mg, 3.95 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (147 mg, 0.25 mmol) and 1-bromo-2,3,5-trifluorobenzene (470 mg, 2.23 mmol) in degassed 1,4-dioxane (2.2ml), was addednbsp;TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (69.6 mg, 0.08 mmol). The suspension was heated in a sealed container up to 85-95Cnbsp;for 24 hours. The reaction mixture was filtered through a short pad of dicalite, concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 0 to 5% methanol in dichloromethane. The solvent was evaporated to dryness to afford the N,N-dimethyl-2-morpholino-4-oxo-8-(1-(2,3,5-trifluorophenylamino)ethyl)-4H-chromene-6-carboxamide (400 mg, 83 %) as a yellow gum, which still containing some impurities. The product mixture was then re-purified by preparative HPLC using a Waters X-Bridge reverse-phaseumn (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford N,N-dimethyl-2-morpholino-4-oxo-8-(1-(2,3,5-trifluorophenylamino)ethyl)-4H-chromene-6-carboxamide (135 mg, 28 %)nbsp;as a clear yellow solid.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C1=CC(=CC2=C1OC(=CC2=O)N3CCOCC3)C(=O)N(C)C)NC4=C(C(=CC(=C4)F)F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 83.02 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "12/21/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "973" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000322 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)N)NC(=O)C" + } + amount { + moles { + value: 0.000292 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CN1C=CC(=N1)NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.000292 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 2.92e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.46e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "in microwave tube was 5-chloro-7-(1-methyl-1H-pyrazol-3-ylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (80 mg, 0.29 mmol), N-(5-amino-2-methylphenyl)acetamide (48.0 mg, 0.29 mmol), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (16.91 mg, 0.03 mmol) in DMA (0.5 mL).Pd2(dba)3 (13.38 mg, 0.01 mmol) and cesium carbonate (105 mg, 0.32 mmol) were added.degassed, filled with N2.capped. then microwave 150C for 30 min.added 2 mL of MeOH, filtered through celite. concentrated. The residue was purified by ISCO (Hex to Hex:EtOAc=1:4 to 1:1 to EtOAc), collected prod fractions. concentrated to give offwhite solid. This solid was washed with 0.5 mL of EtOAc to give pure prod" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=C(C=C(C=C1)NC2=NC3=C(C=NN3C(=C2)NC4=NN(C=C4)C)C#N)NC(=O)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 33.24 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "08/25/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "974" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000685 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC(=C(C=C1NC(=O)C)N)F" + } + amount { + moles { + value: 0.000342 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.000342 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3.42e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.71e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "in microwave tube was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (80 mg, 0.34 mmol), N-(5-amino-4-fluoro-2-methylphenyl)acetamide (62.4 mg, 0.34 mmol), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (19.81 mg, 0.03 mmol) in DMA (0.5 mL).Pd2(dba)3 (15.68 mg, 0.02 mmol) and cesium carbonate (223 mg, 0.68 mmol) were added.degassed, filled with N2.capped. then microwave 150C for 30 min.the organic solvent was removed. The black residue was tried to purifed by ISCO. impurity and prod came out together too quickly. concentrated to give offwhite solid. LCMS showed about 10% impurity.The solid was washed with hot EtOAc(1mL) to give about 21mg white solid.LCMS and NMR are OK, see attachment.low yield was due to hot EtOAc wash, lost some prod." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC1=CC(=C(C=C1NC(=O)C)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 16.17 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/24/2008" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "976" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00123 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.0123 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00123 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C=C1Br)F)C(F)(F)F" + } + amount { + moles { + value: 0.00123 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000123 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 6.17e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 80.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 50 mL round-bottomed flask, PALLADIUM ACETATE (0.014 g, 0.06 mmol) was treated with BINAP (0.077 g, 0.12 mmol) under nitrogen in degassed Toluene (12.35 ml). The reaction was heated to 80 C and was stirred for 10 min. To the flask was then added tert-butyl piperazine-1-carboxylate (0.230 g, 1.23 mmol), cesium carbonate (0.201 g, 0.62 mmol), potassium carbonate (0.171 g, 1.23 mmol), and 18-CROWN-6 (0.033 g, 0.12 mmol). The reaction was then treated with 4-bromo-2-fluoro-1-(trifluoromethyl)benzene (0.300 g, 1.23 mmol) and was allowed to stir at 80C 5 h.bLCMS High pH:bSM Amine Rt = 1.21 minProduct Rt = 2.14 min, Rf = 0.28The reaction mixture was filtered through celite and washed with small amounts of DCM. The filtrate was evaporated in vacuo to a residue that was taken up in a mixture of Heptane and EtOAc (4:1). The residue was purified by flash chromatography on silica gel, eluting with mixtures of EtOAc and heptane, to afford tert-butyl 4-(3-fluoro-4-(tmethyl)phenyl)piperazine-1-carboxylate (0.258 g, 59.9 %) as a solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC(=C(C=C2)C(F)(F)F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 59.92 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/23/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "977" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.000253 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 2.25 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C1=CC(=CC2=C1OC(=CC2=O)N3CCOCC3)C(=O)N(C)C)N" + } + amount { + moles { + value: 0.00101 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=C(C=C(C=C1Cl)Br)F" + } + amount { + moles { + value: 0.00223 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 0.000253 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 7.6e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "To a mixture of 8-(1-aminoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (350 mg, 1.01 mmol), cesium carbonate (1288 mg, 3.95 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (147 mg, 0.25 mmol) and 1-bromo-3-chloro-5-fluorobenzene (467 mg, 2.23 mmol) in degassed 1,4-dioxane (2ml), was addednbsp;TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (69.6 mg, 0.08 mmol). The suspension was heated in a sealed container up to 95Cnbsp;for 16hours. The reaction mixture was filtered through a short pad of dicalite, concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 0 to 8 % iPrOH in CH2Cl2. The solvent was evaporated to dryness tonbsp;afford the 8-(1-(3-chloro-5-fluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (375 mg, 78 %). The product triturated with diethyl ether - CH2Cl2 (9-1) and thenbsp;desired compound was filtered and driednbsp;to afford 320 mg of product P1nbsp;as a clear ow solid.However the final sample product contain some diethyle ether which was removed under vacuum ON before sample mission.nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C1=CC(=CC2=C1OC(=CC2=O)N3CCOCC3)C(=O)N(C)C)NC4=CC(=CC(=C4)Cl)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 78.08 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "12/21/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "978" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.0155 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1COCCO1" + } + amount { + volume { + value: 0.00516 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CCOC(=O)C1CCNCC1" + } + amount { + moles { + value: 0.00516 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)C1=CC=C(C=C1)Br" + } + amount { + moles { + value: 0.00516 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00103 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000516 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 110.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "1. To a microwave tube was added tert-butyl 4-bromobenzoate (1.328 g, 5.16 mmol), ethyl piperidine-4-carboxylate (1.000 g, 5.16 mmol), Cs2CO3 (5.05 g, 15.49 mmol), Pd2dba3 (0.473 g, 0.52 mmol), and BINAP (0.643 g, 1.03 mmol). The mixture was dissolved in [Solvents] and sealed. The tube was de-gassed and inflated with N2.2. The reaction was heated at 110C in oil-bath overnight. LCMS showed reaction complete. The reaction mixture was filter through celite pad and the solution was loaded to column for a ISCO purification (30% EtOAc in Hex). The purification is difficult with multiple by-products. Several ISCO purification was carried out and fractions were combined with other batches. Yield was poor." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CCOC(=O)C1CCN(CC1)C2=CC=C(C=C2)C(=O)OC(C)(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 0.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "09/10/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "979" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.000956 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "C1CNCCN1" + } + amount { + moles { + value: 0.0041 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)C(C2=CC=CC=C2)(C3=CC=CC=C3)N4C=NC5=C4C=CC=C5Br" + } + amount { + moles { + value: 0.000683 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 4.1e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C(Cl)(Cl)Cl.[Pd].[Pd]" + } + amount { + moles { + value: 1.37e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 90.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 2.0-5.0 mL microwave vial was charged with 4-bromo-1-trityl-1H-benzo[d]imidazole (300 mg, 0.68 mmol), Sodium tert-butoxide (92 mg, 0.96 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (25.5 mg, 0.04 mmol), Piperazine (0.321 mL, 4.10 mmol) and toluene (5 mL). The reaction mixture was degassed for 10 minutes with nitrogen, and then Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (14.14 mg, 0.01 mmol) was added. The reaction mixture was stirred at 90C under microwave irradiation for 1h.nbsp;The solution was diluted with EtOAc and washed with water, saturated NaHCO3 solution, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced vacuum.nbsp;The crude material was loaded on a 24g silica gel column and purified on a Teledyne Isco instrument, eluting with 10 : 1 DCM : MeOH containing 0.2% ammonium hydroxide (vv) to provide 4-(piperazin-1-yl)-1-trityl-1H-benzo[d]imidazole (130 mg, 42.8 %) as a solid.nbsp;The product was analyzed by analytical HPLC MS usthe high pH gradient method (mobile phase: 5-95% B; A: H2O with 10 mM NH5CO3 and 0.375% NH4OH vv, B: MeOH, 2.25 min run) on X-Bridge C18, 2.1 x 30 mm, 5 mm particle size. MS imzi 445.6 [M+H]+ (ESI), Rt 2.61 min;nbsp;1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.64 (br. s., 1 H), 3.11 - 3.22 (m, 4 H), 3.48 - 3.59 (m, 4 H), 6.08 (d, J=8.20 Hz, 1 H), 6.54 (d, J=7.42 Hz, 1 H), 6.79 (t, J=8.01 Hz, 1 H), 7.13 - 7.23 (m, 6 H), 7.30 (d, J=3.91 Hz, 9 H), 7.79 (s, 1 H)." + } + outcomes { + products { + identifiers { + type: SMILES + value: "C1CN(CCN1)C2=CC=CC3=C2N=CN3C(C4=CC=CC=C4)(C5=CC=CC=C5)C6=CC=CC=C6" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 42.82 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "11/03/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "982" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.00502 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.03 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00418 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC(=C(C=C1C(F)(F)F)Br)F" + } + amount { + moles { + value: 0.00418 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000418 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000209 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 105.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 250 mL round flask was charged with 2-bromo-1-fluoro-4-(trifluoromethyl)benzene (1.016 g, 4.18 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.260 g, 0.42 mmol), Sodium tert-butoxide (0.482 g, 5.02 mmol), tert-butyl piperazine-1-carboxylate (0.779 g, 4.18 mmol) and a mixture of toluene (25 mL) and DMF (5 mL). The reaction mixture was degassed for 10 minutes with nitrogen, and then Tris(dibenzylideneacetone)dipalladium(0) (0.191 g, 0.21 mmol) was added. The reaction mixture was stirred at 105C in an oil bath 12h.nbsp;The solution was diluted with EtOAc and washed with saturated NaHCO3 solution, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The aqueous phase was evaporated and the residue was extracted with EtOAc (3X20mL), concentrated.nbsp;The combined crude material was loaded on a 80g silica gel column and purified on a Teledyne Isco instrument, eluting with 0% to 25% ethyl acetate in heptane to provide tert-butyl 4-(2-fluoro-5-(trifluoromethyl)pl)piperazine-1-carboxylate (0.622 g, 42.7 %) as an oil." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=C(C=CC(=C2)C(F)(F)F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 42.75 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "12/09/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "983" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)[O-].[Na+]" + } + amount { + moles { + value: 0.017 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC1=CC=CC=C1" + } + amount { + volume { + value: 0.03 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.0142 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CN=C(C=C1C(F)(F)F)Cl" + } + amount { + moles { + value: 0.0142 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.00142 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 0.000708 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 105.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A 250 mL round flask was charged with 2-chloro-4-(trifluoromethyl)pyridine (2.57 g, 14.16 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.881 g, 1.42 mmol), Sodium tert-butoxide (1.633 g, 16.99 mmol), tert-butyl piperazine-1-carboxylate (2.64 g, 14.16 mmol) and a mixture of toluene (25 mL) and DMF (5 mL). The reaction mixture was degassed for 10 minutes with nitrogen, and then Tris(dibenzylideneacetone)dipalladium(0) (0.648 g, 0.71 mmol) was added. The reaction mixture was stirred at 105C in an oil bath 12h.nbsp;The solution was diluted with EtOAc and washed with saturated NaHCO3 solution, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The aqueous phase was evaporated and the residue was extracted with EtOAc (3X20mL), concentrated.nbsp;The combined crude material was loaded on a 80g silica gel column and purified on a Teledyne Isco instrument, eluting with 0% to 25% ethyl acetate in heptane to provide tert-butyl 4-(4-(trifluoromethyl)pyridin-2-yl)pipine-1-carboxylate (2.164 g, 46.1 %) as a solid." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=NC=CC(=C2)C(F)(F)F" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 46.13 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "10/13/2010" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "986" + } + identifiers { + type: NAME + details: "reaction type" + value: "0.0 [Unassigned] Unrecognized" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 0.00809 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "C1CCOC1" + } + amount { + volume { + value: 0.03 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCNCC1" + } + amount { + moles { + value: 0.00693 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1=CC2=C(C=CC(=C2N=C1)OS(=O)(=O)C(F)(F)F)Cl" + } + amount { + moles { + value: 0.00578 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" + } + amount { + moles { + value: 0.000289 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "CC(=O)O.CC(=O)O.[Pd]" + } + amount { + moles { + value: 0.000289 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 75.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "A mixture of 5-chloroquinolin-8-yl trifluoromethanesulfonate (1.8 g, 5.78 mmol), Cesium carbonate (2.63 g, 8.09 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.180 g, 0.29 mmol), tert-Butyl 1-piperazinecarboxylate (1.291 g, 6.93 mmol) and Palladium(II) acetate (0.065 g, 0.29 mmol) in THF (30 mL) under a nitrogen atmosphere was stirred at 75 C for 6h.nbsp;The solution was cooled to rt and diluted with ether.nbsp;The mixtture was filtered through celite and the solvent was evaporated under reduced pressure.nbsp;The residue was purified by flash chromatography on silica gel, eluting with a gradient of 25-50% EtOAc in heptane, to afford tert-butyl 4-(5-chloroquinolin-8-yl)piperazine-1-carboxylate (0.489 g, 24.34 %) as an oil.1H NMR (400 MHz, CHLOROFORM-idi) d ppm 1.51 (s, 9 H), 3.28 - 3.37 (m, 4 H), 3.72 - 3.82 (m, 4 H), 7.06 (d, iJi=7.81 Hz, 1 H), 7.48 - 7.57 (m, 2 H), 8.57 (dd, iJi=8.59, 1.95 Hz, 1 H), 8.94 (dd, iJi=4.10, 1.76 Hz, 1 H); MS mz 348.31 ]+ (ESI).nbsp;" + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=C3C(=C(C=C2)Cl)C=CC=N3" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 24.34 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "03/26/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} +reactions { + identifiers { + type: CUSTOM + details: "reaction index" + value: "987" + } + identifiers { + type: NAME + details: "reaction type" + value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" + } + inputs { + key: "Base" + value { + components { + identifiers { + type: SMILES + value: "C(=O)([O-])[O-].[Cs+].[Cs+]" + } + amount { + moles { + value: 3e-05 + units: MOLE + } + } + reaction_role: REAGENT + is_limiting: false + } + } + } + inputs { + key: "Solvent" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)N(C)C" + } + amount { + volume { + value: 0.0005 + units: LITER + } + } + reaction_role: SOLVENT + is_limiting: false + } + } + } + inputs { + key: "amine" + value { + components { + identifiers { + type: SMILES + value: "CC(=O)NC1=C(C=CC(=C1)N)N(C)CCCN(C)C" + } + amount { + moles { + value: 0.0003 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "aryl halide" + value { + components { + identifiers { + type: SMILES + value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" + } + amount { + moles { + value: 0.0003 + units: MOLE + } + } + reaction_role: REACTANT + is_limiting: false + } + } + } + inputs { + key: "metal and ligand" + value { + components { + identifiers { + type: SMILES + value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" + } + amount { + moles { + value: 3e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + components { + identifiers { + type: SMILES + value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" + } + amount { + moles { + value: 1.5e-05 + units: MOLE + } + } + reaction_role: CATALYST + is_limiting: false + } + } + } + conditions { + temperature { + setpoint { + value: 150.0 + precision: 10.0 + units: CELSIUS + } + } + } + notes { + procedure_details: "In a 40mL vialnbsp;(t=g) was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (70mg, 0.30 mmol), N-(5-amino-2-((3-(dimethylamino)propyl)(methyl)amino)phenyl)acetamide (79 mg, 0.30 mmol), and cesium carbonate (195 mg, 0.60 mmol) in DMA (0.5 mL) (),Pd2(dba)3 (13.72 mg, 0.01 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (17.33 mg, 0.03 mmol) were added.to give a brown suspension. The vial was filled with N2,150C microwave for 30 min. LCMS comletion.nbsp;MeOH (2 mL) was added to the reaction mixture.nbsp;filtered. The mother liquid solvent was removed by ratovapor to yield sticky oil. The crude product was loaded on ISCO (Hex to Hex:EtOAc To EtOAc to EtOAc:MeOH=10:1) to give sticky oil.The product was not pure. It was purified by Gilson to givenbsp;N-(5-(3-cyano-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)-2-((3-(dimethylamino)propyl)(methyl)amino)phenyl)acetamide (50.0 mg, 29.0 %) as TFA saltNMR and LCMS showed desired product, see attachment." + } + outcomes { + products { + identifiers { + type: SMILES + value: "CC(=O)NC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)N(C)CCCN(C)C" + } + is_desired_product: true + measurements { + type: YIELD + percentage { + value: 29.0 + } + } + reaction_role: PRODUCT + } + } + provenance { + experimenter { + organization: "AstraZeneca" + } + experiment_start { + value: "04/14/2009" + } + publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" + record_created { + time { + value: "10/19/2021, 12:16:25 PM" + } + person { + name: "Bozhao Nan" + organization: "Notre Dame" + email: "bnan@nd.edu" + } + } + } +} From 7795dc74334809f0fa97c9c29ba20b1d869fa40e Mon Sep 17 00:00:00 2001 From: github-actions Date: Fri, 22 Oct 2021 22:20:02 +0000 Subject: [PATCH 2/3] Update submission --- AZ_dataset.pbtxt | 125803 --------------- ...set-00005539a1e04c809a9a78647bea649c.pb.gz | 3 + 2 files changed, 3 insertions(+), 125803 deletions(-) delete mode 100644 AZ_dataset.pbtxt create mode 100644 data/00/ord_dataset-00005539a1e04c809a9a78647bea649c.pb.gz diff --git a/AZ_dataset.pbtxt b/AZ_dataset.pbtxt deleted file mode 100644 index a50bc0a1..00000000 --- a/AZ_dataset.pbtxt +++ /dev/null @@ -1,125803 +0,0 @@ -name: "750 AstraZeneca ELN dataset" -description: "This dataset includes 750 Buchwald-Hartwig reactions generated from AstraZeneca ELN which is used in yield prediction work:\302\24010.26434/chemrxiv.14589498.v2" -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "0" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00222 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)N1CCNCC1" - } - amount { - moles { - value: 0.00177 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC1=C(C=C2C(=C1)N=CC(=C2NC3=C(C=C(C=C3)F)F)C(=O)OCC)Br" - } - amount { - moles { - value: 0.000886 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 8.86e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 4.43e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a solution of ethyl 6-bromo-4-(2,4-difluorophenylamino)-7-ethoxyquinoline-3-carboxylate (400 mg, 0.89 mmol) and 1-(Isopropyl)piperazine (254 l, 1.77 mmol) in dioxane was added cesium carbonate (722 mg, 2.22 mmol), tris(dibenzylideneacetone)dipalladium(0) (40.6 mg, 0.04 mmol) and rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (55.2 mg, 0.09 mmol). Reaction vessel in oil bath set to 110 C. 11amAfter 5 hours, MS shows product (major peak 499), and SM (minor peak 453).on, MS shows product peak. Reaction cooled, concentrated onto silica, and purified on ISCO. 40g column, 1:1 EA:Hex, then 100% EA.289mg yellow solid. NMR (EN00180-62-1) supports product, but some oxidised BINAP impurity (LCMS 6" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC1=C(C=C2C(=C1)N=CC(=C2NC3=C(C=C(C=C3)F)F)C(=O)OCC)N4CCN(CC4)C(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 65.39 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/01/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "1" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.019 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC=CC=C1" - } - amount { - volume { - value: 0.0332 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=NC2=C1C=C(C(=C2F)N)C(=O)OC" - } - amount { - moles { - value: 0.00762 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)I" - } - amount { - moles { - value: 0.00914 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000762 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000305 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (441 mg, 0.76 mmol) andnbsp;Tris(dibenzylideneacetone)dipalladium(0) (279 mg, 0.30 mmol) were added to a round bottom flask which was evacuated and flushed with nitrogen 3 times, anisole (16.600 ml) was added and the mixture evacuated and flushed with nitrogen 3 times and then heated to 50C for 10 minutes. Cesium carbonate (6204 mg, 19.04 mmol), methyl 5-amino-4-fluoro-1-methyl-1H-benzo[d]imidazole-6-carboxylate (1700 mg, 7.62 mmol) and Iodobenzene (1.023 ml, 9.14 mmol) were stirred in anisole (33.2 ml), the flask was evacuated and flushed with nitrogen three times and then heated to 50C. The catalyst mixture was transferred into the flask with the reactants (by syringe) and the mixture heated to 100 C for 18 hours. The reaction mixture was diluted with isohexane (60 ml) and the solid collected by filtration and washed with more isohexane (30 ml). The solid was slurried in DCM MeOH and adsorbed onto silica then purified by flash silica ch eluting with 2% 3.7N NH3 MeOH in DCM to give methyl 4-fluoro-1-methyl-5-(phenylamino)-1H-benzo[d]imidazole-6-carboxylate (1310 mg, 57.5 %) as anbsp;yellow solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1C=NC2=C1C=C(C(=C2F)NC3=CC=CC=C3)C(=O)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 57.47 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/16/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "3" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0168 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC=CC=C1" - } - amount { - volume { - value: 0.0149 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=NC2=C1C=C(C(=C2F)N)C(=O)OC" - } - amount { - moles { - value: 0.00672 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)I" - } - amount { - moles { - value: 0.00806 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000672 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000269 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (389 mg, 0.67 mmol) andnbsp;Tris(dibenzylideneacetone)dipalladium(0) (246 mg, 0.27 mmol) were added to a round bottom flask which was evacuated and flushed with nitrogen 3 times, anisole (14.900 ml) was added and the mixture evacuated and flushed with nitrogen 3 times and then heated to 50C for 10 minutes. Cesium carbonate (5474 mg, 16.80 mmol), methyl 5-amino-4-fluoro-1-methyl-1H-benzo[d]imidazole-6-carboxylate (1500 mg, 6.72 mmol) and Iodobenzene (0.902 ml, 8.06 mmol) were stirred in anisole (29.8 ml), the flask was evacuated and flushed with nitrogen three times and then heated to 50C. The catalyst mixture was transferred into the flask with the reactants (by syringe) and the mixture heated to 100 C for 18 hours. The reaction mixture was diluted with isohexane (50 ml) the solid collected by filtration and washed with more isohexane (25 ml). The solid was slurried in dichloromethane (40 ml) and methanol (10 ml) and filtered, washing the rid with more dichloromethane methanol. The filtratre (containing product) was evaporated onto silica and purified by flash silica chromatography, eluting with 2% 3.7N NH3 MeOH in DCM. Pure fractions were evaporated to dryness to afford methyl 4-fluoro-1-methyl-5-(phenylamino)-1H-benzo[d]imidazole-6-carboxylate (1316 mg, 65.4 %) as a light yellow solid. nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1C=NC2=C1C=C(C(=C2F)NC3=CC=CC=C3)C(=O)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 65.43 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/06/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "4" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0168 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC=CC=C1" - } - amount { - volume { - value: 0.0298 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=NC2=C1C=C(C(=C2F)N)C(=O)OC" - } - amount { - moles { - value: 0.00672 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)I" - } - amount { - moles { - value: 0.00806 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000672 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000269 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (389 mg, 0.67 mmol) andnbsp;Tris(dibenzylideneacetone)dipalladium(0) (246 mg, 0.27 mmol) were added to a round bottom flask which was evacuated and flushed with nitrogen 3 times, anisole (14.900 ml) was added and the mixture evacuated and flushed with nitrogen 3 times and then heated to 50C for 10 minutes. Cesium carbonate (5474 mg, 16.80 mmol), methyl 5-amino-4-fluoro-1-methyl-1H-benzo[d]imidazole-6-carboxylate (1500 mg, 6.72 mmol) and Iodobenzene (0.902 ml, 8.06 mmol) were stirred in anisole (29.800 ml), the flask was evacuated and flushed with nitrogen three times and then heated to 50C. The catalyst mixture was transferred into the flask with the reactants (by syringe) and the mixture heated to 100 C for 18 hours. The reaction mixture was diluted with isohexane (50 m) and the solid collected by filtration and washed with more isohexane (25 ml). The solid was slurried in DCM MeOH and adsorbed onto silica then purified by flash silica cy eluting with 2% 3.7N NH3 MeOH in DCM to give methyl 4-fluoro-1-methyl-5-(phenylamino)-1H-benzo[d]imidazole-6-carboxylate (1510 mg, 75 %) as a light yellow solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1C=NC2=C1C=C(C(=C2F)NC3=CC=CC=C3)C(=O)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 75.07 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/08/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "7" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00276 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.13 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1N)S(=O)(=O)N" - } - amount { - moles { - value: 0.0358 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)Cl)C" - } - amount { - moles { - value: 0.0276 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00276 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00193 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;3-(2-chloropyridin-4-yloxy)-2,6-dimethylpyridine (6.47 g, 27.57 mmol), Sulfanilamide (6.17 g, 35.84 mmol), CESIUM CARBONATE (13.47 g, 41.35 mmol) and XANTPHOS (1.595 g, 2.76 mmol) were stirred in DMA (130 ml). Purged this stirred mixture by bubbling nitrogen through for an hour, then added the Palladium acetate. Heated to 130C in a metal block (block at 150C) and held at this temperature for 3 hours. LCMS (monitorbase) then showed DP as MH+ = 370.99 and MH- = 369.03 at 1.82 minutes, 84%. Allowed to cool to room temperature. The reaction mixture was evaporated to dryness at 50C givingi ia dirty-yellow solid residue. Treated with 150 ml water and the resulting yellow solid filtered off and washed with water. Dried by desiccation under high vacuum over phosphorous pentoxide at room temperature to constant weight. This afforded 11.98 g pale-yellow solid [A].LCMS(monitorbase) showed it to be DP as MH+ = 370.99 and MH- = 36 minutes, 90%.inbsp;iThis material was crystallised from acetonitrile; dissolved up in ~1 litre boiling acetonitrile and the cloudy solution filtered hot through a fluted paper. Crystallisation of product from the filtrate was eventually achieved, with difficulty, by rapid cooling in drikoldacetone and seedingscratching as it warmed up.nbsp;Cooled in icewater then the solid was collected by filtration and washed with chilled acetonitrile. Dried by desiccation under high vacuum at room temperature to constant weight. This afforded 6.03 g creamy-whitenbsp;solid [B].LCMS (monitorbase) then showed DP as MH+ = 370.99 and MH- = 369.03 at 1.49 minutes, 96%.Material B was combined with the same product from P14-A and this total of 7.32 g recrystallised from the minimum of acetonitrile (~550 ml) with hot filtration again to remove trace insoluble matter. Cooled in icewater and seededscratched to induce crystallisation then stood in the fridge overnight. The solid was collected by filtration and washed with chilled acetonitrile. Dried by desiccation under high vacuum initially at room temperature, then at 60C, to constant weight. This afforded 5.04 g creamy-whitenbsp;solid [C].LCMS (monitorbase) then showed DP as MH+ = 371.06 and MH- = 369.08 at 1.85 minutes, 99%.Unfortunately nmr showed entrapped acetonitrile at an unacceptable level (~0.5 equiv.). To remove this material C was stirred in ~100 ml ether for an hour, recollected and washed with ether. Dried at 60C as before to constant weight. This afforded 4.73 g creamy-white solid " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)NC3=CC=C(C=C3)S(=O)(=O)N)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 46.32 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/15/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "8" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00426 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.2 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1N)S(=O)(=O)N" - } - amount { - moles { - value: 0.0554 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)Cl)C" - } - amount { - moles { - value: 0.0426 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00426 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00298 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 130.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "XANTPHOS (2.466 g, 4.26 mmol) was added to 3-(2-chloropyridin-4-yloxy)-2,6-dimethylpyridine (10g, 42.61 mmol), Sulfanilamide (9.54 g, 55.39 mmol) and CESIUM CARBONATE (20.83 g, 63.92 mmol) in DMA (200 ml) at 20C. Nitrogen was bubbled through the reaction mixture for 1 hour then PALLADIUM(II) ACETATE (0.670 g, 2.98 mmol) added. The suspension was stirred at 130 C for 3 hours. The reaction mixture was filtered then evaporated to dryness. The residue was triturated with water (150 mL) and filtered to give crude product as a cream solid - 90% pure. The crude solid was triturated with hot acetonitrile (300 mL) and filtered to afford crude product as a cream solid - 98% by LCMS. This was combined with the product from EN02084-31 and dissolved in boiling acetonitrile (approx 1 L). The solution was concentrated to 500 mL and cooled to ice bath temperature with stirring. A precipitate formed which and the suspension was stirred at room temperature overnight. The solid was filtered to afford 4-(4-(2,6-diridin-3-yloxy)pyridin-2-ylamino)benzenesulfonamide (12.00 g, 76 %) as a cream solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)NC3=CC=C(C=C3)S(=O)(=O)N)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 76.03 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/11/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "9" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000847 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.04 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1N)S(=O)(=O)N" - } - amount { - moles { - value: 0.0111 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)Cl)C" - } - amount { - moles { - value: 0.00852 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000847 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000579 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 130.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;3-(2-chloropyridin-4-yloxy)-2,6-dimethylpyridine (2 g, 8.52 mmol), Sulfanilamide (1.91 g, 11.09 mmol), CESIUM CARBONATE (4.17 g, 12.80 mmol) and XANTPHOS (490 mg, 0.85 mmol) were stirred in DMA (40 ml). Purged this stirred mixture by bubbling nitrogen through for an hour, then added the Palladium acetate. Heated to 130C in a metal block (block at 150C) and held at this temperature for 3 hours. LCMS (monitorbase) then showed DP as MH+ = 370.99 and MH- = 369.03 at 1.83 minutes, 83%. Allowed to cool to room temperature. The reaction mixture was evaporated to dryness at 50C giving a light-green solid residue. Attempted to partition this residue between DCM (~50 ml) and saturated aqueous sodium hydrogen carbonate (~50 ml). The insoluble matter was filtered off and washed through with water, then DCM. This dirty-yellow solid was dried by desiccation overnight. Wt = 2.04 g. LCMS showed it to be DP, 94%. This material was crystallised from acetonitrile;p in ~150 ml boiling acetonitrile and the cloudy solution treated with a little Norit SX4 decolourising carbon. Filtered hot through a fluted paper. Slow crystallisation of a creamy-white solid occurred on cooling to room temperature. Cooled in icewater then the bulky solid was collected by filtration and washed with chilled acetonitrile. Dried by desiccation under high vacuum at room temperature overnight. This afforded 1.29 g creamy-white bulky solid [A].LCMS (monitorbase) then showed DP as MH+ = 370.99 and MH- = 369.03 at 1.83 minutes, 99%." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)NC3=CC=C(C=C3)S(=O)(=O)N)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 40.86 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/01/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "10" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00277 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.13 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1N)S(=O)(=O)N" - } - amount { - moles { - value: 0.036 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)Cl)C" - } - amount { - moles { - value: 0.0277 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00277 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00194 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 130.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "XANTPHOS (1.603 g, 2.77 mmol) was added to 3-(2-chloropyridin-4-yloxy)-2,6-dimethylpyridine (6.5 g, 27.70 mmol), Sulfanilamide (6.20 g, 36.01 mmol) and CESIUM CARBONATE (13.54 g, 41.55 mmol) in DMA (130 ml) at 20C. Nitrogen was bubbled through the reaction mixture for 1 hour then PALLADIUM(II) ACETATE (0.435 g, 1.94 mmol) added. The suspension was stirred at 130 C for 3 hours. The reaction mixture was cooled to ambient temperature and filtered then evaporated to dryness. The residue was triturated with water (150 mL) and filtered to give crude product as a cream solid which was 90% pure by LCMS. The crude solid was triturated with hot MeCN (300 mL) to give a solid which was collected by filtration and dried under vacuum to give a cream solid (7.86g) which was 95% pure by LCMS. The solid was dissolved in the minimum amount of boiling MeCN (650 mL) and filtered to remove remaining trace solids. The filtrate was concentrated to approximately 400 mL and stirred at ice bath temperature until a preciormed. The suspension was stirred at room temperature overnight then filtered to afford a cream solid (6.4g) which was 100% pure by LCMS. Combined with EN02084-42 to get a single larger batch." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)NC3=CC=C(C=C3)S(=O)(=O)N)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 62.38 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/05/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "11" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0156 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00573 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=NC=C1Br)Br" - } - amount { - moles { - value: 0.0052 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000625 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00052 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 140.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "3,5-dibromopyridine (1.233 g, 5.20 mmol), 1-(piperazin-1-yl)ethanone (0.734 g, 5.73 mmol), PdOAc2 (0.117 g, 0.52 mmol), XANTPHOS (0.361 g, 0.62 mmol), Cs2CO3 (5.09 g, 15.61 mmol), 1,4-dioxane as added to a 10 mL microwave vial. This was degassed and refilled with N2 and then heated at 140 C in microwave for 1h.LCMS showed reaction done with the peak at Rf1.24 showed a fragment mass of 284.Evaporated solvent. Residue purified by ISCO (0-20% MeOH in EtOAc )to get the desired product 1-(4-(5-bromopyridin-3-yl)piperazin-1-yl)ethanone (0.470 g, 31.8 %).Trial # 1:3,5-dibromopyridine (407 mg, 1.72 mmol), 1-(piperazin-1-yl)ethanone (231 mg, 1.81 mmol), PdOAc2 (38.6 mg, 0.17 mmol), XANTPHOS (119 mg, 0.21 mmol), Cs2CO3 (1681 mg, 5.16 mmol), 1,4-dioxane as added to a 10 mL microwave vial. This was degassed and refilled with N2 and then heated at 140 C in microwave for 1h.LCMS showed reaction done with the peak at Rf1.22 showed a fragment mass of 284.Evaporatnt. Residue purified by ISCO (0-20% MeOH in EtOAc )to get the desired product 1-(4-(5-bromopyridin-3-yl)piperazin-1-yl)ethanone (118mg, 24%)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)N1CCN(CC1)C2=CC(=CN=C2)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 31.78 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/15/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "12" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00131 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.0025 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1N)N2C=CN=C2" - } - amount { - moles { - value: 0.000437 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CC(OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.000437 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 4.37e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.37e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "[Reactants], 8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.120 g, 0.44 mmol), Palladium(II) acetate (9.81 mg, 0.04 mmol), 2-(Dicyclohexylphosphino)biphenyl (0.015 g, 0.04 mmol) and Cesium carbonate (0.427 g, 1.31 mmol) in DME (2.5 mL) were placed in a microwave vial and flushed with argon. The reaction mixture was then run in the microwave at 100C for 1 hr. Reaction not complete. Run for another 30 minutes in the microwave. Still not complete. Added 0.1 eq of Palladium(II)acetate and 0.1 eq of 2-(Dicyclohexylphosphino)biphenyl and let the reaction mixture run in the microwave for additional 45 minutes. Reaction complete. The reaction mixture was filtrated through celite and the filtrate was concentrated. The crude product was purified by preparative chromatography giving 0.072 g (41%) of the product. N-(4-(1H-imidazol-1-yl)phenyl)-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CC(OC2=C(C1)C=CC(=N2)NC3=CC=C(C=C3)N4C=CN=C4)C5=CC=CC=C5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 41.47 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/18/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "13" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000425 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" - } - amount { - moles { - value: 0.00017 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N1CC(OC2=C(C1)C=CC(=N2)Cl)C3=CN=CC=C3" - } - amount { - moles { - value: 0.000142 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 1.42e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.42e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "1-(8-chloro-2-(pyridin-3-yl)-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)ethanone (0.043 g, 0.14 mmol), Palladium(II) acetate (3.18 mg, 0.01 mmol), 2-(Dicyclohexylphosphino)biphenyl (4.96 mg, 0.01 mmol) and Cesium carbonate (0.138 g, 0.42 mmol) were placed in a microwave vial and flushed with argon. DME (2 mL) was added and the reaction mixture was run in the microwave at 100C for 60 minutes. No product according to LCMS. Added 0.1 eq of Palladium(II) acetate (3.18 mg, 0.01 mmol) and 0.1 eq of 2-(Dicyclohexylphosphino)biphenyl (4.96 mg, 0.01 mmol) and flushed with argon. Run in the microwave at 100C for 30 minutes and the reaction was complete. The reaction mixture was filtrated through celite and concentrated. The crude product was purified by prep-HPLC. The solvent was evaporated and partitioned between sat. NaHCO3 and dichloromethane. The organic layer was separated, dried (MgSO4) and concentrated giving 0.0234 g (35%) of the prod" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(CN(CC(O4)C5=CN=CC=C5)C(=O)C)C=C3)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 35.13 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/09/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "14" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000707 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000259 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CC(OC2=C(C1)C=CC(=N2)Cl)C3=CN=CC=C3" - } - amount { - moles { - value: 0.000236 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 2.36e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.36e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "[Reactants], Palladium(II) acetate (5.29 mg, 0.02 mmol), 2-(Dicyclohexylphosphino)biphenyl (8.26 mg, 0.02 mmol) and Cesium carbonate (0.230 g, 0.71 mmol) were placed in a microwave vial and flushed with argon. DME (2 mL) was added and the reaction mixture was run in the microwave at 100C for 60 minutes. Reaction not complete. Added 0.1 eq of Palladium(II) acetate (5.29 mg, 0.02 mmol) and 0.1 eq of 2-(Dicyclohexylphosphino)biphenyl (8.26 mg, 0.02 mmol) and flushed with argon. Run in the microwave at 100C for 60 minutes and the reaction was complete. The reaction mixture was filtrated through celite and concentrated. The crude product was purified by prep-HPLC. The solvent was evaporated and partitioned between sat. NaHCO3 and dichloromethane. The organic layer was separated, dried (MgSO4) and concentrated giving 0.029 g (28%) of the prod" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(CN(CC(O4)C5=CN=CC=C5)C)C=C3)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 27.8 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/09/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "17" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 8e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0025 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N" - } - amount { - moles { - value: 0.00105 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1F)Cl" - } - amount { - moles { - value: 0.001 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 8e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 4e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-chloro-4-fluoropyridine (132 mg, 1 mmol), tert-butyl carbamate (123 mg, 1.05 mmol), CESIUM CARBONATE (652 mg, 2.00 mmol) ,TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (36.6 mg, 0.04 mmol) and 9,9-DIMETHYL-4,5-BIS(DIPHENYLPHOSPHINO)XANTHENE (46.3 mg, 0.08 mmol) were suspended in 1,4-dioxane (2.5 ml) ,degased with argon andnbsp;heated to 90 C for 4 hours.After cooling the reaction wasnbsp;quenched with waternbsp;and extracted with ethyl acetate ( x 2 ). The combined organic phasesnbsp;were washed with waternbsp;, a saturated aqueous solution of brine , dried over magnesium sulfate , concentrated thennbsp;purified bynbsp;preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to affordnbsp;tert-butyl 4-fluoropyridin-2-ybamate (41.3 mg, 19.46 %)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC1=NC=CC(=C1)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 19.46 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/10/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "18" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C1CCC2=NCCCN2CC1" - } - amount { - moles { - value: 0.00151 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.12 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=CC(=C1)C=O)N" - } - amount { - moles { - value: 0.0377 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC2=NC=C(N2C=C1)C3=NC(=NC=C3Cl)Cl" - } - amount { - moles { - value: 0.0151 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00151 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000377 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "3-(2,5-dichloropyrimidin-4-yl)imidazo[1,2-a]pyridine (4 g, 15.09 mmol), 4-amino-3-methoxybenzaldehyde (2.281 g, 15.09 mmol), 9,9-DIMETHYL-4,5-BIS(DIPHENYLPHOSPHINO)XANTHENE (0.873 g, 1.51 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (0.345 g, 0.38 mmol) andnbsp;1,8-DIAZABICYCLO [5.4.0] UNDEC-7-ENE (5.64 ml, 37.72 mmol) were dissolved in Dioxane (120 ml) then degazed and purged with argon. The reaction was heated to reflux (bath 120C) for 2H30. Reaction mixture was filtered through a filter cup and concentrated. FR01132-77-01 w=14.65 gThe crude product was purified by flash chromatography (NOVASEP) on silica gel ( 15-40m ) eluting with 0 to 5% methanol in dichloromethane. The solvent was evaporated to dryness to afford 4-(5-chloro-4-(imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-ylamino)-3-methoxybenzaldehyde (34.9 %)nbsp;as a clear yellow solid.PBO-01132-77-02 w=" - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=C(C=CC(=C1)C=O)NC2=NC=C(C(=N2)C3=CN=C4N3C=CC=C4)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 34.9 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/02/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "19" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CCC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000721 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" - } - amount { - moles { - value: 0.000361 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1CC2=CC(=C(C=C2)Br)F" - } - amount { - moles { - value: 0.000397 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000162 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "[Pd]" - } - amount { - moles { - value: 0.000108 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "The aim of the reaction is testoptimization:5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (100 mg, 0.36 mmol), 4-(4-bromo-3-fluorobenzyl)morpholine (109 mg, 0.40 mmol), Palladium, 10% On Charcoal (115 mg, 0.11 mmol), racemic-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (101 mg, 0.16 mmol) and Sodium tert-pentoxide (79 mg, 0.72 mmol) were dissolved in toluene (1.5 mL) and heated to 110 C under argon.The reaction was monitorred by HPLC. After 16 h 81 % conversion was achieved. The reaction was stopped and the mixture was discarded." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=C(C=C(C=C4)CN5CCOCC5)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/28/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "20" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CCC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000721 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" - } - amount { - moles { - value: 0.000361 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1CC2=CC(=C(C=C2)Br)F" - } - amount { - moles { - value: 0.000397 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1P(C2=CC=CC=C2C)C3=CC=CC=C3C" - } - amount { - moles { - value: 0.000162 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "[Pd]" - } - amount { - moles { - value: 0.000108 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "The aim of the reaction is testoptimization:5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (100 mg, 0.36 mmol), 4-(4-bromo-3-fluorobenzyl)morpholine (109 mg, 0.40 mmol), Palladium, 10% On Charcoal (115 mg, 0.11 mmol), Tri-o-tolylphosphine (49.4 mg, 0.16 mmol) and Sodium tert-pentoxide (79 mg, 0.72 mmol) were dissolved in toluene (1.5 mL) and heated to 110 C under argon.The reaction was monitorred by HPLC. After 16 h 88 % conversion was achieved. The reaction was stopped and the mixture was discarded." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=C(C=C(C=C4)CN5CCOCC5)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/28/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "21" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CCC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000721 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" - } - amount { - moles { - value: 0.000361 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1CC2=CC(=C(C=C2)Br)F" - } - amount { - moles { - value: 0.000397 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3" - } - amount { - moles { - value: 0.000162 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "[Pd]" - } - amount { - moles { - value: 0.000108 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "The aim of the reaction is testoptimization:5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (100 mg, 0.36 mmol), 4-(4-bromo-3-fluorobenzyl)morpholine (109 mg, 0.40 mmol), Palladium, 10% On Charcoal (115 mg, 0.11 mmol), Triphenylphosphine (0.038 mL, 0.16 mmol) and Sodium tert-pentoxide (79 mg, 0.72 mmol) were dissolved in toluene (1.5 mL) and heated to 110 C under argon.The reaction was monitorred by HPLC. After 16 h 73 % conversion was achieved. The reaction was stopped and the mixture was discarded." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=C(C=C(C=C4)CN5CCOCC5)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/28/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "22" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CCC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000721 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" - } - amount { - moles { - value: 0.000361 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1CC2=CC(=C(C=C2)Br)F" - } - amount { - moles { - value: 0.000397 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 0.000162 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "[Pd]" - } - amount { - moles { - value: 0.000162 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "The aim of the reaction is testoptimization:5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (100 mg, 0.36 mmol), 4-(4-bromo-3-fluorobenzyl)morpholine (109 mg, 0.40 mmol), Palladium, 10% On Charcoal (115 mg, 0.11 mmol), (R)-(-)-1-[(S)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (91 mg, 0.16 mmol) and Sodium tert-pentoxide (79 mg, 0.72 mmol) were dissolved in toluene (1.5 mL) and heated to 110 C under argon.The reaction was monitorred by HPLC. After 16 h 79 % conversion was achieved. The reaction was stopped and the mixture was discarded." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=C(C=C(C=C4)CN5CCOCC5)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/28/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "23" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CCC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000721 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" - } - amount { - moles { - value: 0.000361 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1CC2=CC(=C(C=C2)Br)F" - } - amount { - moles { - value: 0.000397 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000162 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "[Pd]" - } - amount { - moles { - value: 0.000108 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "The aim of the reaction is testoptimization:5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (100 mg, 0.36 mmol), 4-(4-bromo-3-fluorobenzyl)morpholine (109 mg, 0.40 mmol), Palladium, 10% On Charcoal (115 mg, 0.11 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (94 mg, 0.16 mmol) and Sodium tert-pentoxide (79 mg, 0.72 mmol) were dissolved in toluene (1.5 mL) and heated to 110 C under argon.The reaction was monitorred by HPLC. After 16 h 85 % conversion was achieved. The reaction was stopped and the mixture was discarded." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=C(C=C(C=C4)CN5CCOCC5)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/28/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "24" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CCC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000721 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" - } - amount { - moles { - value: 0.000361 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1CC2=CC(=C(C=C2)Br)F" - } - amount { - moles { - value: 0.000397 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C(=CC=C1)OC)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 0.000162 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "[Pd]" - } - amount { - moles { - value: 0.000108 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "The aim of the reaction is testoptimization:5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (100 mg, 0.36 mmol), 4-(4-bromo-3-fluorobenzyl)morpholine (109 mg, 0.40 mmol), Palladium, 10% On Charcoal (115 mg, 0.11 mmol), 2-Dicyclohexylphosphino-2\',6\'-dimethoxy-1,1\'-biphenyl (66.6 mg, 0.16 mmol) and Sodium tert-pentoxide (79 mg, 0.72 mmol) were dissolved in toluene (1.5 mL) and heated to 110 C under argon.The reaction was monitorred by HPLC. After 16 h 85 % conversion was achieved. The reaction was stopped and the mixture was discarded." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=C(C=C(C=C4)CN5CCOCC5)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/28/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "25" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0117 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.024 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1OC2=C(O1)C(=C(C=C2)Cl)N" - } - amount { - moles { - value: 0.00583 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)NC1=NC=CC(=C1)Cl" - } - amount { - moles { - value: 0.00583 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000699 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000291 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Reaction carried out in two batches in 20 ml microwave tubes. 5-chlorobenzo[d][1,3]dioxol-4-amine (1 g, 5.83 mmol), N-(4-chloropyridin-2-yl)acetamide (0.994 g, 5.83 mmol), XANTPHOS (0.405 g, 0.70 mmol), PALLADIUM(II) ACETATE (0.065 g, 0.29 mmol) and CESIUM CARBONATE (3.80 g, 11.66 mmol) were suspended in 2x DMA (12mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT.nbsp;LCMS showed completion.The reaction mixture was concentrated and diluted with EtOAc , and washed sequentially with water and saturated brine. The organic layer was dried over MgSO4, filtered and evaporated. The crude oil was triturated with EtOAc, Et2O and hexane to give a solid which was collected by filtration and dried under vacuum to give P1 N-(4-(5-chlorobenzo[d][1,3]dioxol-4-ylamino)pyridin-2-yl)acetamide (680mg, 38%)as a tan solid. NMR of this product showed product plus some DMA and aromatic impurities.The filtrate from the above was concentrated and triturated again to give P2 N-(4-(5-chlorobenzo[d][1,3]dioxol-4-ylamino)pyridin-2-yl)acetamide (800mg, 45%) as a pale orange solid. NMR of this product showed it to be much cleaner than P1.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)NC1=NC=CC(=C1)NC2=C(C=CC3=C2OCO3)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 83.06 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/06/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "26" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0274 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.1 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCC2=C(C1=O)C(=CC=C2)N" - } - amount { - moles { - value: 0.0183 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C(=CN=C1Cl)Cl)I" - } - amount { - moles { - value: 0.0183 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00183 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000913 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (0.205 g, 0.91 mmol) was added to a stirred suspension of 2,5-dichloro-4-iodopyridine (5 g, 18.26 mmol), 8-amino-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (3.22 g, 18.26 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.056 g, 1.83 mmol) and cesium carbonate (8.92 g, 27.38 mmol) dissolved in 1,4-dioxane (100 mL). The resulting suspension was degassed (3 times) with nitrogen and was stirred at 100C for 16 hours. The reaction mixture was allowed to cool to room temperature, diluted with DCM (100 mL) and filtered. The residue was washed with DCM. The filtrates was combined evaporated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 0 to 10% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford 8-(2,5-dichloropyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (2.500 g, 42.5 %) as a pale yellow solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 42.5 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/09/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "27" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00329 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCC2=C(C1=O)C(=CC=C2)N" - } - amount { - moles { - value: 0.00219 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C(=CN=C1Cl)Cl)I" - } - amount { - moles { - value: 0.00219 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000219 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00011 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (24.59 mg, 0.11 mmol) was added to a stirred suspension of 2,5-dichloro-4-iodopyridine (600 mg, 2.19 mmol), 8-amino-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (386 mg, 2.19 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (127 mg, 0.22 mmol) and cesium carbonate (1071 mg, 3.29 mmol) in 1,4-dioxane (10 mL). The resulting suspension was degassed with nitrogen and was stirred at 100 C for 18 hours. Reaction was allowed to cool to room temperature, quenched with water and extracted with EtOAc. Combined organic phases were washed with water, brine, dried over MgSO4 and concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 0 to 10% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford 8-(2,5-dichloropyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (447 mg, 63.3 %) as a pale yellow crystalline solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 63.33 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/10/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "28" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0203 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.07 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCC2=C(C1=O)C(=CC=C2)N" - } - amount { - moles { - value: 0.0136 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C(=CN=C1Cl)Cl)I" - } - amount { - moles { - value: 0.0136 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00136 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000678 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (0.152 g, 0.68 mmol) was added to a stirred suspension of 2,5-dichloro-4-iodopyridine (3.71 g, 13.56 mmol), 8-amino-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (2.39 g, 13.56 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.785 g, 1.36 mmol) and cesium carbonate (6.63 g, 20.34 mmol) in 1,4-dioxane (70 mL). The resulting suspension was degassed with nitrogen and was stirred at 100 C for 18 hours. Reaction was allowed to cool to room temperature, quenched with water (100 mL) and extracted with EtOAc*. Combined organic phases were washed with water, brine, dried over MgSO4 and concentrated to dryness. The crude product was purified by flash chromatography* on silica gel eluting with 0 to 10% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford 8-(2,5-dichloropyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (2.160 g, 49.4 %) as a yellow crystalline solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 49.43 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/30/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "29" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0766 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.3 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCC2=C(C1=O)C(=CC=C2)N" - } - amount { - moles { - value: 0.0511 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C(=CN=C1Cl)Cl)I" - } - amount { - moles { - value: 0.0511 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00511 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00255 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (0.573 g, 2.55 mmol) was added to a stirred suspension of 2,5-dichloro-4-iodopyridine (13.99 g, 51.07 mmol), 8-amino-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (9 g, 51.07 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.96 g, 5.11 mmol) and cesium carbonate (24.96 g, 76.61 mmol) dissolved in 1,4-dioxane (300 mL). The resulting suspension was degassed (3 times) with nitrogen and was stirred at 100C for 16 hours. The reaction mixture was allowed to cool to room temperature, diluted with DCM (100 mL) and filtered. The residue was washed with DCM. The filtrates was combined and evaporated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 0 to 10% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford 8-(2,5-dichloropyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (9.80 g, 59.6 %) as a clear white solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 59.55 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/16/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "30" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.329 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.913 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CONC(=O)C1=CC=CC=C1N" - } - amount { - moles { - value: 0.288 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C(=CN=C1Cl)Cl)I" - } - amount { - moles { - value: 0.274 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.0205 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.0137 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2,5-dichloro-4-iodopyridine (75 g, 273.84 mmol), 2-amino-N-methoxybenzamide (47.8 g, 287.53 mmol), cesium carbonate (107 g, 328.60 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (11.88 g, 20.54 mmol) were suspended in 1,4-dioxane (913 ml). Nitrogen was bubbled through the mixture for 20 minutes then diacetoxypalladium (3.07 g, 13.69 mmol) was added. Reaction was heated to reflux overnight under nitrogen. Reaction was allowed to cool to ~50C and filtered. Filtered cake was washed with hot EtOH (2x300 mL)i. iFiltrate was concentrated to dryness to afford crude as a black solid (57 g). Filtered cake was re-washed with CH2Cl2MeOH 91 (3x300 mL). Filtrate was combined with previous crude and concentrated to dryness to afford crude as a black solid (93 g).Crude was stirred in boiling EtOH (380 mL). Insoluble was filtered =gt; iseemed to contain expected product instantaneous cristallisation occured in the filtratei. Flask was left standing overnight. Resug crystals were filtered, washed with Et2O (x2) and dried to afford 2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (33.4 g, 39.1%, EN03787-93-02) as a dark grey crystalline solid =gt; iproduct crystallised with 1eq of EtOH.iInsoluble material was washed with EtOH, CH2Cl2 and dried overnight to afford 2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (26.6 g, EN03787-93-01) =gt; inot fully soluble in DMSO, seemed contaminated by minerals. iIt was suspended in H2O (200 mL) and stirred at room temperature for 20 minutes. It was filtered, washed with EtOH (x2) and dried to afford an orange solid (3.8 g !!) =gt; inot soluble in DMSO, probably only a few expected product in it !!i" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 39.07 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/01/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "31" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0456 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.13 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CONC(=O)C1=CC=CC=C1N" - } - amount { - moles { - value: 0.0399 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C(=CN=C1Cl)Cl)I" - } - amount { - moles { - value: 0.038 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00285 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.0019 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2,5-dichloro-4-iodopyridine (10.4 g, 37.97 mmol), 2-amino-N-methoxybenzamide (6.63 g, 39.87 mmol), cesium carbonate (14.85 g, 45.57 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.648 g, 2.85 mmol) were suspended in 1,4-dioxane (130 mL). Nitrogen was bubbled through the mixture for 10 minutes then diacetoxypalladium (0.426 g, 1.90 mmol) was added. Flask was purged with nitrogen 3 times and heated to reflux for 16 hours. Reaction was allowed to cool to room temperature and diluted with CH2Cl2 (100 mL) (=gt; itroublei) + MeOH (10 mL). Mixture was filtered i(filtrate is clear)i and washed with CH2Cl2MeOH 91 (2x100 mL) =gt; ifiltrate became troubled. iFiltrate was concentrated to dryness to afford crude as a dark brown solid (17.5 g).Filtered cake seemed to contain some product. It was suspended in H2O (200 mL) and stirred for 20 minutes. It was then filtered (ilong and tricky filtration !!i). Solid was dissolved in CH2Cl2MeOH (ibig volume compare to the amount of solid !! it\'s quite insolublei), dried over MgSO4 and concentrated to dryness to afford crude product (0.5 g...) as a dark green solid.Solids were combined (18 g) and recristallised from EtOH (85 mL). Flask was left standing over the weekend. Resulting crystals were filtered, washed with Et2O and dried to afford 2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (8.20 g, 69.2 %) as a dark yellow crystalline solid =gt; iproduct crystallised with 1eq of EtOH.iFiltrate was concentrated. Residue (7.7 g) was recristallised from EtOH (30 mL). Hot solution was seeded with crystals, from 1st batch, and flask was left standing overnight. Resulting crystals were filtered, washed with Et2O and dried to afford a dark yellow crystalline solid (1.68 g, EN03787-82-02) =gt; iimpure material (see UPLCMS amp; 1H NMR 03787-82-02)i" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 69.18 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/18/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "32" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0011 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC=CC=C1N" - } - amount { - moles { - value: 0.00073 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C(=CN=C1Cl)Cl)I" - } - amount { - moles { - value: 0.00073 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.3e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.65e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-amino-N-methylbenzamide (110 mg, 0.73 mmol), 2,5-dichloro-4-iodopyridine (200 mg, 0.73 mmol), diacetoxypalladium (8.20 mg, 0.04 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (42.3 mg, 0.07 mmol) and cesium carbonate (357 mg, 1.10 mmol) suspended in 1,4-dioxane (4 mL) was weighed out in a microwave vial and sealed. argon was let to bubble into the mixture for 5 minutes at rt then the resulting mixture was stirred at 100 C for 1 hour. The reaction mixture was allowed to cool to room temperature under stirring and diluted with dichloromethane. Insolubles were removed by filtration and the filtrate was concentrated. The residue was triturated in DCM, collected by filtration and dried to afford 2-(2,5-dichloropyridin-4-ylamino)-N-methylbenzamide (150 mg, 69.4 %) as anbsp;off-white solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 69.36 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/23/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "33" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0219 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.15 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC=CC=C1N" - } - amount { - moles { - value: 0.011 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C(=CN=C1Cl)Cl)I" - } - amount { - moles { - value: 0.011 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000657 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000438 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;Palladium(II) acetate (0.098 g, 0.44 mmol) was added to 2,5-dichloro-4-iodopyridine (3 g, 10.95 mmol), 2-amino-N-methylbenzamide (1.645 g, 10.95 mmol), Cesium carbonate (7.14 g, 21.91 mmol) and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (0.380 g, 0.66 mmol) in dioxane (150 mL) under nitrogen. The resulting suspension was stirred at 80 C for 18 hours. The reaction mixture was filtered and the filtrate was evaporated to dryness. The crude residue was triturated with DCM to give a solid which was collected by filtration and dried under vacuum to give 2-(2,5-dichloropyridin-4-ylamino)-N-methylbenzamide (1.58 g, 49 %)nbsp;as a tan solid, LCMS indicated 87% pure.nbsp;This was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 2-(2,5-dichloropyridin-4-ylamino)-N-methylbenzamide (1.040 g, 32.1 %) as a yellow solid. nbsp;nbsp;nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 32.06 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/01/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "34" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[K+]" - } - amount { - moles { - value: 0.00181 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0139 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" - } - amount { - moles { - value: 0.00139 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1CC2=CC(=C(C=C2)Cl)F" - } - amount { - moles { - value: 0.00139 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.00042 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000139 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 102.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To degassed 1,4-dioxane (13.900 ml) in a flame-dried and argonflushed 50 mL roundbottomed flask were added 5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (386 mg, 1.39 mmol) and 4-(4-chloro-3-fluorobenzyl)morpholine (320 mg, 1.39 mmol) followed by POTASSIUM TERT-BUTOXIDE (203 mg, 1.81 mmol) whilst stirring. The resulting slurry was flushed with argon followed by addition of TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (128 mg, 0.14 mmol) and 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (200 mg, 0.42 mmol), whereafter the dark violet reaction mixture was again flushed with argon and heated to 102 C and stirred under argon for 15 h. The completion of the reaction was controlled by HPLC and the crude mixture was cooled to ambient temperatuer and then filtrated through Celite and washed through with dichloromethane. The solution was concentrated in vacuo and dissolved in a minimum amount of DMSO and purified via Preparative HPLC. The pooled fract were concentrated in vacuo and added HCl. 5-fluoro-N-(2-fluoro-4-(morpholinomethyl)phenyl)-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (60.0 mg, 9.15 %)nbsp;nbsp;nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=C(C=C(C=C4)CN5CCOCC5)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 9.15 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/27/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "35" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[K+]" - } - amount { - moles { - value: 0.00509 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0392 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" - } - amount { - moles { - value: 0.00388 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1CC2=CC(=C(C=C2)Cl)F" - } - amount { - moles { - value: 0.00392 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.000784 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000392 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 102.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To degassed 1,4-dioxane (39.2 ml) in a flame-dried and argonflushed 250 mL roundbottomed flask were added 5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (1.076 g, 3.88 mmol) and 4-(4-chloro-3-fluorobenzyl)morpholine (0.9 g, 3.92 mmol) followed by POTASSIUM TERT-BUTOXIDE (0.572 g, 5.09 mmol) whilst stirring. The resulting slurry was flushed with argon and stirred for 5-10 minutes followed by addition of TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.359 g, 0.39 mmol) and 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (0.374 g, 0.78 mmol), whereafter the reaction mixture was flushed with argon again and heated to 102 C and stirred under argon for 3 h. No further conversion occurred after 2 hours.The completion of the reaction was controlled by HPLC and the crude mixture was cooled to ambient temperatuer and then filtrated through Celite and washed through with dichloromethane. The solution was concentrated in vacuo and dissolved in 14 ml dichlorhane and purified by ISCO and then by prep-HPLC. The pooled fractions were concentrated in vacuo and added HCl to give 5-fluoro-N-(2-fluoro-4-(morpholinomethyl)phenyl)-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (0.227 g, 11.43 %)nbsp;nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=C(C=C(C=C4)CN5CCOCC5)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 11.43 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/03/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "36" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000736 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.000589 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN=C(S1)N" - } - amount { - moles { - value: 0.000441 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C[C@@H](C1=NC=C(C=N1)F)NC2=NC(=NC(=N2)Cl)N3CCOCC3" - } - amount { - moles { - value: 0.000294 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 2.94e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.47e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 95.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(S)-4-chloro-N-(1-(5-fluoropyrimidin-2-yl)ethyl)-6-morpholino-1,3,5-triazin-2-amine (100 mg, 0.29 mmol), 5-methylthiazol-2-amine (50.4 mg, 0.44 mmol), BINAP (18.33 mg, 0.03 mmol), Pd2(dba)3 (13.48 mg, 0.01 mmol) and Cs2CO3 (240 mg, 0.74 mmol) were combined in a microwave reaction tube and vacuum purged.nbsp;The tube was then charged with nitrogen and dioxane (0.589 mL) was added.nbsp;The tube was then evacuated again and placed under a nitrogen balloon for 8 hours.nbsp;LCMS confirmed formation of the product (m+1 = 418) at t= 2.07 min.nbsp;The reaction mixture was concentrated in vacuo leaing a brown solid (472 mg).nbsp;This material was the redissolved in EtOAc, filtered through Celite, washed with water and dried with Na2SO4.nbsp;Concentration in vacuo gave a rust solid (272 mg).nbsp;This material was purified by ISCO (0-10% MeOHDCM).nbsp;Concentration of the fractions in vacuo gave an orange oil.nbsp;This material was then repurifed by ISCO (4-8% MeOHDCM) and (0-4% MeOHDCM).nbsp;Both gradients resulted in impure material, so the recovered orange oil was purified again by ISCO (60-100% EtOAcHex).nbsp;Concentration in vacuo gave a yellow solid (34.8 mg).nbsp;LCMS showed this material to still be only 80% pure, so it was purified again by ISCO (55-95% EtOAcHex).nbsp;A yellow solid (25.4 mg) was again collected.nbsp;Although LCMS and HPLC showed this material to be only ~80% pure, the NMR confirmed this material to be the desired product, (S)-N2-(1-(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methylthiazol-2-yl)-6-morpholino-1,3,5-triazine-2,4-diamine, with 95% purity.nbsp;1H NMR (300 MHz, CHLOROFORM-idi) d ppm 11.87 (br. s., 1 H) 9.48 (br. s., 1 H) 8.58 (s, 2 H) 7.01 (s, 1 H) 5.35 (t, 1 H) 3.28 - 4.23 (m, 8 H) 2.38 (s, 3 H) 1.59 (d, 4 H)nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN=C(S1)NC2=NC(=NC(=N2)N3CCOCC3)N[C@@H](C)C4=NC=C(C=N4)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 20.67 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/28/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "37" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 8.37e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1N)C" - } - amount { - moles { - value: 0.0014 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C#N)Cl" - } - amount { - moles { - value: 0.000698 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 8.37e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 5.58e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-(2-chloro-5-cyanopyridin-4-ylamino)-N-methylbenzamide (200 mg, 0.70 mmol), Palladium(II) acetate (12.53 mg, 0.06 mmol), 1,3-dimethyl-1H-pyrazol-4-amine (155 mg, 1.40 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (48.4 mg, 0.08 mmol) and Cesium carbonate (273 mg, 0.84 mmol) were suspended in dioxane (5 mL)nbsp;into a test tube.nbsp;The reaction was purged for 5 mins with nitrogen and then heated to 90 C for 24 hours with stirring.nbsp;The reaction was cooled to cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desirednbsp;crude product was eluted from the column using 7M NH3MeOH andnbsp;fractions were evaporated to dryness to afford crude product .The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dr afford 2-(5-cyano-2-(1,3-dimethyl-1H-pyrazol-4-ylamino)pyridin-4-ylamino)-N-methylbenzamide (126 mg, 50.0 %) as a beige solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NC)C#N)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 49.98 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/07/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "39" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 4.19e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C(=CC(=N1)OC)N" - } - amount { - moles { - value: 0.000698 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C#N)Cl" - } - amount { - moles { - value: 0.000349 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 4.19e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.79e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-(2-chloro-5-cyanopyridin-4-ylamino)-N-methylbenzamide (100 mg, 0.35 mmol), Palladium(II) acetate (6.26 mg, 0.03 mmol), [Reactants], 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (24.22 mg, 0.04 mmol) and Cesium carbonate (136 mg, 0.42 mmol) were suspended in dioxane (3 mL)nbsp;into a test tube.nbsp;The reaction was purged for 5 mins with nitrogen and then heated to 90 C for 18 hours with stirring.nbsp;The reaction was cooled to cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desirednbsp;crude product was eluted from the column using 7M NH3MeOH andnbsp;fractions were evaporated to dryness to afford crude product .The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-(5-cyano-2-(3-methoxy--1H-pyrazol-5-ylamino)pyridin-4-ylamino)-N-methylbenzamide (72.0 mg, 54.7 %) as a beige solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C#N)NC3=CC(=NN3C)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 54.7 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/07/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "43" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000228 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.04 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1N)C" - } - amount { - moles { - value: 0.0038 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3C#N)Cl" - } - amount { - moles { - value: 0.0019 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000228 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000152 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "6-chloro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-8-ylamino)nicotinonitrile (595 mg, 1.90 mmol), Palladium(II) acetate (34.2 mg, 0.15 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (132 mg, 0.23 mmol), 1,3-dimethyl-1H-pyrazol-4-amine (423 mg, 3.80 mmol) and Cesium carbonate (744 mg, 2.28 mmol) were suspended in dioxane (40 mL).nbsp;The reaction was purged for 5 mins with nitrogen and then heated to 90 C for 2 hour with stirring.nbsp;The reaction was cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desired crude product was eluted from the column using 7M NH3MeOH andnbsp;fractions were evaporated to dryness to afford crude product .The crude product was purified by preparative basic HPLC. Fractions containing the desired compound were evaporated to dryness to afford 6-(1,3-dimethyl-1H-pyrazol-4-ylamino)-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-8-ylamino)nicotinonitrile (54.0 mg, 7.33 %) as a beige solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC4=C3C(=O)N(CC4)C)C#N)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 7.33 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/21/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "45" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)[O-].[Na+]" - } - amount { - moles { - value: 0.00016 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.001 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1N)C" - } - amount { - moles { - value: 0.00032 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3C#N)Cl" - } - amount { - moles { - value: 0.00016 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 2e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.28e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "1,3-dimethyl-1H-pyrazol-4-amine (35.5 mg, 0.32 mmol), 6-chloro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-8-ylamino)nicotinonitrile (50 mg, 0.16 mmol)sodium phenolate (18.56 mg, 0.16 mmol),(R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (8.74 mg, 0.02 mmol) and diacetoxypalladium (2.87 mg, 0.01 mmol) were suspended in DME (1 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT. LCMS indicated 47% product, ~8% dimer, ~8% hydrolysed Starting material , Starting material 25% and an unknown 17% @ 2.66 and unknown 12% @ 0.77.Sample combined with en01521-027 and en01521-034, SCX\'d and sent to purification group. The crude product was purified by preparative basic HPLC. Fractions containing the desired compound were evaporated to dryness to afford 6-(1,3-dimethyl-1H-pyrazol-4-ylamino)-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-8-ylamino)nicotinonitrile (34.0 mg, 54.9 %) as a brownid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC4=C3C(=O)N(CC4)C)C#N)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 54.89 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/12/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "46" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00192 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1N)C" - } - amount { - moles { - value: 0.00319 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3C#N)Cl" - } - amount { - moles { - value: 0.0016 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 0.00016 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00016 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "1,3-dimethyl-1H-pyrazol-4-amine (355 mg, 3.19 mmol), 6-chloro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-8-ylamino)nicotinonitrile (500 mg, 1.60 mmol), Cesium carbonate (625 mg, 1.92 mmol), Palladium(II) acetate (28.7 mg, 0.13 mmol)and (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (87 mg, 0.16 mmol) were suspended in DME (10 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness. The crude product was handed to the purification group and purified by basic preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford 6-(1,3-dimethyl-1H-pyrazol-4-ylamino)-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-8-ylamino)nicotinonitrile (271 mg, 43.8 %) as a brown solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC4=C3C(=O)N(CC4)C)C#N)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 43.75 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/13/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "49" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00192 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1N)C" - } - amount { - moles { - value: 0.0032 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3C#N)Cl" - } - amount { - moles { - value: 0.0016 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 0.00016 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00016 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "6-chloro-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-8-ylamino)nicotinonitrile (500 mg, 1.60 mmol), 1,3-Dimethyl-1H-pyrazol-4-ylamine (355 mg, 3.20 mmol) and Cesium carbonate (625 mg, 1.92 mmol), Palladium(II) acetate (28.7 mg, 0.13 mmol) and (R)-(-)-1-[(S)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (90 mg, 0.16 mmol) were suspended in DME (10 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT.nbsp;This was combined with reactions EN01370-84-87 and concentrated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM.nbsp;Mixed fractions were combined and re-columned. This prcess was repeated a further 3 times! quot;Purequot; fractions were combined and evaporated to dryness to afford 6-(1,3-dimethyl-1H-pyrazol-4-ylamino)-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-8-ylamino)nicotinonitrile (484 mg, 15.63 %) as a yellow solid (1.08g) - 100% by LCMS anean by TLC but the NMR is not great. Passed onto the purification group.The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the required product.200mg trial purification - resulted in 137mg pure - EN01370-88-1Rest of the material processed to give EN01370-88-2 (347mg and 177mg) " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC4=C3C(=O)N(CC4)C)C#N)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 15.63 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/24/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "50" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C1CCC2=NCCCN2CC1" - } - amount { - moles { - value: 5.09e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.001 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CC1C(=O)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000509 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1OC2=C(C(=CN=C2O1)Cl)N" - } - amount { - moles { - value: 0.00061 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 5.09e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" - } - amount { - moles { - value: 4.58e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 130.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.190 mL, 1.27 mmol) was added to a mixture of N-(4-chloropyridin-2-yl)cyclopropanecarboxamide (100 mg, 0.51 mmol), 6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-amine (105 mg, 0.61 mmol) and BIS(DIBENZYLIDENEACETONE)PALLADIUM(0) (26.3 mg, 0.05 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (29.4 mg, 0.05 mmol) in toluene (1 mL) in a microwave tube. The reaction was degased, purged with argon and heated to 130 C over a period of 7 hours in an oil bath. The mixture was diluted with dichloromethane, washed with water (emulsion), with brine, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 3% methanol in dichloromethane. The solvent was evaporated to dryness to afford N-(4-(6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-ylamino)pyridin-2-yl)cyclopropanecarboxamide (55.0 mg, 32.5 %) as a yellow solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CC1C(=O)NC2=NC=CC(=C2)NC3=C4C(=NC=C3Cl)OCO4" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 32.5 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/11/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "51" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0407 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.075 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CC1C(=O)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.0203 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1OC2=C(C(=CN=C2O1)Cl)N" - } - amount { - moles { - value: 0.0203 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00244 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00102 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "N-(4-chloropyridin-2-yl)cyclopropanecarboxamide (4 g, 20.34 mmol), 6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-amine (3.51 g, 20.34 mmol),nbsp;(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.412 g, 2.44 mmol), diacetoxypalladium (0.228 g, 1.02 mmol) and cesium carbonate (13.26 g, 40.68 mmol) were suspended in 1,4-dioxane (75 mL) and sealed into 5 microwave tubes. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT. The reaction mixture was diluted with EtOAc (250 mL) and washed with water (250 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford and orange gum.nbsp;The gum was dissolved in a little ether, then isohexane was added to precipitate N-(4-(6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-ylamino)pyridin-2-yl)cyclopropanecarboxamide (2.180 g, 32.2 %) as a e solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CC1C(=O)NC2=NC=CC(=C2)NC3=C4C(=NC=C3Cl)OCO4" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 32.21 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/24/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "52" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00814 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CC1C(=O)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.00407 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1OC2=C(C(=CN=C2O1)Cl)N" - } - amount { - moles { - value: 0.00407 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000488 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000203 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "N-(4-chloropyridin-2-yl)cyclopropanecarboxamide (0.8 g, 4.07 mmol), 6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-amine (0.702 g, 4.07 mmol),nbsp;(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.282 g, 0.49 mmol), diacetoxypalladium (0.046 g, 0.20 mmol) and cesium carbonate (2.65 g, 8.14 mmol) were suspended in 1,4-dioxane (15 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT. The reaction mixture was evaporated and partitioned between EtOAc (50 mL) and water (50 mL).nbsp;The mixture was filtered and the organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford N-(4-(6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-ylamino)pyridin-2-yl)cyclopropanecarboxamide (0.384 g, 28.4 %) as a white solid. Impure fractions were combined and purified by flash silicromatography, elution gradient 0 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford more crude material.nbsp;This material was triturated with DCM to afford a second batch of the material." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CC1C(=O)NC2=NC=CC(=C2)NC3=C4C(=NC=C3Cl)OCO4" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 28.37 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/17/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "55" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0127 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.018 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CC1C(=O)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.00509 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1OC2=C(C(=CN=C2O1)Cl)N" - } - amount { - moles { - value: 0.00509 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000559 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.0004 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of N-(4-chloropyridin-2-yl)cyclopropanecarboxamide (1 g, 5.09 mmol), 6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-amine (0.878 g, 5.09 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.324 g, 0.56 mmol), diacetoxypalladium (0.090 g, 0.40 mmol), cesium carbonate (4.14 g, 12.71 mmol) and dioxane (18 mL) was degased, purged (x3) with argon and heated to reflux over a period of 4 hours in an oil bath (110C). The reaction was complete. The reaction mixture was allowed to warm to room temperature diluted with water (25ml), a saturated solution of NH4Cl (35ml). Extraction with dichloromethane (x2), the organic was washed with a saturated aqueous solution of brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 2% methanol in dichloromethane. The solvent was evaporated, the product was diluted in dichloromethane. The solution was filtered through PTFE filter 0.45m, the filtrate was conceno dryness to afford N-(4-(6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-ylamino)pyridin-2-yl)cyclopropanecarboxamide (1.200 g, 70.9 %) as anbsp;white crystalline solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CC1C(=O)NC2=NC=CC(=C2)NC3=C4C(=NC=C3Cl)OCO4" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 70.91 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/17/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "56" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00814 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CC1C(=O)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.00407 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1OC2=C(C(=CN=C2O1)Cl)N" - } - amount { - moles { - value: 0.00407 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000488 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000203 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "N-(4-chloropyridin-2-yl)cyclopropanecarboxamide (0.8 g, 4.07 mmol), 6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-amine (0.702 g, 4.07 mmol),nbsp;(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.282 g, 0.49 mmol), diacetoxypalladium (0.046 g, 0.20 mmol) and cesium carbonate (2.65 g, 8.14 mmol) were suspended in 1,4-dioxane (15 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford N-(4-(6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-ylamino)pyridin-2-yl)cyclopropanecarboxamide (0.592 g, 43.7 %) as a white solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CC1C(=O)NC2=NC=CC(=C2)NC3=C4C(=NC=C3Cl)OCO4" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 43.73 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/27/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "58" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00742 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.025 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCN1CCNCC1" - } - amount { - moles { - value: 0.00742 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1C2=CC(=O)C3=C(O2)C(=CC=C3)C4=C5C(=C(C=C4)I)C6=CC=CC=C6S5" - } - amount { - moles { - value: 0.00371 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000742 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000742 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "8-(1-iododibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (2 g, 3.71 mmol), 2,2\'-BIS(DIPHENYLPHOSPHINO)-1,1\'-BINAPHTHYL (0.462 g, 0.74 mmol), CESIUM CARBONATE (3.62 g, 11.12 mmol) and PALLADIUM (II) ACETATE (0.166 g, 0.74 mmol) were weighed out in a flask and inerted with argon. toluene (25 ml) and 1-ethylpiperazine (0.942 ml, 7.42 mmol) were added and the mixture was degassed several times with argon. The reaction was stirred at 110 C (bath) for 2 hours.The reaction was incomplete. 2,2\'-BIS(DIPHENYLPHOSPHINO)-1,1\'-BINAPHTHYL (0.462 g, 0.74 mmol) and PALLADIUM (II) ACETATE (0.166 g, 0.74 mmol) were added, the reaction mixture was purged with argon, and the mixture was stirred at 110 C for 5 hours. Reaction was quite clean: Crude LCMS showed very little de-iodo by-product and starting material left.The reaction was diluted with dichloromethane and insolubles were removed by filtration. The filtrate was concentrated to dryness. The crude product was purified by flash chrphy on silica gel eluting with 0 to 5% methanol in dichloromethane. The solvent was evaporated, the resulting solid was stirred in diethyl ether (40 ml) for 2 days. The product was filtered to give a solid which was collected by filtration and dried under vacuum to give 8-(1-(4-ethylpiperazin-1-yl)dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (0.950 g, 48.7 %) as a pale beige solid.Melting point: 221-224CPurity check: 99%, Et2O: 0.06 molemole, H2O: 0.3 molemoleH NMR strength: 97% +- 3%nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCN1CCN(CC1)C2=C3C4=CC=CC=C4SC3=C(C=C2)C5=CC=CC6=C5OC(=CC6=O)N7CCOCC7" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 48.74 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/22/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "60" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 5.56e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.00025 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCN1CCNCC1" - } - amount { - moles { - value: 7.42e-05 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1C2=CC(=O)C3=C(O2)C(=CC=C3)C4=C5C(=C(C=C4)I)C6=CC=CC=C6S5" - } - amount { - moles { - value: 3.71e-05 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.71e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 9.27e-07 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 130.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "8-(1-iododibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one (20 mg, 0.04 mmol), 1-ethylpiperazine (9.42 l, 0.07 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.145 mg, 3.71 mol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (0.849 mg, 0.93 mol) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (16.62 l, 0.11 mmol) were suspended in dioxane (250 l) and sealed into a microwave tube. The reaction was degased, purged with argon and heated to 130 C over a period of 45 minutes in the microwave reactor. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCN1CCN(CC1)C2=C3C4=CC=CC=C4SC3=C(C=C2)C5=CC=CC6=C5OC(=CC6=O)N7CCOCC7" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/16/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "61" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0155 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.2 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.129 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)Br)[N+](=O)[O-]" - } - amount { - moles { - value: 0.129 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.0155 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.0103 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;4-bromo-1-methoxy-2-nitrobenzene (30 g, 129.29 mmol), 1-(piperazin-1-yl)ethanone (16.57 g, 129.29 mmol), cesium carbonate (84 g, 258.59 mmol),diacetoxypalladium (2.322 g, 10.34 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (8.98 g, 15.52 mmol) in dioxane (200 mL) were degazed with nitrogen and stirred at 100C for 1 hour.nbsp;The reaction mixture was allowed to cool to room temperature, water (1000mL) was added and mixture was filtered on celite.nbsp;The aq. layer was extracted with CH2Cl2 (2X500mL). The organic layer was dried on MgSO4, filtered and concentrated to dryness to afford the crude product. This product was purified by flash chromatography on silica gel eluting with ethyl acetate - methanol (92-8), the solvents were evaporated to dryness to afford 1-(4-(4-methoxy-3-nitrophenyl)piperazin-1-yl)ethanone (10.80 g, 29.9 %)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)OC)[N+](=O)[O-]" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 29.91 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "12/18/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "62" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00931 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.12 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.0776 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)Br)[N+](=O)[O-]" - } - amount { - moles { - value: 0.0776 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00931 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00621 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "1-(piperazin-1-yl)ethanone (9.94 g, 77.58 mmol), Cesium carbonate (50.6 g, 155.15 mmol), XANTPHOS (5.39 g, 9.31 mmol) and Pd(OAc)2 (1.393 g, 6.21 mmol) were added to a stirred solution of 4-bromo-1-methoxy-2-nitrobenzene (18 g, 77.58 mmol) dissolved in dioxane (120 ml). The resulting suspension was heated to 120 C (bath) over a period of 1 hour. The reaction mixture was allowed to cool and the residual cesium carbonate was removed by filtration through a pad of Dicalite speed plus, washing with dichloromethane. The solvent was removed under reduced pressure to give a dark oil. PBO-02628-53-01 w= 45 gThe crude product in solution in DCM was added to a silica gel column and was eluted with methanol 0 to 20% in EtOAc (NOVASEP). Collected fractions to dryness to afford 1-(4-(4-methoxy-3-nitrophenyl)piperazin-1-yl)ethanone (17.96 g, 83 %) as a yellow solid. PBO-02628-53-02 nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)OC)[N+](=O)[O-]" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 82.89 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/25/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "63" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000776 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00646 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)Br)[N+](=O)[O-]" - } - amount { - moles { - value: 0.00646 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000776 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000517 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "4-bromo-1-methoxy-2-nitrobenzene (1.5 g, 6.46 mmol), 1-(piperazin-1-yl)ethanone (0.829 g, 6.46 mmol), CESIUM CARBONATE (4.21 g, 12.93 mmol), XANTPHOS (0.449 g, 0.78 mmol) and PdOAc2 (0.116 g, 0.52 mmol) were suspended in dioxane (20 ml) and sealed into a microwave tube. The reaction was heated to 120 C for 90 minutes in the microwave reactor and cooled to RT.nbsp;The reaction mixture was filtered through celite with ethyl acetate (50 mL).nbsp;The filtrate was evaporated to dryness.nbsp;The crude product was purified by flash silica chromatography in EtOAc. Pure fractions were evaporated to dryness to afford 1-(4-(4-methoxy-3-nitrophenyl)piperazin-1-yl)ethanone (0.022 g, 1.218 %) as a brown solid.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)OC)[N+](=O)[O-]" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 1.22 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/06/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "64" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000776 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00646 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)Br)[N+](=O)[O-]" - } - amount { - moles { - value: 0.00646 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000776 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000517 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "4-bromo-1-methoxy-2-nitrobenzene (1.5 g, 6.46 mmol) was added in one portion to 1-(piperazin-1-yl)ethanone (0.829 g, 6.46 mmol), CESIUM CARBONATE (4.21 g, 12.93 mmol), XANTPHOS (0.449 g, 0.78 mmol) and PdOAc2 (0.116 g, 0.52 mmol) in dioxane (20 ml) under nitrogen. The resulting mixture was stirred at 120 C for 3 hours.nbsp;The reaction mixture was filtered through celite and the fitrate evaporated to dryness. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 1-(4-(4-methoxy-3-nitrophenyl)piperazin-1-yl)ethanone (0.025 g, 1.385 %) as a brown oil. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)OC)[N+](=O)[O-]" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 1.38 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/08/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "65" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 9.61e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1N)C" - } - amount { - moles { - value: 0.0012 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" - } - amount { - moles { - value: 0.000801 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 9.61e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 6.41e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (250 mg, 0.80 mmol), 1,3-dimethyl-1H-pyrazol-4-amine (134 mg, 1.20 mmol), Sodium tert-butoxide (115 mg, 1.20 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (55.6 mg, 0.10 mmol) and BIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (58.7 mg, 0.06 mmol) were suspended in dioxane (15 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT. Reaction not complete by LCMS so more 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (55.6 mg, 0.10 mmol), BIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (58.7 mg, 0.06 mmol) and 1,3-dimethyl-1H-pyrazol-4-amine (134 mg, 1.20 mmol) were added and the reaction heated to 150 C for a further 30 minutes in the microwave reactor and cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness to afford crude as a tan gum. The sample was given to the purification group for purification by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford 2-(5-chloro-2-(1,3-dimethyl-1H-pyrazol-4-ylamino)pyridin-4-ylamino)-N-methoxybenzamide (44.3 mg, 14.30 %) as a tan solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)Cl)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 14.3 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/02/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "66" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00248 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1CNCC(N1)C" - } - amount { - moles { - value: 0.000248 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=CC(=C1)Br)NC2=NC=C(C(=N2)C3=CN=C4N3C=CC=C4)Cl" - } - amount { - moles { - value: 0.000248 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 9.94e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.97e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 140.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "N-(4-bromo-2-methoxyphenyl)-5-chloro-4-(imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-amine (107 mg, 0.25 mmol), 2,6-dimethylpiperazine (28.4 mg, 0.25 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (5.75 mg, 9.94 mol), diacetoxypalladium (1.116 mg, 4.97 mol) and cesium carbonate (162 mg, 0.50 mmol) were suspended in 1,4-dioxane (2 mL) . The reaction was purged with nitrogen and heated to 140 C for 6 hours in an oil bath. Control LCMS : no traces of expected " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1CN(CC(N1)C)C2=CC(=C(C=C2)NC3=NC=C(C(=N3)C4=CN=C5N4C=CC=C5)Cl)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/28/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "67" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000521 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.05 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)N)OC" - } - amount { - moles { - value: 0.00521 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN=C(N=C1C2=CN(C3=CC=CC=C32)S(=O)(=O)C4=CC=CC=C4)Cl" - } - amount { - moles { - value: 0.00521 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000521 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000261 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Cesium carbonate (2.55 g, 7.82 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.301 g, 0.52 mmol) and diacetoxypalladium (0.058 g, 0.26 mmol) were added to a stirred suspension of 3-(2-chloro-5-methylpyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (2 g, 5.21 mmol) and 1-(4-(4-amino-3-methoxyphenyl)piperazin-1-yl)ethanone (1.299 g, 5.21 mmol) in 1,4-dioxane (50 ml). The resulting suspension was degassed with argon and stirred at 90 C for 2 hours.After cooling, the mixture was filtered through a pad of Dicalite speed plus and washed with dichloromethane. The solvent were evaporated. PBO-01132-93-01The crude product was purified by flash chromatography on silica gel (Merck cartrige SVP D40 - SI60 16-40m - 90g) eluting with 0 up to 100% EtOAc in dichloromethane . The 1-(4-(3-methoxy-4-(5-methyl-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (1.760 g, 56.6 %) was obtained as a yellow oil. PBO-01132-93-02An impure batch wned. PBO-01132-93-03nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN=C(N=C1C2=CN(C3=CC=CC=C32)S(=O)(=O)C4=CC=CC=C4)NC5=C(C=C(C=C5)N6CCN(CC6)C(=O)C)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 56.61 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/11/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "70" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000289 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0018 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" - } - amount { - moles { - value: 0.000184 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1CC2=CC=C(C=C2)Br" - } - amount { - moles { - value: 0.000199 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 8.81e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 4.91e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "The aim of the reaction is optimization.Tris(dibenzylideneacetone)dipalladium(0) (4.5 mg, 4.91 mol) and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (5.1 mg, 8.81 mol) were dissolved in dioxane (1.8 mL) in a 10 mL Schlenk tube and activated at 100 C for 6 min under argon. Then 5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (51 mg, 0.18 mmol), 4-(4-bromobenzyl)morpholine (51 mg, 0.20 mmol) and Cesium carbonate (94 mg, 0.29 mmol) were added. It was degassed again and stirred at 100 C under argon.The reaction was followed by HPLC. After 26 h 85.5 % conversion was obtained. 20 % by-product formation was detected.Finally, the reaction mixture wa" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=CC=C(C=C4)CN5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/03/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "71" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CCC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0576 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.36 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" - } - amount { - moles { - value: 0.036 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1CC2=CC=C(C=C2)Br" - } - amount { - moles { - value: 0.037 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000648 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.00054 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Tris(dibenzylideneacetone)dipalladium(0) (0.494 g, 0.54 mmol) and9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (0.375 g, 0.65 mmol)nbsp;were dissolved in toluene (160 mL) in a 1 L reactor equipped with a condensor and activated at 100 C for 6 min under argon. Then 5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (9.98 g, 36 mmol), 4-(4-bromobenzyl)morpholine (9.48 g, 37 mmol), Sodium tert-pentoxide (6.34 g, 57.60 mmol) and toluene (200 mL) were added. The reaction mixture became sticky yellowish green. It was stirred at 100 C under argon. The reaction was followed by HPLC. After 3 h no conversion was obtained. The mixture was stirred overnight but the conversion did not move. Then the mixture was cooled to 50 C, Pd-complex (5 mol%) and Xantphos (6 mol%) as preactivated catalyst in toluene (100 ml) were added to the mixture, it was degassed carefully, then it was put under argon. Then the reaction mixture was heated at 100 C. After 1 h fas detected.The reaction mixture was cooled to room temperature, diluted with dichloromethane (600 mL), extracted with water (4*500 mL), washed with brine (1*500 mL) and dried over Na2SO4. Filtration and concentration afforded orange brown solid. This solid was slurried in EtOAc ( 50 mL) and stirred at reflux point (78 C) for 10 min. Then it was cooled to room temperature with stirring and filtered. The filtercake was washed with ini-pentane (80 mL). Orange filtercake was obtained which still had some impurity.The above obtained orange filtercake was slurried in EtOAc (80 mL) and stirred at 80 C for 30 min. Then it was cooled to room t emperature and the precipitation was filtered. Yellow fine powder was obtai" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=CC=C(C=C4)CN5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 53.72 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/09/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "72" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CCC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0741 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.3 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" - } - amount { - moles { - value: 0.0463 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1CC2=CC=C(C=C2)Br" - } - amount { - moles { - value: 0.0532 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00446 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.00186 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Tris(dibenzylideneacetone)dipalladium(0) (1.703 g, 1.86 mmol) and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (2.58 g, 4.46 mmol) were dissolved in toluene (50 ml) in a 500 mL two-necked round-bottomed flask equipped with a condensor and activated at 50 C for 40 min under argon. 5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (12.84 g, 46.30 mmol), 4-(4-bromobenzyl)morpholine (13.64 g, 53.25 mmol), Sodium tert-pentoxide (8.16 g, 74.09 mmol) and extra toluene (250 mL) were added. The total volume of the reaction mixture was deoxygenized carefully by switching vacuum-argon 10-times and heated to 110 C under argon. After 10 min the mixture turned into green. The reaction was monitored by HPLC, after 22 h only ca 65 %. The reactuion was stopped and the mixture was cooled to room temperature. Toluene was removed in vacuo. The residual was dissolved in dichloromethane ( 1.2 L) and extracted with water (2*1 L). The aqueous phase was extracted with EtOAc. The combined orange organic phases were filtered through a celitepad and concetrated in vacuo. Dark orange brown sticky gum was obtained which solidified over 2 weeks.This solid was slurried in EtOAc (60 mL) at reflux point for 1 h, then it was cooled to rt slowly with vigorous stirring. Filtration afforded a light yellow solid and an orange filtrate.0.5 g of the filtercake was purified by preparative HPLC, it afforded 303 mg light yellow solid which was mitted to PARD directly (EN01460-38-001).1.8 g of the filtercake was purified by preparative HPLC, it afforded 1.02 g light yellow solid and 1.015 g was mitted to PARD directly in a standard bascoded bottle (EN01460-38-002) (barcode: 30152995).The residual material was used for recrystallization studies in the RSL group." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=CC=C(C=C4)CN5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 6.31 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/02/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "80" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CCC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000294 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CCCCOC(=O)C" - } - amount { - volume { - value: 0.0018 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" - } - amount { - moles { - value: 0.000184 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1CC2=CC=C(C=C2)Br" - } - amount { - moles { - value: 0.000193 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 9.2e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 4.91e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Tris(dibenzylideneacetone)dipalladium(0) (4.5 mg, 4.91 mol) and 2-Dicyclohexylphosphino-2\',4\',6\'-triisopropylbiphenyl (4.38 mg, 9.20 mol) were dissolved in butyl acetate (1.8 mL) in a 10 mL Schlenk tube and activated at 100 C for 6 min under argon. Then 5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (51 mg, 0.18 mmol), 4-(4-bromobenzyl)morpholine (49.5 mg, 0.19 mmol) and Sodium tert-pentoxide (32.4 mg, 0.29 mmol) were added. It was degassed again and stirred at 100 C under argon.The reaction was followed by HPLC. After 4.5 h no conversion was observed. Hence the whole reaction mixture wa" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=CC=C(C=C4)CN5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/07/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "81" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CCC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 6.48e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.035 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" - } - amount { - moles { - value: 0.0036 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1CC2=CC=C(C=C2)Br" - } - amount { - moles { - value: 0.00378 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 6.48e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 5.4e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Tris(dibenzylideneacetone)dipalladium(0) (0.049 g, 54 mol) and9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (0.037 g, 0.06 mmol)nbsp;were dissolved in toluene (15 mL) in a 50 mL two-necked round-bottomed flask equipped with a condensor and activated at 100 C for 6 min under argon. Then 5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (0.998 g, 3.6 mmol), 4-(4-bromobenzyl)morpholine (0.968 g, 3.78 mmol), Sodium tert-pentoxide (0.634 g, 5.76 mmol) and toluene (20 mL) were added. The reaction mixture became sticky yellowish green maybe by addition of the base. It was degassed carefully and stirred at 100 C under argon. In 1 hour the sticky mixture turned from yellowish green into orange brown muddy mixture. The reaction was followed by HPLC. After 22 h 98 % conversion was obtained. Then it was cooled to rt and filtered. The obtained dark brown crapy filtercake was discarded. The brown filtrate was diluted with dichloromethane (80 mL), extracted 3*100 mL), washed with brine (1*100 mL) and dried over Na2SO4. Filtration and concentration afforded orange solid (1.400 g). To this orange solid EtOAcnbsp;(7 mL) was added and heat to 80 C. At 60 C it started to form light precipitation. Extra EtOAc (10 mL) was added and stirred at 80 C for 10 min. Then it was cooled to rt with a continuous stirring. The light precipitation was filtered off, washed with EtOAc (7 mL) and ini-pentane (15 mL), and dried in vacuo. Light yellow powder was o" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=CC=C(C=C4)CN5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 33.82 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/08/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "86" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CCC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.208 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 1.0 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" - } - amount { - moles { - value: 0.13 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1CC2=CC=C(C=C2)Br" - } - amount { - moles { - value: 0.136 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00234 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.00195 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Tris(dibenzylideneacetone)dipalladium(0) (1.786 g, 1.95 mmol) and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (1.354 g, 2.34 mmol)nbsp;were dissolved in toluene (40 mL) in a 100 mL two-necked round-bottomed flask equipped with a condensor and activated at 50 C for 30 min under argon. In a 2 L reactor 5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (36.0 g, 130 mmol), 4-(4-bromobenzyl)morpholine (34.8 g, 136 mmol), Sodium tert-pentoxide (22.91 g, 208.00 mmol) were dissolved in degassed toluene (960 mL) by heating at 100 C. The preactivated catalyst solution was added to the mixture. It was put under nitrogen atmosphere carefully and stirred at 100 C. The reaction was monitored by HPLC. After 20 h 38 % conversion was obtained. An extra batch of preactivated catalyst (3 %) in toluene (40 mL) was added and the mixture was stirred at 100 C under nitrogen. After 52 h 92 % conversion was detected.Then the reaction mixture was cooledture, diluted with DCM (8 L) and extracted with water (3*5L). The separated organic phase was washed with brine and dried over Na2SO4. Filtration and concentration afforded orange solid which was slurried in EtOAc (100 mL) and stirred at reflux point for 30 min. Then it was cooled to room temperature and filtered. Yellow filtercake was obtained which was washed with EtOAc (150 ml). It was reslurried in EtOAc (100 mL) and stirred at reflux point for 30 min. Then it was cooled to room temperature and filtered. The filtercake was washed with EtOAc (150 ml) and dried in vacuo. Light yellow fine powder was obtained." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=CC=C(C=C4)CN5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 79.28 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/16/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "87" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CCC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00146 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.0017 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)N" - } - amount { - moles { - value: 0.001 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1CC2=CC=C(C=C2)Br" - } - amount { - moles { - value: 0.0011 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 0.01 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "The aim of the reaction is only optimization and test. The reaction described below was carried out under argon atmosphere.Palladium(II) acetate (2.245 mg, 10.00 mol) and (R)-(-)-1-[(S)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (5.61 mg, 10.00 mol) were mixed in DME (0.2 mL) in a 1.4 ml vial under argon and stirred for 1 minute at room temperature.The orange pre-mixed Pd-catalyst solution were added to a 10 mL Schlenk-tube containing 4-(4-bromobenzyl)morpholine (0.282 g, 1.1 mmol) and Sodium tert-pentoxide (0.161 g, 1.46 mmol) in DME (1.5 mL). Finally, 5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (0.277 g, 1 mmol) was added and the bright orange reaction mixture was stirred at 90 C.The mixture turned from bright orange into bright yellow in 1 h. The reaction was followed by HPLC. No reaction took place, hence the mixture was di" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC=C(N1C2CCOCC2)C3=NC(=NC=C3F)NC4=CC=C(C=C4)CN5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/14/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "88" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000364 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C(=NN1C)C)N" - } - amount { - moles { - value: 0.000607 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C(F)(F)F)Cl" - } - amount { - moles { - value: 0.000303 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 4.85e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.43e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide (100 mg, 0.30 mmol), 1,3,5-trimethyl-1H-pyrazol-4-amine (76 mg, 0.61 mmol), cesium carbonate (119 mg, 0.36 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (28.1 mg, 0.05 mmol) and diacetoxypalladium (5.45 mg, 0.02 mmol) were suspended in dioxane (1.5 mL) and sealed into a tube. The reaction was degased, purged with nitrogen and heated to 100 C for 18 hours. Reaction was filtered. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford N-methyl-2-(5-(trifluoromethyl)-2-(1,3,5-trimethyl-1H-pyrazol-4-ylamino)pyridin-4-ylamino)benzamide (31.0 mg, 24.43 %) as a pale yellow solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C(=NN1C)C)NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NC)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 24.43 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/15/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "89" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00162 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.008 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1N)C" - } - amount { - moles { - value: 0.00162 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" - } - amount { - moles { - value: 0.00135 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 0.00014 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.4e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "1,3-dimethyl-1H-pyrazol-4-amine (180 mg, 1.62 mmol), 2-(2,5-dichloropyridin-4-ylamino)-N-methylbenzamide (400 mg, 1.35 mmol), Sodium t-Butoxide (156 mg, 1.62 mmol),(R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (73.8 mg, 0.14 mmol) and diacetoxypalladium (24.26 mg, 0.11 mmol) were suspended in DME (8 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT. Incomplete reaction, the reaction was heated to 150 C for a further 1 hour in the microwave reactor and cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH andnbsp;fractions were evaporated to dryness. The crude product was then purified by Basic prep HPLC, fractions containing the desired compound were evaporated to dryness to afford 2-(5-chloro-2-(1,3-dimethyl-1H-pyrazol-4-ylamino)pyridin-4-ylamino)-N-methylbenzamide (267 mg, 53.3 brown solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NC)Cl)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 53.31 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/06/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "90" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.002 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.008 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC1=C2C(=CC=C1)SC(=N2)N" - } - amount { - moles { - value: 0.0012 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)I" - } - amount { - moles { - value: 0.001 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.0001 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 3e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "4-methoxybenzo[d]thiazol-2-amine (0.216 g, 1.20 mmol), iodobenzene (0.112 mL, 1.00 mmol), XANTPHOS (0.058 g, 0.10 mmol), Pd2(dba)3 (0.027 g, 0.03 mmol) and SODIUM TERT-BUTOXIDE (0.192 g, 2.00 mmol) placed in a sealed reaction via under an atmosphere of nitrogen and heated at 90C for 1 hour. LCMS indicated mainly product, little SM. Cooled, diluted DCM and washed with water and brine. Org phase driedMgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with dichloromethane. Pure fractions were evaporated to dryness to afford 4-methoxy-N-phenylbenzo[d]thiazol-2-amine (0.039 g, 15.22 %) as an colorless solid. EN01327-44-1 (0.039 g, 0.15 mmol, 15.22 %)Not sure why yield so low, crude lcms looked fine. Reaction left for several days before working up." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=C2C(=CC=C1)SC(=N2)NC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 15.22 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/01/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "92" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0015 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC1CCNCC1" - } - amount { - moles { - value: 0.000499 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC2=NC=CC(=C2C=C1Cl)Cl" - } - amount { - moles { - value: 0.000449 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 4.99e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (5.60 mg, 0.02 mmol) was added in one portion to tert-butyl piperidin-4-ylcarbamate (100 mg, 0.50 mmol), 4,6-dichloroquinoline (89 mg, 0.45 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (28.9 mg, 0.05 mmol) and cesium carbonate (488 mg, 1.50 mmol) in DMA (5 mL). The resulting mixture was stirred at 150 C for 1 hour. LCMS analysis showed formation of a small amount of the desired product. The mixture was heated for a further 2 hours, after which time LCMS analysis showed loss of this small peak.Abandoned.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CN(CCC1N)C2=C3C=C(C=CC3=NC=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/22/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "93" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 3.02e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.001 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CC(C1)OC2=CC(=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000377 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC2=NC=C(N2C=C1)C3=NC(=NC=C3Cl)Cl" - } - amount { - moles { - value: 0.000377 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.02e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.51e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 105.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "3-(2,5-dichloropyrimidin-4-yl)imidazo[1,2-a]pyridine (100 mg, 0.38 mmol)i, itert-butyl 3-(4-amino-3-methoxyphenoxy)azetidine-1-carboxylate (111 mg, 0.38 mmol)i, iCESIUM CARBONATE (246 mg, 0.75 mmol)i ,idiacetoxypalladium (3.39 mg, 0.02 mmol)i and i9,9-DIMETHYL-4,5-BIS(DIPHENYLPHOSPHINO)XANTHENE (17.46 mg, 0.03 mmol)i iiwereii iisuspendedii in i1,4-dioxane (1 ml)i and degased with argon.The reactionnbsp;was heated from 60C to 105C for 3 hours.Doubt about the LCMS,deprotection of the BOC with TFA to confirm the dialkylation.iNo good pro" - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=C(C=CC(=C1)OC2CNC2)NC3=NC=C(C(=N3)C4=CN=C5N4C=CC=C5)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/22/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "94" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.135 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.25 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)N" - } - amount { - moles { - value: 0.0676 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.0676 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00203 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00135 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (0.303 g, 1.35 mmol) was added in one portion to a degassed mixture of 2,4-dichloropyridine (10 g, 67.57 mmol), aniline (6.29 g, 67.57 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.173 g, 2.03 mmol) and cesium carbonate (44.0 g, 135.14 mmol) in dioxane (250 mL) under argon. The resulting mixture was stirred at 100 C for 24 hours. The mixture was then cooled to room temperature, filtered and concentrated to dryness to give the crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-chloro-N-phenylpyridin-2-amine (7.72 g, 55.8 %) as a pale orange solid.nbsp;nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 55.82 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/04/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "96" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000364 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C(=CC=N1)N" - } - amount { - moles { - value: 0.000607 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C(F)(F)F)Cl" - } - amount { - moles { - value: 0.000303 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 4.85e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.43e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide (100 mg, 0.30 mmol), 1-methyl-1H-pyrazol-5-amine (58.9 mg, 0.61 mmol), cesium carbonate (119 mg, 0.36 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (28.1 mg, 0.05 mmol) and diacetoxypalladium (5.45 mg, 0.02 mmol) were suspended in dioxane (1.5 mL) and sealed into a tube. The reaction was degased, purged with nitrogen and heated to 100 C for 18 hours. Reaction was filtered. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford N-methyl-2-(2-(1-methyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)benzamide (62.0 mg, 52.4 %) [salt] as a pale orange solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C(F)(F)F)NC3=CC=NN3C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 52.37 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/12/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "97" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0168 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.08 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC=CC=C1N" - } - amount { - moles { - value: 0.014 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C(=CN=C1Cl)C(F)(F)F)I" - } - amount { - moles { - value: 0.014 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00224 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00112 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-chloro-4-iodo-5-(trifluoromethyl)pyridine (4.305 g, 14.00 mmol), 2-amino-N-methylbenzamide (2.103 g, 14.00 mmol), diacetoxypalladium (0.251 g, 1.12 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.296 g, 2.24 mmol) and cesium carbonate (5.47 g, 16.80 mmol) were mixed together in dioxane (80 mL). Reaction was degassed with argon and was stirred at 90 C overnight (15 hours) under argon.Reaction was filtered, washed with CH2Cl2 and filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 10 to 40% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford 2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide (3.39 g, 73.4 %) as a white crystalline solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C(F)(F)F)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 73.43 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/09/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "98" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0273 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.14 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC=CC=C1N" - } - amount { - moles { - value: 0.0228 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C(=CN=C1Cl)C(F)(F)F)I" - } - amount { - moles { - value: 0.0228 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00364 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00182 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-chloro-4-iodo-5-(trifluoromethyl)pyridine (7 g, 22.77 mmol), 2-amino-N-methylbenzamide (3.42 g, 22.77 mmol), diacetoxypalladium (0.409 g, 1.82 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.108 g, 3.64 mmol) and cesium carbonate (8.90 g, 27.32 mmol) were mixed together in dioxane (140 mL). Reaction was degassed with nitrogen and was stirred at 90 C overnight under nitrogen. Reaction was filtered, washed with CH2Cl2 and filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 10 to 50% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford 2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide (5.06 g, 67.4 %) as a pale yellow solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C(F)(F)F)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 67.4 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/10/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "99" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00195 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC=CC=C1N" - } - amount { - moles { - value: 0.00163 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C(=CN=C1Cl)C(F)(F)F)I" - } - amount { - moles { - value: 0.00163 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00026 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00013 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-chloro-4-iodo-5-(trifluoromethyl)pyridine (500 mg, 1.63 mmol), 2-amino-N-methylbenzamide (244 mg, 1.63 mmol), diacetoxypalladium (29.2 mg, 0.13 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (151 mg, 0.26 mmol) and cesium carbonate (636 mg, 1.95 mmol) were mixed together in dioxane (10 mL). Reaction was degassed with nitrogen and was stirred at 90 C overnight under nitrogen. Reaction was filtered, washed with CH2Cl2 and filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 10 to 50% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford 2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide (340 mg, 63.4 %) as a pale yellow solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C(F)(F)F)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 63.41 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/09/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "100" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00166 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCC(CC1)(CN=C(C2=CC=CC=C2)C3=CC=CC=C3)C(=O)N" - } - amount { - moles { - value: 0.00119 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1C(F)(F)F)Br" - } - amount { - moles { - value: 0.00119 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 5.34e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.56e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "tert-butyl 4-carbamoyl-4-((diphenylmethyleneamino)methyl)piperidine-1-carboxylate (500 mg, 1.19 mmol), 2-bromo-4-(trifluoromethyl)pyridine (268 mg, 1.19 mmol), and cesium carbonate (541 mg, 1.66 mmol) were suspended in dioxane (2 mL) . The reaction was purged with nitrogen for 10 minutes then 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (30.9 mg, 0.05 mmol) and palladium(II) acetate (7.99 mg, 0.04 mmol) were added. The reaction was heated at 90 C for 48 hours.The reaction was cooled to room temperature, diluted with DCM, filtered and concentrated.The crude product was purified by flash silica chromatography, elution gradient 0 to 40% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 4-((diphenylmethyleneamino)methyl)-4-(4-(trifluoromethyl)pyridin-2-ylcarbamoyl)piperidine-1-carboxylate (480 mg, 71.4 %) as a white solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCC(CC1)(CN=C(C2=CC=CC=C2)C3=CC=CC=C3)C(=O)NC4=NC=CC(=C4)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 71.42 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/16/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "102" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00347 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00301 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=CC=C1Br)[N+](=O)[O-]" - } - amount { - moles { - value: 0.00231 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000347 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000231 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "1-bromo-2-methyl-3-nitrobenzene (500 mg, 2.31 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (201 mg, 0.35 mmol) and cesium carbonate (1131 mg, 3.47 mmol) and diacetoxypalladium (52.0 mg, 0.23 mmol) were dissolved in toluene (10 mL)nbsp;and sealed into a microwave tube degazed and purged with argon. The reaction was heated to 100 C, over a period ofnbsp;12 hours. The reaction mixture was cooled down to room temperature, filtered and the residue was evaporated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 10% methanol in dichloromethane. The solvent was evaporated to dryness to afford 1-(4-(2-methyl-3-nitrophenyl)piperazin-1-yl)ethanone (600 mg, 98 %) as a solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=CC=C1[N+](=O)[O-])N2CCN(CC2)C(=O)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 98.46 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/10/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "103" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00695 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=C(C=CC(=C1)F)N" - } - amount { - moles { - value: 0.00348 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C(=CN=C1Cl)Cl)I" - } - amount { - moles { - value: 0.00365 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000209 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000139 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "palladium acetate (31.2 mg, 0.14 mmol) was added to 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (121 mg, 0.21 mmol), Cesium carbonate (2266 mg, 6.95 mmol), 2-amino-5-fluoro-N-methylbenzamide (585 mg, 3.48 mmol) and 2,5-dichloro-4-iodopyridine (1000 mg, 3.65 mmol) in dioxane (20 mL) under nitrogen. The resulting suspension was stirred at 80 C for 18hrs then cooled. Product appeared to be out of solution. Product and bis product suggested. Disappointing! The reaction mixture was evaporated to dryness and redissolved in EtOAc (100 mL), and washed sequentially with saturated Na2CO3 (50 mL), water (50 mL), and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford desired product as an beige solid.nbsp;nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CNC(=O)C1=C(C=CC(=C1)F)NC2=CC(=NC=C2Cl)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 13.27 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/12/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "104" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[K+]" - } - amount { - moles { - value: 0.00251 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1C#N)N" - } - amount { - moles { - value: 0.00151 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)NC(=O)C2=CN=C(C=C2)Cl" - } - amount { - moles { - value: 0.00126 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000251 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000126 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 50 mL round-bottomed flask a TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.115 g, 0.13 mmol),POTASSIUM TERT-BUTOXIDE (0.282 g, 2.51 mmol)and BINAP (0.157 g, 0.25 mmol) in dry 1,4-dioxane (10 mL) was mixed under N2.Followed by 6-chloro-N-cyclohexylnicotinamide (.300 g, 1.26 mmol) and 4-aminobenzonitrile (0.178 g, 1.51 mmol) was added and resulting mixture(dark brown) was heated at 100oC for 3 hrs.LCMS analysis showed the formation of required product.Reaction stopped,crude was passed through celite and washed with dioxane and finally with methanol.The filtrate was dried and dissolved in 3 ml DMSO for Waters MS Purification system.Pure fractions collected and concentrated.A White solid obtained as a product 6-(4-cyanophenylamino)-N-cyclohexylnicotinamide (0.040 g, 9.93 %).32 mg of above product was mitted for MGyrx2 projetct.LCMSNMR confirmed the product." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CCC(CC1)NC(=O)C2=CN=C(C=C2)NC3=CC=C(C=C3)C#N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 9.93 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/15/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "105" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000405 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.0025 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1N)C" - } - amount { - moles { - value: 0.000347 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C(F)(F)F)Cl" - } - amount { - moles { - value: 0.000289 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 3e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium(II) acetate (7.79 mg, 0.03 mmol), (R)-(-)-1-[(S)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (19.46 mg, 0.03 mmol), Cesium carbonate (0.032 mL, 0.40 mmol), 1,3-dimethyl-1H-pyrazol-4-amine (38.6 mg, 0.35 mmol) and 2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-N-methoxybenzamide (100 mg, 0.29 mmol) were suspended in DME (2.5 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness to afford crude product as a orange gum. The sample was given to the purification group to be purified by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford 2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N-methoxybenzamide (13.60 mg, 11.18 %) as a tum. The sample was not pure enough to register so will be re-made. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 11.18 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/13/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "106" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00201 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CC2=CC=CC=C2NC1" - } - amount { - moles { - value: 0.00134 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(N=C1Cl)Cl" - } - amount { - moles { - value: 0.00134 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000134 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 6.71e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2,4-dichloropyrimidine (200 mg, 1.34 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (78 mg, 0.13 mmol), Tris(dibenzylideneacetone)dipalladium(0) (61.5 mg, 0.07 mmol) and Cesium carbonate (656 mg, 2.01 mmol) was added to a microwave vial. toluene (2 mL) was added.nbsp;1,2,3,4-tetrahydroquinoline (179 mg, 1.34 mmol) was added. Heated to 120C in microwave oven for 90min. Crude filtered through celite and then added to prepHPLC. 30-70% acetonitrile in water. Pure fractions pooled and then freezedried over night. Yielded 1-(2-chloropyrimidin-4-yl)-1,2,3,4-tetrahydroquinoline (24.00 mg, 7.28 %)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CC2=CC=CC=C2N(C1)C3=NC(=NC=C3)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 7.28 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/02/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "107" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000425 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.0025 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1N)C" - } - amount { - moles { - value: 0.000364 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C(F)(F)F)Cl" - } - amount { - moles { - value: 0.000303 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 4e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium(II) acetate (8.17 mg, 0.04 mmol), (R)-(-)-1-[(S)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (20.40 mg, 0.04 mmol), Sodium tert-butoxide (0.052 mL, 0.42 mmol), 1,3-dimethyl-1H-pyrazol-4-amine (40.5 mg, 0.36 mmol) and 2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide (100 mg, 0.30 mmol) were suspended in DME (2.5 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness to afford 2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide (41.3 mg, 33.7 %) as a orange gum. The sample was given to the purification group to be purified by preparative HPLC. Fractions containing the desired compound were evaporated to dryness to afford 2-(2-(1,3-dimethyl-1razol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide (41.3 mg, 33.7 %) as a yellow solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 33.67 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/02/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "108" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00113 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COC(=O)N1" - } - amount { - moles { - value: 0.000566 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1C#N)C2=CSC(=N2)Br" - } - amount { - moles { - value: 0.000377 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.77e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.64e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "4-(2-bromothiazol-4-yl)benzonitrile (100 mg, 0.38 mmol), 2-Oxazolidinone (49.3 mg, 0.57 mmol), diacetoxypalladium (5.93 mg, 0.03 mmol), cesium carbonate (369 mg, 1.13 mmol), water (10 l)nbsp;and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (21.82 mg, 0.04 mmol) were suspended in dioxane (2 mL), thoroughly degassed and sealed into a microwave tube and stirred at RT for 20 mins. The reaction was then heated to 150 C for 10 minutes in the microwave reactor and cooled to RT. Load of rubbish... ABAND" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1COC(=O)N1C2=NC(=CS2)C3=CC=C(C=C3)C#N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/30/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "111" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00116 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=C(C=C(C=C1)F)NC2=CC(=NC=C2Cl)Cl" - } - amount { - moles { - value: 0.000525 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1N)C.Cl.Cl" - } - amount { - moles { - value: 0.00105 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 8.4e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.2e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-(2,5-dichloropyridin-4-ylamino)-4-fluoro-N-methylbenzamide (165 mg, 0.53 mmol), 1,3-dimethyl-1H-pyrazol-4-amine dihydrochloride (193 mg, 1.05 mmol), cesium carbonate (376 mg, 1.16 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (48.6 mg, 0.08 mmol) and diacetoxypalladium (9.43 mg, 0.04 mmol) were suspended in dioxane (3 mL) and sealed into a tube. The reaction was degased, purged with nitrogen and heated to 100 C for 16 hours =gt; ireaction not complete. i(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine), diacetoxypalladium and cesium carbonate were added. The reaction was degased, purged with nitrogen and heated to 110 C for 4 hours =gt; ireaction still not complete, no progress ...iReaction was filtered, washed with CH2Cl2 and concentrated to dryness. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containcetic acid) and acetonitrile as eluent. The pure fractions were combined, basified with a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2. Organic layer was washed with brine, dried over MgSO4 and concentrated to dryness to afford 2-(5-chloro-2-(1,3-dimethyl-1H-pyrazol-4-ylamino)pyridin-4-ylamino)-4-fluoro-N-methylbenzamide (8.00 mg, 3.92 %) as a green dry film." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=C(C=CC(=C3)F)C(=O)NC)Cl)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 3.92 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/23/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "112" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00146 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1OC2=CC=CC(=C2O1)N" - } - amount { - moles { - value: 0.000729 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CC1C(=O)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000729 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 8.75e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.65e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "benzo[d][1,3]dioxol-4-amine (100 mg, 0.73 mmol), N-(4-chloropyridin-2-yl)cyclopropanecarboxamide (143 mg, 0.73 mmol), XANTPHOS (50.6 mg, 0.09 mmol), PALLADIUM(II) ACETATE (8.19 mg, 0.04 mmol) and CESIUM CARBONATE (475 mg, 1.46 mmol) were suspended in DMA (3mL) and sealed into a microwave tube. The reaction was heated to 150 C for 1.5 hours in the microwave reactor and cooled to RT.nbsp;LCMS showed completion.The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 0.35M NH3MeOH and pure fractions were evaporated to dryness to afford N-(4-(benzo[d][1,3]dioxol-4-ylamino)pyridin-2-yl)cyclopropanecarboxamidenbsp;as a brown oil. The crude product was purified by preparative HPLCnbsp;using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-(4-(benzo[d][1,3]dioxol-4-ylamino)pyridin-2-yl)cyclopropanecarmide (110 mg, 50.7 %) as a cream solid. nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CC1C(=O)NC2=NC=CC(=C2)NC3=C4C(=CC=C3)OCO4" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 50.74 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/09/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "113" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00223 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCNCC1" - } - amount { - moles { - value: 0.00168 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC=C(C=C1)OCC2=C(C=CC=N2)Br" - } - amount { - moles { - value: 0.00112 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000447 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000223 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of methyl 4-((3-bromopyridin-2-yl)methoxy)benzoate (360 mg, 1.12 mmol), Pd2dba3 (205 mg, 0.22 mmol), BINAP (278 mg, 0.45 mmol), cesium carbonate (728 mg, 2.23 mmol) and 1-methylpiperazine (168 mg, 1.68 mmol) in DMA (10 mL) was stirred at 100 C for overnight. Sat. NaHCO3 aq was added to the mixture, extracted with ethyl acetate three times, the combined organics were dried over anhydrous Na2SO4, filtered, the filtrate was conc. in vacuo, the residue was purified with ISCO (50% ethyl acetate in hexant to 100% ethyl acetate to 40% mthanol in ethyl acetate) to yield a brown oil as methyl 4-((3-(4-methylpiperazin-1-yl)pyridin-2-yl)methoxy)benzoate (245 mg, 64.2 %)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CCN(CC1)C2=C(N=CC=C2)COC3=CC=C(C=C3)C(=O)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 64.22 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/24/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "114" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00462 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN(C)[C@H]1CCNC1" - } - amount { - moles { - value: 0.00277 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C=C1Cl)Br)C#N" - } - amount { - moles { - value: 0.00231 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000462 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000231 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of 2-bromo-4-chlorobenzonitrile (500 mg, 2.31 mmol), (S)-N,N-dimethylpyrrolidin-3-amine (317 mg, 2.77 mmol), cesium carbonate (1505 mg, 4.62 mmol), tris(dibenzylideneacetone)dipalladium(0) (212 mg, 0.23 mmol) and BINAP (288 mg, 0.46 mmol) in toluene (15 mL) was stirred at 100 C for overnight. Conc. in vacuo, the residue was purified with ISCO (100% ethyl acetate to 30% methanol in ethyl acetate) to yield a light yellow solid as (S)-4-chloro-2-(3-(dimethylamino)pyrrolidin-1-yl)benzonitrile (400 mg, 69.3 %)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(C)[C@H]1CCN(C1)C2=C(C=CC(=C2)Cl)C#N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 69.34 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/29/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "115" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 1.01e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCC2=C(C1=O)C(=CC=C2)N" - } - amount { - moles { - value: 0.000202 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)Cl)C#N)C" - } - amount { - moles { - value: 0.000101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 1.01e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 5.05e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "8-amino-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (35.6 mg, 0.20 mmol), 4-chloro-6-(1,3-dimethyl-1H-pyrazol-4-ylamino)nicotinonitrile (25 mg, 0.10 mmol), diacetoxypalladium (1.133 mg, 5.05 mol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (5.84 mg, 10.09 mol) and cesium carbonate (39.5 mg, 0.12 mmol) were dissolved in dioxane (0.5 mL) and sealed into a microwave tube. nitrogen was let to bubble into the mixture then the reaction was heated to 100 C for 90 minutes. Crude LCMS showed the expected product P3 and no hydrolysis by-product at all like in uEN01775-20u !!The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. b10 days laterb, the fractions containing the desired compound were evaporated to dryness to afford impure 6-(11H-pyrazol-4-ylamino)-4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-8-ylamino)nicotinonitrile (13.00 mg, 33.2 %): it has probably gone off after 10 days in solution (aqueous ammonium carbonate and acetonitrile)ENCOURAGING, THOUGH. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC4=C3C(=O)N(CC4)C)C#N)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 33.24 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/11/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "116" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=CC(=C1)N2CCOCC2)N" - } - amount { - moles { - value: 0.00076 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" - } - amount { - moles { - value: 0.000506 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 5.06e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.53e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-methoxy-4-morpholinoaniline (158 mg, 0.76 mmol), 2-(2,5-dichloropyridin-4-ylamino)-N-methylbenzamide (150 mg, 0.51 mmol),diacetoxypalladium (5.69 mg, 0.03 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (29.3 mg, 0.05 mmol) and cesium carbonate (330 mg, 1.01 mmol) were weighed out in a microwave vial and sealed. dioxane (3 mL) was added and argon was let to bubble for 5 minutes at rt. The resulting mixture was stirred at 110 C for 1 hour. The reaction mixture was allowed to cool to room temperature and concentrated in presence of decalite speed plus. The crude product was purified by flash chromatography on silica gel eluting with 0 to 4% methanol in ethyl acetateDCM (11). The solvent was evaporated to dryness. The foam was triturated in terbutyl methyl ether and the resulting precipitate was collected by filtration and washed with tBuOMe to afford 2-(5-chloro-2-(2-methoxy-4-morpholinophenylamino)pyridin-4-ylamino)-N-methylbenzamide (193 mg, 81 %) as a pale pink solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)NC3=C(C=C(C=C3)N4CCOCC4)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 81.43 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/23/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "117" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0159 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.025 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.0127 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=CC(=C1)F)Br" - } - amount { - moles { - value: 0.0106 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00127 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000635 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 200ml flask was added 1-bromo-4-fluoro-2-methylbenzene (2 g, 10.58 mmol) and TERT-BUTYL 1-PIPERAZINECARBOXYLATE (2.365 g, 12.70 mmol), CESIUM CARBONATE (5.17 g, 15.87 mmol) , BINAP (0.791 g, 1.27 mmol) 18-CROWN-6 (0.336 g, 1.27 mmol), followed by toluene (25 ml). Degass the mixture. TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.581 g, 0.63 mmol) was added. Heat at 110oC under nitrogen in an oil bath for overnight. The reaction mixture was diluted with ethyl acetate and filtered through celite. The Celite was washednbsp;with EtOAC. The EtOAC was concentrated down to give a brown oil.The crude product was purified by silica gel column(40g) and was eluted with 0% EtOACHexane -50% EtOACHexane.Yield: 0.5g Yellow oil. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=CC(=C1)F)N2CCN(CC2)C(=O)OC(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 16.05 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/20/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "118" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00545 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00436 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C=C1F)C(F)(F)F)Br" - } - amount { - moles { - value: 0.00363 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000436 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000218 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 100ml sealtube was added 1-bromo-4-fluoro-2-(trifluoromethyl)benzene (0.91 g, 3.63 mmol), CESIUM CARBONATE (1.775 g, 5.45 mmol), CESIUM CARBONATE (1.775 g, 5.45 mmol), BINAP (0.271 g, 0.44 mmol), TERT-BUTYL 1-PIPERAZINECARBOXYLATE (0.812 g, 4.36 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.200 g, 0.22 mmol) and 18-CROWN-6 (0.115 g, 0.44 mmol). Followed by 15mL toluene. The mixture was degassed by N2 bubbling for 15min. The reaction mixture was heated at 110oC under nitrogen in an oil bath for overnight. The reaction mixture was diluted with ethyl acetate and filtered through celite. The Celite was washednbsp;with EtOAC. The EtOAC was concentrated down to give a brown oil.The crude product was purified by silica gel column(40g) and was eluted with 0% EtOACHexane -25% EtOACHexane.Yield: 0.93g Yellow oil. .nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=C(C=C(C=C2)F)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 73.5 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/21/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "119" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "[O-]P(=O)([O-])[O-].[K+].[K+].[K+]" - } - amount { - moles { - value: 0.000291 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N1CC2CNCC(C1)O2" - } - amount { - moles { - value: 0.000213 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)Br)[N+](=O)[O-]" - } - amount { - moles { - value: 0.000194 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 3.1e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.94e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "1-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)ethanone (36.3 mg, 0.21 mmol), 4-bromo-1-methoxy-2-nitrobenzene (45 mg, 0.19 mmol), diacetoxypalladium (4.35 mg, 0.02 mmol), biphenyl-2-yldicyclohexylphosphine (10.88 mg, 0.03 mmol) and potassium phosphate (61.8 mg, 0.29 mmol) in DME (0.5 mL) were degassed with nitrogen and stirred at 80 C overnight =gt; ino product formed, degradationibiABANDONEDib" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)N1CC2CN(CC(C1)O2)C3=CC(=C(C=C3)OC)[N+](=O)[O-]" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/19/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "120" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[K+].[K+]" - } - amount { - moles { - value: 0.00147 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCC[C@@H](CO)N" - } - amount { - moles { - value: 0.00147 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C(=NC(=N1)N)Cl)CC2=CC=C(C=C2)CC#N" - } - amount { - moles { - value: 0.000733 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.33e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.67e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium(II) acetate (8.23 mg, 0.04 mmol) and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (42.4 mg, 0.07 mmol) were added to dioxane (3 mL) and the solution was stirred at room temperature for 10 minutes.nbsp;2-(4-((2-amino-4-chloro-6-methylpyrimidin-5-yl)methyl)phenyl)acetonitrile (200 mg, 0.73 mmol), (S)-(+)-2-Amino-1-pentanol (151 mg, 1.47 mmol) and POTASSIUM CARBONATE (203 mg, 1.47 mmol) were added and the mixture was heated at 100 C for 15 hours. LCMS showed no product and reaction not progressed." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCC[C@@H](CO)NC1=NC(=NC(=C1CC2=CC=C(C=C2)CC#N)C)N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/23/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "121" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[K+].[K+]" - } - amount { - moles { - value: 0.00146 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC[C@H]1CNC(=O)O1" - } - amount { - moles { - value: 0.00146 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C(=NC(=N1)/N=C/N(C)C)Cl)CC2=CC=C(C=C2)CC#N" - } - amount { - moles { - value: 0.000732 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.32e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.66e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium(II) acetate (8.22 mg, 0.04 mmol) and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (42.4 mg, 0.07 mmol) were added to dioxane (3 mL) and the solution was stirred at room temperature for 10 minutes.(E)-N\'-(4-chloro-5-(4-(cyanomethyl)benzyl)-6-methylpyrimidin-2-yl)-N,N-dimethylformimidamide (240 mg, 0.73 mmol),nbsp;(S)-5-ethyloxazolidin-2-one (169 mg, 1.46 mmol) and POTASSIUM CARBONATE (202 mg, 1.46 mmol) were added and the mixture was heated at 100 C for 1 hour. The solvent was evaporated under reduced pressure and the crude product was purified by flash silica chromatography, elution gradient 2 to 5% methanol in dichloromethane. Pure fractions were evaporated to dryness to afford (S,E)-N\'-(5-(4-(cyanomethyl)benzyl)-4-(5-ethyl-2-oxooxazolidin-3-yl)-6-methylpyrimidin-2-yl)-N,N-dimethylformimidamide (136 mg, 45.7 %) as a colorless solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC[C@H]1CN(C(=O)O1)C2=NC(=NC(=C2CC3=CC=C(C=C3)CC#N)C)/N=C/N(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 45.7 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/30/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "122" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000822 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0025 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=C(C=C(C=C1)F)N" - } - amount { - moles { - value: 0.000548 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C(=CN=C1Cl)Cl)I" - } - amount { - moles { - value: 0.000548 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 5.48e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.74e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (6.15 mg, 0.03 mmol) was added to a stirred suspension of 2,5-dichloro-4-iodopyridine (150 mg, 0.55 mmol), 2-amino-4-fluoro-N-methylbenzamide (92 mg, 0.55 mmol) (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (31.7 mg, 0.05 mmol) and cesium carbonate (268 mg, 0.82 mmol)nbsp;in 1,4-dioxane (2.5 mL) under nitrogen. The resulting suspension was stirred at 100 C for 16 hours.The mixture was cooled to RT; filtered the solvent was evaporated.The crude product was absorbed on silica gel and purified by flash chromatography on silica gel eluting with 20 to 80% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford 2-(2,5-dichloropyridin-4-ylamino)-4-fluoro-N-methylbenzamide (60.0 mg, 34.9 %) as anbsp;beige solid.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CNC(=O)C1=C(C=C(C=C1)F)NC2=CC(=NC=C2Cl)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 34.87 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/10/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "123" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00137 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0025 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=C(C=C(C=C1)F)N" - } - amount { - moles { - value: 0.001 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C(=CN=C1Cl)Cl)I" - } - amount { - moles { - value: 0.000913 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 9.13e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.56e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 140.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2,5-dichloro-4-iodopyridine (250 mg, 0.91 mmol), 2-amino-4-fluoro-N-methylbenzamide (169 mg, 1.00 mmol) diacetoxypalladium (10.25 mg, 0.05 mmol) (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (52.8 mg, 0.09 mmol) and cesium carbonate (446 mg, 1.37 mmol) were dissolved in 1,4-dioxane (2.5 mL) and sealed into a microwave tube. The reaction was degased, purged with nitrogen and heated to 140 C over a period of 30 minutes in the microwave reactor. The mixture was cooled to RT; filtered the solvent was evaporated.The crude product was absorbed on silica gel and purified by flash chromatography on silica gel eluting with 20 to 80% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford 2-(2,5-dichloropyridin-4-ylamino)-4-fluoro-N-methylbenzamide (175 mg, 61.0 %) as anbsp;beige solid.nbsp;nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CNC(=O)C1=C(C=C(C=C1)F)NC2=CC(=NC=C2Cl)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 61.03 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/15/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "124" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00695 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.04 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=C(C=C(C=C1)F)N" - } - amount { - moles { - value: 0.00348 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C(=CN=C1Cl)Cl)I" - } - amount { - moles { - value: 0.00365 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000209 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000139 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "palladium acetate (31.2 mg, 0.14 mmol) was added to 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (121 mg, 0.21 mmol), Cesium carbonate (2266 mg, 6.95 mmol), 2-amino-4-fluoro-N-methylbenzamide (585 mg, 3.48 mmol) and 2,5-dichloro-4-iodopyridine (1000 mg, 3.65 mmol) in dioxane (40 mL) under nitrogen. The resulting suspension was stirred at 80 C for 18hrs then cooled. Product and bis product suggested. Disappointing! The reaction mixture wasnbsp;evaporated to dryness and redissolved innbsp;EtOAc (150 mL), and washed sequentially with saturated NaHCO3 (2 x 100 mL), water (100 mL), and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered then evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford desired product as a yellow solid.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CNC(=O)C1=C(C=C(C=C1)F)NC2=CC(=NC=C2Cl)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 10.99 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/12/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "126" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000291 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N1CC2CNCC(C1)O2" - } - amount { - moles { - value: 0.000213 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)Br)[N+](=O)[O-]" - } - amount { - moles { - value: 0.000194 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 1.55e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.55e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "1-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)ethanone (36.3 mg, 0.21 mmol), 4-bromo-1-methoxy-2-nitrobenzene (45 mg, 0.19 mmol), diacetoxypalladium (3.48 mg, 0.02 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (8.98 mg, 0.02 mmol) and sodium 2-methylpropan-2-olate (28.0 mg, 0.29 mmol) in dioxane (0.5 mL) were degassed with nitrogen and stirred at 110 C for 4 hours =gt; isome product formed, by-products are major + degradationibiABANDONEDib" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)N1CC2CN(CC(C1)O2)C3=CC(=C(C=C3)OC)[N+](=O)[O-]" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/19/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "127" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00473 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00335 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CS(=O)(=O)C1=CC=C(C=C1)COC2=NC=C(C=N2)Br" - } - amount { - moles { - value: 0.003 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000161 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000169 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "5-bromo-2-(4-(methylsulfonyl)benzyloxy)pyrimidine (1.03 g, 3.00 mmol), tert-butyl piperazine-1-carboxylate (624.6 mg, 3.35 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (154.3 mg, 0.17 mmol),2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (100.0 mg, 0.16 mmol) andnbsp;sodium 2-methylpropan-2-olate (454.4 mg, 4.73 mmol) were mixed with toluene (20 mL). N2 was bubbled through the solvent for 15 minutes.The resulting mixture was stirred at 80 C for over night under N2.The reaction mixture was filtered through celite. The reaction mixture was evaporated to dryness and redissolved in EtOAc (75 mL), and washed sequentially with water (2x75 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(2-(4-(methylsulfonyl)benzyloxy)pyrimidin-5-yl)piperazine-1-carboxylate (1.6) as a white solid. The product was not pure! The crude product was purified by flash alumina chromatography, elution gradient 0 to 70% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(2-(4-(methylsulfonyl)benzyloxy)pyrimidin-5-yl)piperazine-1-carboxylate (1.664 %) as a white solid. The product was still not pure but was handed in for testing anyway, as 92% pure by NMR. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CN=C(N=C2)OCC3=CC=C(C=C3)S(=O)(=O)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 1.66 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/28/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "128" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00327 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.0024 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CS(=O)(=O)C1=CC=C(C=C1)COC2=NC=C(C=N2)Br" - } - amount { - moles { - value: 0.00218 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000109 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000109 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "5-bromo-2-(4-(methylsulfonyl)benzyloxy)pyrimidine (748.8 mg, 2.18 mmol), tert-butyl piperazine-1-carboxylate (447 mg, 2.40 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (100 mg, 0.11 mmol),2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (67.9 mg, 0.11 mmol) andnbsp;sodium 2-methylpropan-2-olate (315 mg, 3.27 mmol) were mixed with toluene (20 mL). N2 was bubbled through the solvent for 15 minutes.The resulting mixture was stirred at 80 C for over night under N2.The reaction mixture was filtered through celite. The reaction mixture was evaporated to dryness and redissolved in EtOAc (75 mL), and washed sequentially with water (2x75 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(2-(4-(methylsulfonyl)benzyloxy)pyrimidin-5-yl)piperazine-1-carboxylate (55.0 %) yellow solid. Was not pure and tailed on the coloumn. The crude product was purified by preparative HPLC (Phenomenex Gemini C18 110A (axia) column, 5 silica, 21 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.5% NH3 and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford as a white solid. The product crashed out on the HPLC coloumn and blocked the system, which gave bad recovery.Turns out the product is not stable. 2D TLC shows tailing of product.." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CN=C(N=C2)OCC3=CC=C(C=C3)S(=O)(=O)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 55.01 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/22/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "129" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00125 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.000864 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CS(=O)(=O)C1=CC=C(C=C1)COC2=NC=C(C=C2)Br" - } - amount { - moles { - value: 0.000754 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 7.76e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 5.58e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (48.3 mg, 0.08 mmol) was added in one portion to 5-bromo-2-(4-(methylsulfonyl)benzyloxy)pyridine (257.9 mg, 0.75 mmol), tert-butyl piperazine-1-carboxylate (160.9 mg, 0.86 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (51.1 mg, 0.06 mmol) and sodium 2-methylpropan-2-olate (120.1 mg, 1.25 mmol) in toluene (10 mL). N2 was bubbled through the solvent for 15 minutes.The resulting mixture was stirred at 80 C for over night under N2.The reaction mixture was filtered through celite. The reaction mixture was evaporated to dryness and redissolved in EtOAc (75 mL), and washed sequentially with water (2x75 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 70% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(6-(4-(methylsulfonyl)benzyloxy)pyridin-3-yl)piperazine-1-carboxylate.6 %) as a yellow solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CN=C(C=C2)OCC3=CC=C(C=C3)S(=O)(=O)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 42.6 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/21/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "130" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00222 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.008 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N1CCC2=C1C=CC(=C2)CCN3CCNCC3" - } - amount { - moles { - value: 0.00179 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)Br" - } - amount { - moles { - value: 0.00171 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.000171 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 8.55e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 95.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "0605 2009 14:53:56 +0200To ethyl 7-bromobenzofuran-2-carboxylate (0.460 g, 1.71 mmol) and 1-(5-(2-(piperazin-1-yl)ethyl)indolin-1-yl)ethanone (0.491 g, 1.79 mmol) (from EN02198-74) in dry degassed dioxane (8 mL) were added Cesium carbonate (0.724 g, 2.22 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-triisopropylbiphenyl (0.081 g, 0.17 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (0.078 g, 0.09 mmol) under argon and the reaction heated at 95C overnight. After cooling to rt, water and DCM were added and the layers separated. The aq phase was extracted with DCM (3x). The combined org phases were washed with water, dried (MgSO4), filtered and evaporated. The crude was purified by flash (SiO2; DCMMeOH 955) to give 0.485 g (61%) of the product as a yellow solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)N3CCN(CC3)CCC4=CC5=C(C=C4)N(CC5)C(=O)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 61.47 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/06/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "131" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000459 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N1CCC2=C1C=CC(=C2)CCN3CCNCC3" - } - amount { - moles { - value: 0.000371 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)Br" - } - amount { - moles { - value: 0.000353 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 3.53e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.77e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 95.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2204 2009 09:43:42 +0200To ethyl 7-bromobenzofuran-2-carboxylate (0.095 g, 0.35 mmol) and 1-(5-(2-(piperazin-1-yl)ethyl)indolin-1-yl)ethanone (0.101 g, 0.37 mmol) (from EN02198-74) in dry degassed dioxane (1.5 mL) were added Cesium carbonate (0.150 g, 0.46 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-triisopropylbiphenyl (0.017 g, 0.04 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (0.016 g, 0.02 mmol) under argon and the reaction heated at 95C for 5.5h. After cooling to rt, water and DCM were added and the layers separated. The aq phase was extracted with DCM (3x). The combined org phases were washed with water, dried (MgSO4), filtered and evaporated. The crude was purified by flash (SiO2; DCMMeOH 955) to give 0.105 g of the product as a yellow solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)N3CCN(CC3)CCC4=CC5=C(C=C4)N(CC5)C(=O)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 64.44 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/21/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "132" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0111 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.03 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CN(CCN1)CCC2=CC=CC=N2" - } - amount { - moles { - value: 0.0094 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)Br" - } - amount { - moles { - value: 0.00855 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.000855 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000427 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 95.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2705 2009 13:35:19 +0200To dry degassed dioxane (30 mL) were added ethyl 7-bromobenzofuran-2-carboxylate (2.30 g, 8.55 mmol) and 1-(2-(pyridin-2-yl)ethyl)piperazine (1.798 g, 9.40 mmol), Cesium carbonate (3.62 g, 11.11 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-triisopropylbiphenyl (0.407 g, 0.85 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (0.391 g, 0.43 mmol) under argon and the reaction heated at 95C for 4h. The reaction mixture was filtered and solvent evaporated. The material was purified by flash (SiO2; DCMMeOH 973) to give 0.620 g, but it was not pure enough (EN02198-94-001). A second flash was performed (SiO2; DCMMeOH 973) to give 0.540 g of the product as a yellow solid (EN02198-94-002). 100% pure according to HPLC.The reaction mixture was combined with the reaction mixture in EN02745-56 and hydrolysed. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)N3CCN(CC3)CCC4=CC=CC=N4" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 35.77 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/27/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "133" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0111 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.03 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CN(CCN1)CCC2=CC=CC=N2" - } - amount { - moles { - value: 0.00818 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)Br" - } - amount { - moles { - value: 0.00743 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.00104 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.00052 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 95.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "The reaction mixture of ethyl 7-bromobenzofuran-2-carboxylate (2.0 g, 7.43 mmol), 1-(2-(pyridin-2-yl)ethyl)piperazine (1.564 g, 8.18 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.476 g, 0.52 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (0.496 g, 1.04 mmol) and Cesium carbonate (3.63 g, 11.15 mmol) in dioxane (30 mL) (degassed with argon for 10 min) was heated at 95 C under argon for 5 h. After cooling, the reaction mixture was filtered and concentrated. The product was purified twice by isco, the first using DCM:MeOH (0-5%) and the second time using DCM:MeOH (0-3%). " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)N3CCN(CC3)CCC4=CC=CC=N4" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 18.97 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/27/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "134" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000483 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CN(CCN1)CCC2=CC=CC=N2" - } - amount { - moles { - value: 0.00039 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)Br" - } - amount { - moles { - value: 0.000372 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 3.72e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.86e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 95.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "0701 2009 12:44:11 +0100To ethyl 7-bromobenzofuran-2-carboxylate (0.100 g, 0.37 mmol) and 1-(2-(pyridin-2-yl)ethyl)piperazine (0.075 g, 0.39 mmol) in dry degassed dioxane (1.5 mL) were added Cesium carbonate (0.157 g, 0.48 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-triisopropylbiphenyl (0.018 g, 0.04 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (0.017 g, 0.02 mmol) under argon and the reaction heated at 95C on. All starting material consumed.nbsp;Water and DCM were added and the layers separated. The aq phase was extracted with DCM (3x). The combined org phases were washed with water, dried (MgSO4), filtered and evaporated. The crude was purified by flash (SiO2; DCMMeOH 955) to give 0.0661 g of the product as a pale yellow semisolid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)N3CCN(CC3)CCC4=CC=CC=N4" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 46.88 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/07/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "135" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00435 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.013 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CN(CCN1)CCC2=CC=CC=N2" - } - amount { - moles { - value: 0.00351 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)Br" - } - amount { - moles { - value: 0.00334 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.000334 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000167 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 95.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "1201 2009 15:21:58 +0100To ethyl 7-bromobenzofuran-2-carboxylate (0.900 g, 3.34 mmol) and 1-(2-(pyridin-2-yl)ethyl)piperazine (0.672 g, 3.51 mmol) in dry degassed dioxane (13 mL) were added Cesium carbonate (1.417 g, 4.35 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-triisopropylbiphenyl (0.159 g, 0.33 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (0.153 g, 0.17 mmol) under argon and the reaction heated at 95C on. All starting material consumed.nbsp;Water and DCM were added and the layers separated. The aq phase was extracted with DCM (3x). The combined org phases were washed with water, dried (MgSO4), filtered and evaporated. The crude was purified by flash chrom. (SiO2; DCMMeOH 955) to give EN02198-25-001:47.3 mg (fraction 12 from the flash) of the product as a pale yellow solid. This batch was mitted to test.EN02198-25-002:0.460 g (fractions 11 and 13-18 from the flash) of the product as a pale brown solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)N3CCN(CC3)CCC4=CC=CC=N4" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 39.97 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/12/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "136" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00725 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CN(CCN1)CCC2=CC=CC=N2" - } - amount { - moles { - value: 0.00585 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)Br" - } - amount { - moles { - value: 0.00557 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.000557 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000279 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 95.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "1702 2009 12:47:13 +0100To ethyl 7-bromobenzofuran-2-carboxylate (1.50 g, 5.57 mmol) and 1-(2-(pyridin-2-yl)ethyl)piperazine (1.120 g, 5.85 mmol) in dry degassed dioxane (20 mL) were added Cesium carbonate (2.361 g, 7.25 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-triisopropylbiphenyl (0.266 g, 0.56 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (0.255 g, 0.28 mmol) under argon and the reaction heated at 95C on. The reaction was allowed to reach rt. Starting material left1802 2009 14:51:20 +0100Additional2-Dicyclohexylphosphino-2\',4\',6\'-triisopropylbiphenyl (0.266 g, 0.56 mmol) andnbsp;Tris(dibenzylideneacetone)dipalladium(0) (0.255 g, 0.28 mmol) were added and the reaction stirred at 95C on. The reaction mixture was pooled with the reaction mixture in EN02198-44.nbsp;Water and DCM were added and the layers separated. The aq phase was extracted with DCM (3x). The combined org phases were washed with water, dried (Na2SO4), filtered and evaporated. The crude was puriflash chrom. (SiO2; DCMMeOH 955) to give 1.48 g (35% calculated from EN02198-44+45) of the product as a pale brown solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(O1)C(=CC=C2)N3CCN(CC3)CCC4=CC=CC=N4" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 69.5 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/17/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "138" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0133 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.03 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.0105 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)COC2=CN=C(C=C2)Cl" - } - amount { - moles { - value: 0.00953 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 9.53e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" - } - amount { - moles { - value: 9.53e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "BIS(DIBENZYLIDENEACETONE)PALLADIUM (0.055 g, 0.10 mmol) was added to tert-butyl piperazine-1-carboxylate (1.952 g, 10.48 mmol), 5-(benzyloxy)-2-chloropyridine (2.093 g, 9.53 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.059 g, 0.10 mmol) and sodium 2-methylpropan-2-olate (1.282 g, 13.34 mmol) in toluene (30 mL) at 20Cnbsp;under nitrogen. The resulting solution was stirred at 80 C for 16 hours then cooled to room temperature. The reaction mixture was filtered through celite, filtrate partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase was dried (Na2SO4), filtered and evaporated to give a brown gum. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(5-(benzyloxy)pyridin-2-yl)piperazine-1-carboxylate (2.420 g, 68.7 %) as a yellow solid. n" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=NC=C(C=C2)OCC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 68.75 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/23/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "139" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00628 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0175 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCC(CC1)CN" - } - amount { - moles { - value: 0.00236 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)OC(F)(F)F)C2=CN=C3N2N=C(C=C3)Cl.Cl" - } - amount { - moles { - value: 0.00157 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C1=CC=CC=C1C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 0.000471 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000157 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 100 mL round bottom flask was charged with a magnetic stir bar, toluene (17.45 mL), 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine hydrochloride (550 mg, 1.57 mmol) (EN02141-06), Pd2dba3 (144 mg, 0.16 mmol),nbsp;2\'-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (185 mg, 0.47 mmol),sodium tert-butoxide (604 mg, 6.28 mmol), and (1-methylpiperidin-4-yl)methanamine (302 mg, 2.36 mmol).nbsp;The mixture was degassed with argon, the vessel fitted with a reflux condenser, and then placed in an oil bath heated to 110 C with stirring for 16 h.nbsp;The mixture was cooled to rt, pre-absorbed onto silca gel (~ 10 g) and purified on silica gel (80 g) using MeOHDCM (1:3) as eluent to afford the title compound, .N-((1-methylpiperidin-4-yl)methyl)-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-amine (391 mg, 55.6 %) as an off white solid.nbsp;110 mg of this pure free base was dissolved in anhydrous MeOH and 32 uL of conc. H2SO4 were added.nbsp;The mixture was stirred for 10 min rt before being conc. in vacuo.nbsp;The crude solids were triturated with diethyl ether and collected via vacuum filtration to afford the title compound as its bis(bisulfate)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CCC(CC1)CNC2=NN3C(=NC=C3C4=CC(=CC=C4)OC(F)(F)F)C=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 55.56 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/12/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "141" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0295 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.1 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.00983 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=C(C2=CC(=C(C=C2N=C1)OCCOC)Br)NC3=C(C=C(C=C3)C)F" - } - amount { - moles { - value: 0.00983 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00314 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000786 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Reaction reference EN00057-06, EN02095-49, 67, 68, 74, 78, 90In a 50 mL round-bottomed flask was ethyl 6-bromo-4-(2-fluoro-4-methylphenylamino)-7-(2-methoxyethoxy)quinoline-3-carboxylate (4.6911 g, 9.83 mmol), Morpholine (0.857 mL, 9.83 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.720 g, 0.79 mmol), and rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (1.958 g, 3.14 mmol) in Dioxane (100 mL) to give a orange suspension.nbsp;The reaction mixture was heated and stirred at 80C (start 4pm).nbsp;After stirringheating overngiht, reaction is about 30% complete.nbsp;Add rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (1.958 g, 3.14 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.720 g, 0.79 mmol).nbsp;Continue heatingstirring.nbsp;After heating and stirring for another 24hr, reaction is about 85% complete with some starting material.nbsp;Add rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (1.958 g, 3.14 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.720 g, 0.79 mmol)sp;Continue heating and stirring.nbsp;Reaction complete after going another 24 hr.Cool reaction, and concentrate in vacuo (CIV).nbsp;Dissolve in DCM, and purify on ISCO; EtOAcHexanes, 0-100%, some product elutes at end of run.nbsp;Continue eluting column with MeOHDCM, 0-5%; more product elutes at 5%.nbsp;Combine all fractions containing product; 3.5475g isolated of an amber solid.nbsp;LC-MS and NMR indicate that it is a mixture of methyl and ethyl ester products." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=C(C2=CC(=C(C=C2N=C1)OCCOC)N3CCOCC3)NC4=C(C=C(C=C4)C)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 74.65 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/10/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "144" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[K+]" - } - amount { - moles { - value: 0.00033 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1CCOC1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@@H]1CN(CCN1)C(=O)OC(C)(C)C" - } - amount { - moles { - value: 0.0003 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)COC2=CC=C(C=C2)Br" - } - amount { - moles { - value: 0.0006 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" - } - amount { - moles { - value: 0.00033 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C.[Pd]" - } - amount { - moles { - value: 3e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of 1-(benzyloxy)-4-bromobenzene (158 mg, 0.60 mmol), (R)-tert-butyl 3-methylpiperazine-1-carboxylate (60.1 mg, 0.3 mmol), bis(tri-t-butylphosphine)palladium(0) (15.33 mg, 0.03 mmol) and potassium tert-butoxide (37.0 mg, 0.33 mmol) in THF (2 mL) was flushed with nitrogen and sealed into a microwave tube. The reaction was heated to 150 C for 20 minutes in the microwave reactor and cooled to RT.nbsp;The reaction mixture was filtered and the filtrate evaporated to dryness.nbsp;The residue was dissolved in MeOH (5mL) and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 0.35M NH3MeOH and pure fractions were evaporated to dryness.nbsp;The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-methylpiperazine-1-carboxylate (41.0 mg, 35.7 %) as a colourless oil that solidified on standing.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@@H]1CN(CCN1C2=CC=C(C=C2)OCC3=CC=CC=C3)C(=O)OC(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 35.73 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/23/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "145" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00045 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@@H]1CN(CCN1)C(=O)OC(C)(C)C" - } - amount { - moles { - value: 0.0003 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)COC2=CC=C(C=C2)Br" - } - amount { - moles { - value: 0.00036 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 2.4e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of (R)-tert-butyl 3-methylpiperazine-1-carboxylate (0.060 g, 0.3 mmol), 1-(benzyloxy)-4-bromobenzene (0.095 g, 0.36 mmol), palladium(II) acetate (6.74 mg, 0.03 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.015 g, 0.02 mmol) and sodium t-butoxide (0.043 g, 0.45 mmol) in toluene (2 mL) was flushed with nitrogen and sealed into a microwave tube. The reaction was heated to 150 C for 10 minutes in the microwave reactor and cooled to RT. Analysis by LCMS.nbsp;Only a small amount of the product could be detected (MH+ = 383, 5%).The reaction was not progressed further." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@@H]1CN(CCN1C2=CC=C(C=C2)OCC3=CC=CC=C3)C(=O)OC(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/23/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "147" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[K+]" - } - amount { - moles { - value: 0.00165 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1CCOC1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@@H]1CN(CCN1)C(=O)OC(C)(C)C" - } - amount { - moles { - value: 0.0015 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)COC2=CC=C(C=C2)Br" - } - amount { - moles { - value: 0.003 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" - } - amount { - moles { - value: 0.00015 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C.[Pd]" - } - amount { - moles { - value: 0.00015 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 75.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of 1-(benzyloxy)-4-bromobenzene (789 mg, 3.00 mmol), (R)-tert-butyl 3-methylpiperazine-1-carboxylate (300 mg, 1.5 mmol), bis(tri-t-butylphosphine)palladium(0) (77 mg, 0.15 mmol) and potassium tert-butoxide (185 mg, 1.65 mmol) in THF (10 mL) was flushed with nitrogen and heated to 75 C overnight.nbsp;A further 0.1eq of bis(tri-t-butylphosphine)palladium(0) (77 mg, 0.15 mmol) was added and the reaction was heated for a further 2.5 hours.nbsp;The solvent was evaporated and the residue dissolved in MeOH (10mL) and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 0.35M NH3MeOH and purified further by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-methylpiperazine-1-carboxylate (181 mg, 31.5 %) as an orange oil. nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@@H]1CN(CCN1C2=CC=C(C=C2)OCC3=CC=CC=C3)C(=O)OC(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 31.55 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/25/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "148" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00105 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@@H]1CN(CCN1)C(=O)OC(C)(C)C" - } - amount { - moles { - value: 0.00036 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)COC2=CC=C(C=C2)Br" - } - amount { - moles { - value: 0.0003 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 3e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of (R)-tert-butyl 3-methylpiperazine-1-carboxylate (0.072 g, 0.36 mmol), 1-(benzyloxy)-4-bromobenzene (0.079 g, 0.3 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.035 g, 0.06 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.027 g, 0.03 mmol) and sodium 2-methylpropan-2-olate (0.101 g, 1.05 mmol) in toluene (2 mL) was flushed with nitrogen and sealed into a microwave tube. The reaction was heated to 150 C for 10 minutes in the microwave reactor and cooled to RT. Only a small amount of the desired product was visible by LCMS. The reaction was not progressed further.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@@H]1CN(CCN1C2=CC=C(C=C2)OCC3=CC=CC=C3)C(=O)OC(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/20/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "149" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000595 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CCNCC1" - } - amount { - moles { - value: 0.000595 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C=C1Br)F)C#N" - } - amount { - moles { - value: 0.000595 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 2.97e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.97e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 160.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "4-bromo-2-fluorobenzonitrile (119 mg, 0.59 mmol), Piperidine (0.059 mL, 0.59 mmol), Palladium(II) acetate (6.68 mg, 0.03 mmol), dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (14.18 mg, 0.03 mmol) and sodium tert-butoxide (57.2 mg, 0.59 mmol) were suspended in toluene (4 mL) and tBuOH (0.800 mL) andnbsp;heated to 160C for 10 minutes in the microwave. LCMS indicated incomplete reaction, thus, the reaction mixture was heated to 160C for a further 20 minutes.nbsp;Still incomplete reaction however, the reaction mixture was diluted with EtOAc (10 mL), and washed sequentially with water (10 mL), and saturated brine (10 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane. A yellow oil (60mg) was isolated but NMR revealed this not be the desired product.No further work d" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CCN(CC1)C2=CC(=C(C=C2)C#N)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 49.37 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/23/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "151" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0171 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.04 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=CC=C1C2=CC3=CN=C(N=C3C(=C2)Cl)N" - } - amount { - moles { - value: 0.012 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C[C@H](C1=CC=C(C=C1)Br)NC(=O)OC(C)(C)C" - } - amount { - moles { - value: 0.0147 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000268 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000125 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 250 mL roundbottom flask was charged with 8-chloro-6-(pyridin-4-yl)quinazolin-2-amine (EN01547-76-1; 3.09 g, 12.04 mmol), (R)-tert-butyl 1-(4-bromophenyl)ethylcarbamate (EN01547-74-1; 4.42 g, 14.72 mmol), Pd2(dba)3 (114.4 mg, 2.1 mol % Pd), XantPhos (155.0 mg, 2.2 mol %), and Cs2CO3 (5.57 g, 17.10 mmol).nbsp;The flask was evacuated and backfilled with N2 (3x), and then anhydrous dioxane (40 mL) was added.nbsp;The mixture was allowed to stir at room temperature for ~5 minutes and was then heated under N2 in a 100 C oil bath.After heating overnight, LC-MS showed complete conversion of the starting material to the desired product (trace N-phenylated product).nbsp;A significant side product appeared to be present, derived from the starting aminoquinazoline that had undergone two Suzuki couplings in the previous step (see EN01547-76; MW=518.6).nbsp;The reaction was allowed to cool and was partitioned between EtOAc and H2O.nbsp;The aqueous layer was extracted with EtOAc, and the combined organics were concentrated under reduced pressure.nbsp;The crude material was purified by silica gel chromatography (Rf in EtOAc = 0.44) to give a yellow-orange solid.2.92 g (51%) of solid was collected.nbsp;A trace of EtOAc remained by NMR analysis despite being kept under high vacuum over the weekend." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@H](C1=CC=C(C=C1)NC2=NC=C3C=C(C=C(C3=N2)Cl)C4=CC=NC=C4)NC(=O)OC(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 50.96 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/04/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "152" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000563 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.136 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=CC(=N1)N2C=NC=N2)N" - } - amount { - moles { - value: 0.0282 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC(=O)N1CCC(CC1)OC2=C(C(=NC=N2)Cl)OC" - } - amount { - moles { - value: 0.0282 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)CN1CCN2CCN(P1N(CC2)CC(C)C)CC(C)C" - } - amount { - moles { - value: 0.000563 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000282 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Sodium tert-butoxide (8.28 mL, 67.61 mmol) was added portionwise to a mixture of 2-methyl-6-(1H-1,2,4-triazol-1-yl)pyridin-3-amine (4.94 g, 28.17 mmol) isopropyl 4-(6-chloro-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate (9.29 g, 28.17 mmol) and in dioxane (136 mL) at 18C over a period of 1 minute under nitrogen. The mixture was degassed by jecting to vacuum then nitrogen atmosphere (six times). Palladium(II) acetate (0.063 g, 0.28 mmol) and 2,8,9-Triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo{3.3.3}undecane (0.200 mL, 0.56 mmol) was added and the mixture degassed again. The resulting suspension was stirred at 90 C for 3 hours.nbsp;Palladium(II) acetate (0.126 g, 0.56 mmol)nbsp;and 2,8,9-Triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo{3.3.3}undecane (0.400 mL, 1.12 mmol) was added and the reaction stirred at 90 C for 5 hours. The reaction mixture was diluted with water (100 mL) then extracted with EtOAc (300 mL), and washed with saturated brine (100 mL). The aqueous was extEtOAc ( 100 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography (330g column), elution gradient 0 to 10% EtOH in DCM (rising quickly to 5% then more slowly to 10%). Pure fractions were evaporated to dryness to afford impure isopropyl 4-(5-methoxy-6-(2-methyl-6-(1H-1,2,4-triazol-1-yl)pyridin-3-ylamino)pyrimidin-4-yloxy)piperidine-1-carboxylate, EN02029-80-P, as a yellow solid. The chromatography was repeated to give a slightly purer sample, EN02029-80-P2. This was triturated with Et2O (40 mL) to give a mobile solid which was filtered off and washed with Et2O (2 x 10 mL) then hexane (2 x 10 mL) to give a pale yellow solid, EN02029-80-solid 1. Analysis of this compound showed good purity so this mobile pale yellow solid was handed in as EN02029-80-01." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=CC(=N1)N2C=NC=N2)NC3=C(C(=NC=N3)OC4CCN(CC4)C(=O)OC(C)C)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 48.49 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/25/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "155" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 4e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N1CCN(CC1)C2=C(C=C(C(=C2)OC)N)OC" - } - amount { - moles { - value: 0.0005 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC2=NC=C(N2C=C1)C3=NC(=NC=C3Cl)Cl" - } - amount { - moles { - value: 0.0005 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 4e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "i3-(2,5-dichloropyrimidin-4-yl)imidazo[1,2-a]pyridine (132.5 mg, 0.50 mmol)iinbsp;ii1-(4-(4-amino-2,5-dimethoxyphenyl)piperazin-1-yl)ethanone (140 mg, 0.50 mmol)ii ii(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (23.14 mg, 0.04 mmol)iinbsp;iicesium carbonate (244 mg, 0.75 mmol)ii iidiacetoxypalladium (4.49 mg, 0.02 mmol)ii were suspended in ii1,4-dioxane (4 ml)ii,degased with argon . The mixture was heated to ii80 Ciinbsp;for 2 hrs *i" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)N1CCN(CC1)C2=C(C=C(C(=C2)OC)NC3=NC=C(C(=N3)C4=CN=C5N4C=CC=C5)Cl)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/04/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "156" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 1.52e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC=CC=C1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CCNC1" - } - amount { - moles { - value: 0.000304 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)NC3=NC=C(C(=N3)C4=CN=C5N4C=CC(=C5)Cl)Cl)OC" - } - amount { - moles { - value: 0.000203 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 1.52e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 5.07e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 105.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "ipyrrolidine (0.025 mL, 0.30 mmol)ii was added to a suspension of ii1-(4-(4-(5-chloro-4-(7-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-ylamino)-3-methoxyphenyl)piperazin-1-yl)ethanone (104 mg, 0.20 mmol)iinbsp;in iidioxane (3.5 mL)ii, followed by iisodium 2-methylpropan-2-olate (58.5 mg, 0.61 mmol)ii, the mixturenbsp;was degassed by bubbling N2 through , thennbsp;a solutionnbsp;of pre-activated ( 50C 15 min ) solution in dioxannenbsp;(1 ml) of iidicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (7.26 mg, 0.02 mmol)ii ( Xphos) and iiTRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (4.65 mg, 5.07 mol)ii was added . iiThe brown-orange suspension was stirred atnbsp;ii105 Cii 1 hr ( trace of reaction ) iianisole (2 mL)ii w then overnight under nitrogen atmosphere : few of reaction observednbsp;from 1 hr to 16 hrs heatingii andnbsp;TBAC ( 25 mg ) were added and the heating was continued overnight no reactionnbsp;iinbsp;i" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)NC3=NC=C(C(=N3)C4=CN=C5N4C=CC(=C5)N6CCCC6)Cl)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/24/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "157" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000609 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0035 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CCNC1" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)NC3=NC=C(C(=N3)C4=CN=C5N4C=CC(=C5)Cl)Cl)OC" - } - amount { - moles { - value: 0.000203 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 6.09e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 3.04e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 95.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "ipyrrolidine (0.019 mL, 0.22 mmol)ii was added to a suspension of ii1-(4-(4-(5-chloro-4-(7-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-ylamino)-3-methoxyphenyl)piperazin-1-yl)ethanone (104 mg, 0.20 mmol)iinbsp;in iidioxane (3.5 mL)ii, followed by iisodium 2-methylpropan-2-olate (58.5 mg, 0.61 mmol)ii, the mixturenbsp;was degassed by bubbling N2 through , then ii2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (3.79 mg, 6.09 mol)ii and iiTRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (2.79 mg, 3.04 mol)ii were added . iiThe orange suspension was stirred atnbsp;ii95 Cii for 2 hours under nitrogen atmosphere : no reaction observediiThe same quantities of Binap and Pd2dba3 were added : 2 hours later ( no reaction ),nbsp;iipyrro5 mL, 1.01 mmol)i iwas added and the yellow orange mixture was heated at 100C overnight....no reaction iiWater ( 1ml) was added , solution, and the heating was continued :nbsp;mass pick 548, 549 appeared ( trce ? under SM pick ,Uplc, lcms2 acid conditions , trace of product) iiAn activated batch of Xantphos Pd2dba3 ( 1.51 Pd ) was prepared and added and the heating continued no evolution iiNot progressednbsp;isolationrecovery lateriinbsp;iinbsp;i" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)NC3=NC=C(C(=N3)C4=CN=C5N4C=CC(=C5)N6CCCC6)Cl)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/16/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "158" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0803 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.16 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=CC(=N1)S(=O)(=O)C)N" - } - amount { - moles { - value: 0.0318 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(N=CN=C1Cl)OC2CCN(CC2)C(=O)OC(C)C" - } - amount { - moles { - value: 0.0335 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)CN1CCN2CCN(P1N(CC2)CC(C)C)CC(C)C" - } - amount { - moles { - value: 0.000669 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000335 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Sodium tert-butoxide (9.83 mL, 80.31 mmol) was added portionwise to isopropyl 4-(6-chloro-5-methylpyrimidin-4-yloxy)piperidine-1-carboxylate (10.50 g, 33.46 mmol) and 2-methyl-6-(methylsulfonyl)pyridin-3-amine (5.92 g, 31.79 mmol) in dioxane (160 mL) at 18C over a period of 1 minute under nitrogen. The reaction was degassed with vacuum nitrogen (6 times) and 2,8,9-Triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo{3.3.3}undecane (0.238 mL, 0.67 mmol) and Palladium(II) acetate (0.075 g, 0.33 mmol) was added and the suspension was stirred at 90 C for a further 2 hours.nbsp;More 2,8,9-Triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo{3.3.3}undecane (0.238 mL, 0.67 mmol) and Palladium(II) acetate (0.075 g, 0.33 mmol) was added and the suspension was stirred at 90 C for a further another 2 hours before being allowed to cool and stirred at room temperature overnight.nbsp;The reaction was worked up with water (50 mL) and diluted with EtOAc (400 mL), and washed sequentially with water (100 mL) and sat (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography (330g column), elution gradient 0 to 50% EtOAc in DCM (rising quickly to 20% then more slowly to 50%). The impure fractions were collected and combined and purified again in exactly the same way. Pure fractions were evaporated to dryness to afford isopropyl 4-(5-methyl-6-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)pyrimidin-4-yloxy)piperidine-1-carboxylate, EN02029-72-solid-1, as a yellow solid. This solid was recrystallised from MeOH (~ 50 mL) and the resultant solid filtered off and washed with cold MeOH (2 x 5 mL), Et2O (2 x 5 mL) then isohexane (2 x 5 mL). The solid, EN02029-72-solid-2 was combined with the product from EN02029-67-01 and the whole sample was named EN02029-72-01 (8.39 g) and mitted to the collection." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(N=CN=C1OC2CCN(CC2)C(=O)OC(C)C)NC3=C(N=C(C=C3)S(=O)(=O)C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 54.09 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/12/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "159" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00185 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.00462 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=NC=C1Br)N" - } - amount { - moles { - value: 0.000925 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000111 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 9.25e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (20.76 mg, 0.09 mmol) was added to 5-bromopyridin-3-amine (160 mg, 0.92 mmol), morpholine (0.403 mL, 4.62 mmol) (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (64.2 mg, 0.11 mmol) and cesium carbonate (603 mg, 1.85 mmol) in dioxane (5 mL).nbsp;The resulting solution was stirred at 150 C in the microwave for 30 minutes. The major product was the dimer. Rection abandoned.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1COCCN1C2=CN=CC(=C2)N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/24/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "160" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00185 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.0462 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=NC=C1Br)N" - } - amount { - moles { - value: 0.000925 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000111 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 9.25e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (20.76 mg, 0.09 mmol) was added to 5-bromopyridin-3-amine (160 mg, 0.92 mmol), morpholine (4028 l, 46.24 mmol) (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (64.2 mg, 0.11 mmol) and cesium carbonate (603 mg, 1.85 mmol). The resulting suspension was stirred at 150 C for 30 minutes in a microwave. Reaction very messy but some product is visible.nbsp;Reaction abandoned.n" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1COCCN1C2=CN=CC(=C2)N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/28/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "162" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00107 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.008 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC(=NN1C(=O)OC(C)(C)C)N" - } - amount { - moles { - value: 0.000642 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC(C1=C(C=C(C=N1)F)F)NC2=C(C(=NC(=N2)Cl)N3CCOCC3)F" - } - amount { - moles { - value: 0.000535 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 4.82e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 3.21e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (27.9 mg, 0.05 mmol), 2-chloro-N-(1-(3,5-difluoropyridin-2-yl)ethyl)-5-fluoro-6-morpholinopyrimidin-4-amine (200 mg, 0.54 mmol), tert-butyl 3-amino-5-methyl-1H-pyrazole-1-carboxylate (127 mg, 0.64 mmol) and cesium carbonate (349 mg, 1.07 mmol) were added to dioxane (8 mL).nbsp;The mixture was purged with nitrogen for 15 minutes.nbsp;Pd2(dba)3 (29.4 mg, 0.03 mmol) was added and the mixture heated at 110 C for 3h.nbsp;No sign of any reaction." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CC(=NN1)NC2=NC(=C(C(=N2)N3CCOCC3)F)NC(C)C4=C(C=C(C=N4)F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/23/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "163" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.019 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=C(C=C1)C" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCCN1" - } - amount { - moles { - value: 0.076 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CN=C1)Br" - } - amount { - moles { - value: 0.0127 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" - } - amount { - moles { - value: 0.000633 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000253 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 130.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 100 ml RBF, 3-bromopyridine (1.220 mL, 12.66 mmol) was taken in xylenes (20 mL). To this was added tris(dibenzylideneacetone)dipalladium(0) (0.232 g, 0.25 mmol), tri-t-butylphosphine (10%wt in Hexane) (1.281 g, 0.63 mmol) and sodium tert-butoxide (1.825 g, 18.99 mmol). Then piperazine (6.54 g, 75.95 mmol) was added to RM and the RM was then heated at 130 C for 5 hrs. The reaction was monitored by LCMS. It did not show formation of product. The RM was discarded. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CN(CCN1)C2=CN=CC=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/06/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "164" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00228 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.00638 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCC(CC1)CN" - } - amount { - moles { - value: 0.000857 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)OC(F)(F)F)C2=CN=C3N2N=C(C=C3)Cl.Cl" - } - amount { - moles { - value: 0.000571 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C1=CC=CC=C1C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 0.000171 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 5.71e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 50 mL round bottom flask was charged with a magnetic stir bar, toluene (6.376 mL), 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine hydrochloride (200 mg, 0.57 mmol), (1-methylpiperidin-4-yl)methanamine (110 mg, 0.86 mmol), 2\'-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (67.4 mg, 0.17 mmol), Pd2dba3 (52.3 mg, 0.06 mmol), and sodium tert-butoxide (220 mg, 2.28 mmol).nbsp;The mixture was degassed with argon, the vessel fitted with a reflux condenser, and then placed in an oil bath heated to 110 C with stirring for 16 h.nbsp;The mixture was cooled to rt, pre-absorbed onto silca gel (~ 20 g) and purified on silica gel (80 g) using MeOHDCM (1:3) as eluent to afford the title compound ~ 90 % pure.nbsp;This material was then dissolved in DMSO and purified via reverse phase HPLC waterMECN (5-gt;55%, 12 min) as eluent.nbsp;The pure fractions were collected and converted to the corresponding HCl salt to afford N-((1-methylpiperidin-4-yl)methyl)-3-(3-(trifluoromethoxy)phenyl)imi[1,2-b]pyridazin-6-amine (125 mg, 49.5 %) hydrochloride as a white solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CCC(CC1)CNC2=NN3C(=NC=C3C4=CC(=CC=C4)OC(F)(F)F)C=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 49.52 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/08/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "166" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.014 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.03 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.012 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)COC2=NC(=CC=C2)Br" - } - amount { - moles { - value: 0.01 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00015 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.0001 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Reagents split into 2 microwave tubes:-2-(benzyloxy)-6-bromopyridine (2.641 g, 10.00 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.092 g, 0.10 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.093 g, 0.15 mmol) ,morpholine (1.045 g, 12.00 mmol) and sodium t-butoxide (1.345 g, 14.00 mmol) were suspended in toluene (30 mL). Degassed with N2 for 5 mins and sealed into a microwave tube. The reaction was heated to 120 C for 10 minutes in the microwave reactor and cooled to RT. buWork-up*ubThe mixture was diluted with EtOAc and filtered through a short celite pad. The solution was then concentrated to dryness to give an orange viscous liquid (~4.7g).The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 4-(6-(benzyloxy)pyridin-2-yl)morpholine (2.350 g, 87 %) as a yellow oil. nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1COCCN1C2=NC(=CC=C2)OCC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 86.94 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/18/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "168" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000466 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C(=CC=N1)N" - } - amount { - moles { - value: 0.000466 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)Cl" - } - amount { - moles { - value: 0.00031 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 6.21e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 3.1e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "8-(2,5-dichloropyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (100 mg, 0.31 mmol), 1-methyl-1H-pyrazol-5-amine (60.3 mg, 0.62 mmol), sodium 2-methylpropan-2-olate (44.7 mg, 0.47 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (38.7 mg, 0.06 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (28.4 mg, 0.03 mmol) were suspended in dioxane (2 mL) and sealed into a microwave tube. The reaction was degased, purged with nitrogen and heated to 150 C over a period of 30 minutes in the microwave reactor. Reaction was filtered, washed with CH2Cl2 and concentrated to dryness. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 1% acetic acid) and acetonitrile as eluent. The fractions containing product were combined and basified with saturated aqueous solution ofnbsp;NaHCO3. Aqueous layer was extracted with CH2Cl2 (2x15 mL). Organic layer was washedh brine, dried over MgSO4 and concentrated to dryness to afford 8-(5-chloro-2-(1-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (57.0 mg, 48.0 %) as a yellow crystalline solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)NC4=CC=NN4C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 47.97 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/16/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "169" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000466 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C(=CC=N1)N" - } - amount { - moles { - value: 0.000466 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)Cl" - } - amount { - moles { - value: 0.00031 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 6.21e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 3.1e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "8-(2,5-dichloropyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (100 mg, 0.31 mmol), 1-methyl-1H-pyrazol-5-amine (60.3 mg, 0.62 mmol), sodium 2-methylpropan-2-olate (44.7 mg, 0.47 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (35.9 mg, 0.06 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (28.4 mg, 0.03 mmol) were suspended in dioxane (2 mL) and sealed into a microwave tube. The reaction was degased, purged with nitrogen and heated to 150 C over a period of 30 minutes in the microwave reactor. Reaction was filtered, washed with CH2Cl2 and concentrated to dryness. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 1% acetic acid) and acetonitrile as eluent. The fractions containing product were combined and basified with saturated aqueous solution ofnbsp;NaHCO3. Aqueous layer was extracted with CH2Cl2 (2x15 mL). Organic lawas washed with brine, dried over MgSO4 and concentrated to dryness to afford 8-(5-chloro-2-(1-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (52.0 mg, 43.8 %) as a pale purple crystalline solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)NC4=CC=NN4C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 43.76 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/16/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "170" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000466 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C(=CC=N1)N" - } - amount { - moles { - value: 0.000466 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)Cl" - } - amount { - moles { - value: 0.00031 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 6.21e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 3.1e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "8-(2,5-dichloropyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (100 mg, 0.31 mmol), 1-methyl-1H-pyrazol-5-amine (60.3 mg, 0.62 mmol), sodium 2-methylpropan-2-olate (44.7 mg, 0.47 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (38.7 mg, 0.06 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (28.4 mg, 0.03 mmol) were suspended in dioxane (2 mL) and sealed into a tube. The reaction was degased, purged with nitrogen and heated to 100 C for 1 hour. Reaction was filtered, washed with CH2Cl2 and concentrated to dryness. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford 8-(5-chloro-2-(1-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (32.0 mg, 26.9 %) as a white solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)NC4=CC=NN4C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 26.93 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/07/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "171" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000466 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C(=CC=N1)N" - } - amount { - moles { - value: 0.000466 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)Cl" - } - amount { - moles { - value: 0.00031 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 6.21e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 3.1e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 140.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "8-(2,5-dichloropyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (100 mg, 0.31 mmol), 1-methyl-1H-pyrazol-5-amine (60.3 mg, 0.62 mmol), sodium 2-methylpropan-2-olate (44.7 mg, 0.47 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (38.7 mg, 0.06 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (28.4 mg, 0.03 mmol) were suspended in dioxane (2 mL) and sealed into a microwave tube. The reaction was degased, purged with nitrogen and heated to 140 C for 5 minutes in the microwave reactor. Reaction was filtered, washed with CH2Cl2 and concentrated to dryness. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford 8-(5-chloro-2-(1-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (36.0 mg, 30.3 %) as an off-whiolid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)NC4=CC=NN4C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 30.3 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/08/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "172" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000372 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C(=CC=N1)N" - } - amount { - moles { - value: 0.000621 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)Cl" - } - amount { - moles { - value: 0.00031 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 4.97e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.48e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "8-(2,5-dichloropyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (100 mg, 0.31 mmol), 1-methyl-1H-pyrazol-5-amine (60.3 mg, 0.62 mmol), cesium carbonate (121 mg, 0.37 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (28.7 mg, 0.05 mmol) and diacetoxypalladium (5.57 mg, 0.02 mmol) were suspended in dioxane (2 mL) and sealed into a tube. The reaction was degased, purged with nitrogen and heated to 100 C for 12 hours. Reaction was filtered, washed with CH2Cl2 and concentrated to dryness. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford 8-(5-chloro-2-(1-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (83 mg, 69.8 %) as a grey solid.Sample was combined with EN01622-31,32,33,35,3,38,39amp;40. The crude product was purified by flash chromatography on silica gel eluting with 0 to 4% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness to afford 8-(5-chloro-2-(1-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (218 mg, EN01622-42-02) as a pale pink foam." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CCC2=C(C1=O)C(=CC=C2)NC3=CC(=NC=C3Cl)NC4=CC=NN4C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 69.85 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/09/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "173" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00712 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.018 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC" - } - amount { - moles { - value: 0.00356 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1C2=CC(=O)N3C=CC=C(C3=N2)C4=CC=CC5=C4SC6=C5C=C(C=C6)OS(=O)(=O)C(F)(F)F" - } - amount { - moles { - value: 0.00178 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 8.9e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 4.45e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "tert-butyl methylcarbamate (467 mg, 3.56 mmol) dissolved in dioxane (5ml) was added in one portion to 6-(2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)dibenzo[b,d]thiophen-2-yl trifluoromethanesulfonate (1000 mg, 1.78 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (40.8 mg, 0.04 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (51.5 mg, 0.09 mmol) and cesium carbonate (2321 mg, 7.12 mmol) in dioxane (18mL) at 110 C. The reaction flask was evacuated and blanketed with nitrogen 4X. The resulting suspension was stirred at 110 C for 3i ihoursi.nbsp;iThe crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOHDCM (5050) and pure fractions were evaporated to dryness to afford tert-butyl methyl(6-(2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)dibenzo[b,d]thiophen-2-yl)carbamate (771 mg, 80 %) as a yellow solid. Used crude in the next reaction see EN0198" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N(C)C1=CC2=C(C=C1)SC3=C2C=CC=C3C4=CC=CN5C4=NC(=CC5=O)N6CCOCC6" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 79.79 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/12/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "174" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00712 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.018 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC" - } - amount { - moles { - value: 0.00356 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1C2=CC(=O)N3C=CC=C(C3=N2)C4=CC=CC5=C4SC6=C5C=C(C=C6)OS(=O)(=O)C(F)(F)F" - } - amount { - moles { - value: 0.00178 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 8.9e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 4.45e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "tert-butyl methylcarbamate (467 mg, 3.56 mmol) dissolved in dioxane (5ml) was added in one portion to 6-(2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)dibenzo[b,d]thiophen-2-yl trifluoromethanesulfonate (1000 mg, 1.78 mmol) , TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (40.8 mg, 0.04 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (51.5 mg, 0.09 mmol) and cesium carbonate (2321 mg, 7.12 mmol) in degassed dioxane (18 mL), under nitrogen, at 110 C. The reaction flask was evacuated and blanketed with nitrogen 4X. The resulting suspension was stirred at 110 C for 3i ihours with complete reaction observed by LCMS.nbsp;After cooling, the mixture was partitioned between EtOAc (100mL) and water (50ml).nbsp;The organics were separated and dried (MgSO4) and evaporated to give the crude product, tert-butyl methyl(6-(2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)dibenzo[b,d]thiophen-2-yl)carbamate (950 mg, 98 %) which was combined with the crude product from EN02472-66 and (proceedure detailed on that page).mz (ES+) (M+H)+ = 543; HPLC tR= 2.91 min." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N(C)C1=CC2=C(C=C1)SC3=C2C=CC=C3C4=CC=CN5C4=NC(=CC5=O)N6CCOCC6" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 98.31 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/06/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "175" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0463 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.018 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC" - } - amount { - moles { - value: 0.0232 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1C2=CC(=O)N3C=CC=C(C3=N2)C4=CC=CC5=C4SC6=C5C=C(C=C6)OS(=O)(=O)C(F)(F)F" - } - amount { - moles { - value: 0.0116 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000579 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000289 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "tert-butyl methylcarbamate (3.04 g, 23.15 mmol) dissolved in dioxane (5ml) was added in one portion to 6-(2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)dibenzo[b,d]thiophen-2-yl trifluoromethanesulfonate (6.50g, 11.58 mmol) , TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.265 g, 0.29 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.335 g, 0.58 mmol) and cesium carbonate (15.09 g, 46.30 mmol) in degassed dioxane (18 mL), under nitrogen. The reaction flask was evacuated and blanketed with nitrogen 4X. iiThe resulting suspension was stirred at 110 C for 3i ihours with complete reaction observed by LCMS.nbsp;After cooling, the mixture was partitioned between EtOAc (500mL) and water (250ml).nbsp;The organics were separated and dried (MgSO4) and evaporated to give the crude product which was combined with the crude product from EN02472-66.nbsp;The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evapor to dryness to afford tert-butyl methyl(6-(2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)dibenzo[b,d]thiophen-2-yl)carbamate (5.61 g, 89 %) as a yellow solid. 1H NMR (400 MHz, CDCl3, 22C) d 1.48 (9H, s), 3.34 - 3.39 (7H, m), 3.54 - 3.59 (4H, m), 5.63 (1H, s), 6.99 - 7.05 (1H, m), 7.34 (1H, dd), 7.56 (2H, m), 7.72 (1H, d), 7.86 (1H, dt), 8.04 (1H, s), 8.16 (1H, dt), 9.04 (1H, m).mz (ES+) (M+H)+ = 543; HPLC tR= 2.89 min." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N(C)C1=CC2=C(C=C1)SC3=C2C=CC=C3C4=CC=CN5C4=NC(=CC5=O)N6CCOCC6" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 89.31 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/07/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "176" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00132 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=C(C=C1)C" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC(=CC=C1)OC2CCNCC2.Cl" - } - amount { - moles { - value: 0.000451 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC2=NN=C(N2C=C1Br)C(F)(F)F" - } - amount { - moles { - value: 0.000376 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 2.82e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" - } - amount { - moles { - value: 1.88e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "6-bromo-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (100 mg, 0.38 mmol), 4-(3-methoxyphenoxy)piperidine hydrochloride (110 mg, 0.45 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (17.56 mg, 0.03 mmol) and Sodium tert-butoxide (0.161 mL, 1.32 mmol) were suspended in xylenes (5 mL), then de-gassed and purged with nitrogen. Bis(dibenzylideneacetone)palladium (10.81 mg, 0.02 mmol) was added, and the mixture was sealed into a microwave tube. The reaction was heated to 100 C for 20 minutes in the microwave reactor and cooled to RT.nbsp;The reaction mixture was diluted with EtOAc (25 mL), and washednbsp;with water (25 mL). The organic layer was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 19 mm diameter, 100 mm length), using decreasinglyixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-(4-(3-methoxyphenoxy)piperidin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (45.0 mg, 30.5 %) as a white solid. nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=CC(=CC=C1)OC2CCN(CC2)C3=CN4C(=NN=C4C(F)(F)F)C=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 30.51 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/22/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "177" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=C(C=C1)C" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C(=CC=N1)CCOC2=CC=C(C=C2)C3CCNCC3" - } - amount { - moles { - value: 0.000244 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC2=NN=C(N2C=C1Br)C(F)(F)F" - } - amount { - moles { - value: 0.000244 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 1.83e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" - } - amount { - moles { - value: 1.22e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "6-bromo-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (65 mg, 0.24 mmol), 4-(4-(2-(1-methyl-1H-pyrazol-5-yl)ethoxy)phenyl)piperidine (112 mg, 0.24 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (11.41 mg, 0.02 mmol) and Sodium tert-butoxide (0.060 mL, 0.49 mmol) were suspended in xylenes (5 mL), then de-gassed and purged with nitrogen. Bis(dibenzylideneacetone)palladium (7.02 mg, 0.01 mmol) was added, and the mixture was sealed into a microwave tube. The reaction was heated to 110 C for 30 minutes in the microwave reactor and cooled to RT. The reaction mixture was diluted with EtOAc (25 mL), and washed with water (25 mL). The aqueous layer was extraced with further EtOAc (25 mL). The combined organic layers were purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness to afford crude product.nbsp;The crude product was purified by preparative HPLC (Waters XBridge Prep C18 Oolumn, 5 silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-(4-(4-(2-(1-methyl-1H-pyrazol-5-yl)ethoxy)phenyl)piperidin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (22.00 mg, 19.14 %) as a colourless gum. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1C(=CC=N1)CCOC2=CC=C(C=C2)C3CCN(CC3)C4=CN5C(=NN=C5C(F)(F)F)C=C4" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 19.14 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/16/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "178" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0013 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.05 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCCC1CO" - } - amount { - moles { - value: 0.0434 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C=C1Cl)Cl)I" - } - amount { - moles { - value: 0.0434 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00521 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000434 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 125.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "buProcedure:ubTo a flask was added 1,3-Dichloro-4-iodobenzene (5.89 mL, 43.41 mmol), piperidin-4-ylmethanol (5 g, 43.41 mmol), cesium carbonate (28.3 g, 86.83 mmol), 18-Crown-6 (1.377 g, 5.21 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.811 g, 1.30 mmol), and toluene (50 mL).nbsp;The mixture was stirred under nitrogen and Tris(dibenzylideneacetone)dipalladium(0) (0.398 g, 0.43 mmol) was added in one portion.nbsp;The resultant yellow mixture was heated with oil bath temperature set at 125C for 3 hours.nbsp;LCMS shows desired product as well as other impurities.nbsp;The reaction was cooled to room temperature.nbsp;Ethyl acetate (2 x 200 mL) was added and the resultant mixture was extracted with saturated aqueous sodium chloride (200 mL).nbsp;The organics were collected and dried over sodium sulfate.nbsp;Ethyl acetate (100 mL) and hexanes (100 mL) were added to the crude and insoluble material filltered off.nbsp;The filtrate was concentrated and chromatographed on ca gel (divided into 3 40 gram silica gel columns).nbsp;The columns were eluted with hexanes up to ethyl acetate:hexanes (up to 100%).nbsp;The desired product eluted between 40-60% ethyl acetate:hexanes.nbsp;Clean fractions were combined from all columns and concentrated to give EN01972-36-1 (2.47 g, 21.87% yield) as an orange oil.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CN(CCC1CO)C2=C(C=C(C=C2)Cl)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 21.87 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/06/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "179" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0013 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.05 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCCC1CO" - } - amount { - moles { - value: 0.0434 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C=C1Cl)Cl)I" - } - amount { - moles { - value: 0.0434 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00521 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000434 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 125.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "buProcedure:ubTo a flask was added 1,3-Dichloro-4-iodobenzene (5.89 mL, 43.41 mmol), piperidin-4-ylmethanol (5 g, 43.41 mmol), cesium carbonate (28.3 g, 86.83 mmol), 18-Crown-6 (1.377 g, 5.21 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.811 g, 1.30 mmol), and toluene (50 mL).nbsp;The mixture was stirred under nitrogen and Tris(dibenzylideneacetone)dipalladium(0) (0.398 g, 0.43 mmol) was added in one portion.nbsp;The resultant yellow mixture was heated with oil bath temperature set at 125C for 3 hours.nbsp;LCMS shows desired product as well as other impurities.nbsp;The reaction was cooled to room temperature.nbsp;Ethyl acetate (2 x 200 mL) was added and the resultant mixture was extracted with saturated aqueous sodium chloride (200 mL).nbsp;The organics were collected and dried over sodium sulfate.nbsp;The crude was placed in the freezer for several days.The crude was dissolved in 10% methanol:dichloromethane (200 mL) and preabsorbed onto silica gel.nbsp;mn chromatography was performed on silica gel eluting with hexanes up to ethyl acetate:hexanes (10%, 20%, 40%).nbsp;Desired product eluted at 40% ethyl acetate:hexanes.nbsp;Collected clean fractions and concentrated to give EN01972-57-1 (2.83 g, 25.06% yield) as an orange oil.nbsp;Put aside product due to shift in priorities of project." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CN(CCC1CO)C2=C(C=C(C=C2)Cl)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 25.06 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/27/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "180" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00098 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C=O" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN(C)CCN" - } - amount { - moles { - value: 0.0098 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)I" - } - amount { - moles { - value: 0.0049 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00098 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.00049 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 50 mL round-bottomed flask (t=g) was unsym-Dimethylethylenediamine (1.080 mL, 9.80 mmol), Iodobenzene (0.549 mL, 4.90 mmol), and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.449 g, 0.49 mmol)Cesium carbonate (2.396 g, 7.35 mmol) andCesium carbonate (2.396 g, 7.35 mmol)nbsp;were added. in DMF (10 mL) ([VOLUME]) to give a brown suspension. Reaction stirred over night at 100. no reaction." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(C)CCNC1=CC=CC=C1" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/14/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "181" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000447 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC1CNC1" - } - amount { - moles { - value: 0.000383 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=NC=CC(=C1)Br" - } - amount { - moles { - value: 0.000319 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 3.19e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 70.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of all the reactants in toluene was heated in a sealed vial at 70 oC overnight. According to LC-MS the reaction was completed and the product had been formed.Toluene was removed, water was added and the product was extracted with DCM. The organic phase was dried through phase separator and concentrated. The crude was used without further purification in the next step, EN01762-02." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC1CN(C1)C2=CC(=NC=C2)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 100.28 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/21/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "182" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00149 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.006 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC1CNC1" - } - amount { - moles { - value: 0.00128 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=NC=CC(=C1)Br" - } - amount { - moles { - value: 0.00106 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000106 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 5.32e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 70.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of all the reactants in toluene was heated in a sealed vial at 70 oC overnight. According to LC-MS the reaction was completed and the product had been formed.Toluene was removed, water was added and the product was extracted with DCM. The organic phase was dried through phase separator and concentrated." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC1CN(C1)C2=CC(=NC=C2)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 99.96 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/25/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "183" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 1.31e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.001 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCC2=C(C1=O)C(=CC=C2)N" - } - amount { - moles { - value: 0.000131 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" - } - amount { - moles { - value: 0.000131 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 1.31e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 6.54e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A suspension of 8-amino-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (23.06 mg, 0.13 mmol), N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (50 mg, 0.13 mmol), diacetoxypalladium (1.469 mg, 6.54 mol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (7.57 mg, 0.01 mmol) and cesium carbonate (85 mg, 0.26 mmol) was stirred at 80 C overnight under nitrogen. LCMS showed formation of more bis-arylation by-product than in uEN01775-08u (DMA under micorwaves conditions). The crude was combined with EN01775-08-01 and poured onto a silicagel column. The crude product was purified by flash chromatography eluting with 0 to 5% methanol in ethyl acetateDCM (11). The solvent was evaporated to dryness to afford a gummy film in the flask b(37mg: not that bad)b. it was scratched in diethyl ether (soluble) then after Et2O evaporation in a few drops of MeCN. A solid crashed out. The resulting solid was taken up into diethyl ether, collected by filtration and dried to af2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (19.00 mg, 33.7 %) as anbsp;white solid (a bit soluble in Et2O because some P1 remained in the Et2O filtrate).bnot the real yieldb" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC4=C3C(=O)N(CC4)C)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 33.74 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/10/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "184" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0209 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.12 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC=CC=C1N" - } - amount { - moles { - value: 0.0178 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" - } - amount { - moles { - value: 0.0105 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00105 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000523 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.606 g, 1.05 mmol), diacetoxypalladium (0.118 g, 0.52 mmol), 2-amino-N-methylbenzamide (2.67 g, 17.80 mmol) and N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (4 g, 10.47 mmol) were dissolved in dioxane (120 mL) and argon was let to bubble in the mixture for 5 minutes.cesium carbonate (6.82 g, 20.94 mmol) was added and argon was let to bubble in the mixture for 5 minutes. The reaction was stirred at 90 C for 2 hours. After taking 2 aliquotsd to check the reaction it turned from yello to grey. LCMS didn\'t show a complete clean reaction but it stopped.nbsp;The reaction mixture was allowed to cool to room temperature under stirring, diluted with dichloromethane, insoluble was removed by filtration and the filtrate was concentrated. The crude product was purified by flash chromatography on silica gel (150g) eluting with 0 to 5% methanol in ethyl acetateDCM (11). The solvent was evaporated to dryness, giving a gummym. 60 mL of tBuOMe was added and the resulting solution was stirred at rt for 15 minutes. The resulting precipitate was collected by filtration, washed with tBuOMe and dried to a constant weight to afford 2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide (3.60 g, 85 %) as a pale beige solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 85.04 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "12/02/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "185" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000132 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC=CC=C1N" - } - amount { - moles { - value: 0.00224 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" - } - amount { - moles { - value: 0.00132 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000132 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 6.58e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (76 mg, 0.13 mmol) and diacetoxypalladium (14.77 mg, 0.07 mmol) were dissolved in dioxane (15 mL) and argon was let to bubble in the mixture for 5 minutes. 2-amino-N-methylbenzamide (336 mg, 2.24 mmol), N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (503 mg, 1.32 mmol) and cesium carbonate (858 mg, 2.63 mmol) were added and the reaction was heated to 90 C, over a period of 90 minutes under nitrogen. LCMS didn\'t show a complete clean reaction (as Cs2CO3 got stuck on the flask). Vigourous stirring was applied and theaction was heated to 90 C, over a period of 90 minutes under nitrogen. Crude LCMS was as expected.nbsp;The reaction mixture was allowed to cool to room temperature under stirring, diluted with dichloromethane and decalite speed + was added. The mixture was concentrated and the crude product was purified by flash chromatography on silica gel eluting with 0 to 5% methanol in ethyl acetateDCM (11). Tnt was evaporated to dryness, giving a gummy foam of P1 (490mg). A bit of diethyl ether then a lot of pentane were added to obtain a solid, which was dried under vacuum at 50C to afford 2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide (450 mg, 77 %) as an yellow solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 76.94 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/30/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "186" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 1.31e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.001 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC=CC=C1N" - } - amount { - moles { - value: 0.000262 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" - } - amount { - moles { - value: 0.000131 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 1.31e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 6.54e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-amino-N-methylbenzamide (39.3 mg, 0.26 mmol), N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (50 mg, 0.13 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (7.57 mg, 0.01 mmol), diacetoxypalladium (1.469 mg, 6.54 mol) and cesium carbonate (85 mg, 0.26 mmol) were dissolved in dioxane (1 mL) and sealed into a microwave tube. Argon was let to bubble in the mixture for 5 minutes. The reaction was heated to 90 C, over a period of 90 minutes. LCMS showed complete and pretty clean reaction. The reaction mixture was allowed to cool to room temperature under stirring, diluted with dichloromethane and decalite speed + was added. The mixture was concentrated and the crude product was purified by flash chromatography on silica gel eluting with 0 to 5% methanol in ethyl acetateDCM (11). The solvent was evaporated to dryness, a bit of diethyl ether was added in order to crystallised but it didn\'t work. So it was concentrated again to afford 2-(2-(1,3-dimethyl-1H-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide (50.0 mg, 94 %) as anbsp;brown dry film." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 94.49 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/26/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "187" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00353 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.15 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=C(C=CC=C1OC)N" - } - amount { - moles { - value: 0.053 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" - } - amount { - moles { - value: 0.0353 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00353 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00177 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A suspension of 2-amino-6-methoxy-N-methylbenzamide (9.55 g, 52.99 mmol), N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (13.5 g, 35.33 mmol), diacetoxypalladium (0.397 g, 1.77 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.044 g, 3.53 mmol) and cesium carbonate (20.72 g, 63.59 mmol) in dioxane (150 mL) was degassed with argon, which was also let to bubble for 10 minutes then stirred at 100 C overnight (yellow-ish dense suspension turning grey lighter). The reaction mixture was allowed to cool to rt, the insolubles were removed by filtration, washed with EtOAc and the filtrate was concentrated. (Insolubles~25g, which seemed to contain very little P1 by TLC and LCMS).The crude product (24.5g) was purified by flash chromatography on silica gel eluting with 0 to 5% methanol in ethyl acetatenbsp;(pure AcOEt to remove by-product coming from overreaction). The solvent was evaporated to dryness to afford a foam (12.5g) which was dissolved in dichloroane (100ml). The resulting crystalline precipitate was collected by filtration, washed with dichloromethane. The filtrate was concentrated down, taken up into DCM and a second crop was collected by filtration, which was combined with the first batch and dried to a constant weight to afford 2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-6-methoxy-N-methylbenzamide (11.51 g, 75.0 %) as anbsp;white crystalline solid.The filtrate was concentrated to dryness, taken up into DCM and collected by filtration to give a second sample EN02972-35-02 (0.41 g, 0.944 mmol, 2.67 %)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=C(C(=CC=C3)OC)C(=O)NC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 75.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/25/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "188" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0068 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.3 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=C(C=CC=C1OC)N" - } - amount { - moles { - value: 0.102 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" - } - amount { - moles { - value: 0.068 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.0068 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.0034 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a stirred solution of N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (26 g, 68.04 mmol) and 2-amino-6-methoxy-N-methylbenzamide (18.39 g, 102.06 mmol) in dioxane (300 mL) is added cesium carbonate (39.9 g, 122.47 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (3.94 g, 6.80 mmol) and diacetoxypalladium (0.764 g, 3.40 mmol).Mixture was degassed 3 times with N2 and heated to 100C overnight. LCMS crude seems OK.Reaction was cooled to room temperature then salts were filtered and the filtrate concentrated to afford a crude compound which was purified on silica, eluting with 5% MeOH in AcOEt.Solvent were evaporated to afford a gum which finished by crystallize in 100mL of CH2Cl2.Solid was filtered and dried to a constant weight to afford 2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-6-methoxy-N-methylbenzamide (17.30 g, 58.5 %) as a white crystalline product.1H NMR, purity check OK, 98%purity." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=C(C(=CC=C3)OC)C(=O)NC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 58.53 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/17/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "189" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 3.93e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=C(C=CC=C1OC)N" - } - amount { - moles { - value: 0.000785 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" - } - amount { - moles { - value: 0.000393 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.93e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.96e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A suspension of [Reactants], N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (150 mg, 0.39 mmol), diacetoxypalladium (4.41 mg, 0.02 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (22.71 mg, 0.04 mmol) and cesium carbonate (256 mg, 0.79 mmol) in dioxane (2 mL) was degassed with argon then stirred at 100 C for 2 hours sealed in a microwave vial. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford impure product EN01775-26-01. The impure product was repurified by flash chromatography on silica gel eluting with 0 to 5% methanol in ethyl acetateDCM (11) - spillage occurred when collecting. The solvent was evaporated to dryness to afford 110mg ofoam, which was triturated in tBuOMe. The resulting precipitate was collected by filtration and dried to a constant weight to afford [Products] as anbsp;white solid EN01775-26-02 (81 mg, 0.186 mmol, 47.5 %)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=C(C(=CC=C3)OC)C(=O)NC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 47.5 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/07/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "190" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000688 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.037 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=C(C=CC=C1OC)N" - } - amount { - moles { - value: 0.0138 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" - } - amount { - moles { - value: 0.00688 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000688 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000344 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A suspension of [Reactants], N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (2.63 g, 6.88 mmol), diacetoxypalladium (0.077 g, 0.34 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.398 g, 0.69 mmol) and cesium carbonate (4.48 g, 13.77 mmol) in dioxane (37 mL) was degassed with argon then stirred at 100 C for 3 hours . The reaction mixture was concentrated to dryness, diluted with ethyl acetate (80 ml), washed with water (1 x 50 ml), brine, dried over magnesium sulfate and concentrated to afford an oil.The crude product was purified by flash chromatography on silica gel eluting with AcOet pure to remove impurities then 3 to 8% methanol in ethyl acetate. The solvent was evaporated to dryness to afford a foam which was dissolved in dichloromethane ( 12ml ).A solid was formed after a few minutes, which was filtered, dried .A white solid was obtained 2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-6-methoxmethylbenzamide (1.570 g, 52.5 %)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=C(C(=CC=C3)OC)C(=O)NC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 52.51 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/20/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "191" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 3.93e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCOC2=CC=CC(=C2C1=O)N" - } - amount { - moles { - value: 0.000785 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" - } - amount { - moles { - value: 0.000393 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.93e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.96e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A suspension of 6-amino-4-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (151 mg, 0.79 mmol), N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (150 mg, 0.39 mmol), diacetoxypalladium (4.41 mg, 0.02 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (22.71 mg, 0.04 mmol) and cesium carbonate (256 mg, 0.79 mmol) innbsp;dioxane (2 mL) was degassed with argon then stirred at 100 C for 2 hours sealed in a microwave vial. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford impure product EN01775-27-01. The impure product was repurified by flash chromatography on silica gel eluting with 0 to 5% methanol in ethyl acetateDCM (11). The solvent was evated to dryness to afford 118mg of a sticky foam, which was triturated in a mixture of tBuOMe and pentane (~30-40% of tBuOMe). The mixture was concentrated down to get a light white foam, which could be handled." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=C4C(=CC=C3)OCCN(C4=O)C)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 54.21 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/07/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "192" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00015 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)N" - } - amount { - moles { - value: 0.0002 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=NC(=C1Br)Cl)Cl" - } - amount { - moles { - value: 0.0001 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 7.5e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.5e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "BINAP (4.67 mg, 7.50 mol) and Pd2dba3 (2.289 mg, 2.50 mol) were dissolved in dioxane (1ml) and flushed with nitrogen. 3-bromo-2,6-dichloropyridine (0.023 g, 0.1 mmol), aniline (0.018 mL, 0.20 mmol) and sodium tert-butoxide (0.014 g, 0.15 mmol) were weight in another flask and flushed with nitrogen. The ligand-Pd mixture was joined and the reaction mixture was stirred at 100C over night. Detection of the reaction was done by LCMS. LCMS showed the completion of the reation. the 3-bromo-2,6-dichloropyridine as well as the aniline were gone, but no desired product was detected. NMR verified the observations. The products have not been ide" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=C(N=C(C=C2)Cl)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/29/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "193" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "[O-]P(=O)([O-])[O-].[K+].[K+].[K+]" - } - amount { - moles { - value: 2.6e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N" - } - amount { - moles { - value: 0.000625 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=C(N=C1Cl)Cl)C(=O)O" - } - amount { - moles { - value: 0.000521 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 2.6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Reagents were mixed in a 25 mL round bottom flask and flushed well with nitrogen -nbsp;heated at 100 C for 16 h. The mixture looked dark black. Could not detect any starting material or product!It was discarded." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC1=NC(=CC(=C1)C(=O)O)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/12/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "194" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0027 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C(=CC=N1)N" - } - amount { - moles { - value: 0.00162 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.00135 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00027 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000135 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 105.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (124 mg, 0.14 mmol) was added in one portion to 2,4-dichloropyridine (200 mg, 1.35 mmol), 1-methyl-1H-pyrazol-5-amine (158 mg, 1.62 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (156 mg, 0.27 mmol), and cesium carbonate (881 mg, 2.70 mmol) in 1,4-dioxane (20 mL) under nitrogen. The resulting mixture was stirred at 105C for 2 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (50 mL), and washed with water (50 mL). The organic layer was filtered using phase separating paper and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-chloro-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine (66.0 mg, 23.41 %) as a yellow oil which solidified on standing. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1C(=CC=N1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 23.41 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/09/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "195" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 7.97e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C(=CC=N1)N" - } - amount { - moles { - value: 0.000743 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.000676 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.97e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.74e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 200.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;2,4-dichloropyridine (100mg, 0.68 mmol), 1-methyl-1H-pyrazol-5-amine (72.2 mg, 0.74 mmol) and cesium carbonate (330 mg, 1.01 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (46.1 mg, 0.08 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (25.06 mg, 0.03 mmol) were suspended in 1,4-dioxane (5 mL) and sealed into a microwave tube. The reaction was heated to 200C for 1 hour in the microwave reactor and cooled to RT. The reaction mixture was evaporated to dryness and redissolved in DCM (20 mL), and washed with water (20 mL). The organic layer was filtered with phase separating paper and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-chloro-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine (14.00 mg, 9.93 %) as a yellow oil which solidified on standing. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1C(=CC=N1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 9.93 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/11/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "196" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0101 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.075 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C(=CC=N1)N" - } - amount { - moles { - value: 0.00743 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.00676 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000797 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000274 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 105.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (251 mg, 0.27 mmol) was [AP-added] to 2,4-dichloropyridine (1000mg, 6.76 mmol), 1-methyl-1H-pyrazol-5-amine (722 mg, 7.43 mmol), cesium carbonate (3302 mg, 10.14 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (461 mg, 0.80 mmol) in 1,4-dioxane (75 mL) warmed to 105C over a period of 21 hours under nitrogen. The reaction mixture was evaporated to dryness and redissolved in DCM (50 mL), and sequentially with water (25 mL). The organic layer was filtered using phase separating paper and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-chloro-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine (710 mg, 50.4 %) as a brown oil. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1C(=CC=N1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 50.36 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/12/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "197" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0101 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.06 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C(=CC=N1)N" - } - amount { - moles { - value: 0.0101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.00676 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000797 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000274 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 130.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (251 mg, 0.27 mmol) was added in one portion to 2,4-dichloropyridine (1000mg, 6.76 mmol), 1,3-dimethyl-1H-pyrazol-5-amine (826 mg, 7.43 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (461 mg, 0.80 mmol) and sodium tert-butoxide (974 mg, 10.14 mmol) in 1,4-dioxane (60 mL) warmed to 130C over a period of 10 minutes under nitrogen. The resulting mixture was stirred at 130C for 20 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (150 mL).nbsp;Solids were filtered off by suction and the filtrate sequently washed withnbsp;water (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 4% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-chloro-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine (802 mg, 56.9 %) as a yellow oil which crystallised on standi" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1C(=CC=N1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 56.88 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/23/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "198" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.101 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.5 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C(=CC=N1)N" - } - amount { - moles { - value: 0.101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.0676 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00405 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.00135 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 130.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (1.238 g, 1.35 mmol) was added in one portion to 2,4-dichloropyridine (10g, 67.57 mmol), 1-methyl-1H-pyrazol-5-amine (7.22 g, 74.33 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.346 g, 4.05 mmol) and sodium tert-butoxide (9.74 g, 101.36 mmol) in 1,4-dioxane (500 mL) warmed to 130C over a period of 10 minutes under nitrogen. The resulting mixture was stirred at 130 C for 24 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (300 mL), and washed with water (125 mL).nbsp;The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 4% MeOH in DCM. Pure fractions were evaporated to dryness to afford EN01861-14-01 (2.93 g, 20.8 %) as a yellow crystalline solid. EN01861-14-01 (2.93 g) was combined with EN01861-09-01 (2.63g) to give EN01861-14-02 (5.56 g) as a yellow crystalline p" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1C(=CC=N1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 60.25 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/30/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "199" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00203 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C(=CC=N1)N" - } - amount { - moles { - value: 0.00149 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.00135 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00016 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 5.47e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 105.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (50.1 mg, 0.05 mmol) was added in one portion to 2,4-dichloropyridine (200 mg, 1.35 mmol), 1-methyl-1H-pyrazol-5-amine (144 mg, 1.49 mmol), cesium carbonate (660 mg, 2.03 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (93 mg, 0.16 mmol) in 1,4-dioxane (20 mL) warmed to 105C over a period of 24 hours under nitrogen. The reaction mixture was evaporated to dryness and redissolved in DCM (20 mL), and washed with water (25 mL). The organic layer filtered using phase separating paper and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-chloro-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine (171 mg, 60.5 %) as a yellow crystalline solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1C(=CC=N1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 60.54 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/11/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "200" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.101 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.35 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C(=CC=N1)N" - } - amount { - moles { - value: 0.0743 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.0676 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00405 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.00135 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 105.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (1.238 g, 1.35 mmol) was added in one portion to 2,4-dichloropyridine (10g, 67.57 mmol), 1-methyl-1H-pyrazol-5-amine (7.22 g, 74.33 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.346 g, 4.05 mmol) and cesium carbonate (33.0 g, 101.36 mmol) in 1,4-dioxane (350 mL) warmed to 105C over a period of 20 hours under nitrogen. The reaction mixture was evaporated to dryness and redissolved in DCM (250 mL), and washed with water (200 mL) The organic layer was filtered using phase separating paper and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM.nbsp;Relavent fractions were repurified by flash silica chromatography, elution gradient 0 to 5% MeOH in EtOAc. Pure fractions were evaporated to dryness to afford 4-chloro-N-(1-methyl-1H-pyrazol-5-yl)pyridin-2-amine (2.91 g, 20.66 %) as a yellow crystalline solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1C(=CC=N1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 20.66 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/16/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "202" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 4e-06 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)N" - } - amount { - moles { - value: 0.00012 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=NC(=C1I)Cl)Cl" - } - amount { - moles { - value: 0.0001 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 4e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "The reaction vessel was charged with nitrogen,nbsp;BINAP (2.491 mg, 4.00 mol) and diacetoxypalladium (0.898 mg, 4.00 mol) were dilutet in toluene (2 ml) and flushed with nitrogen.2,6-dichloro-3-iodopyridine (0.027 g, 0.1 mmol), aniline (10.96 l, 0.12 mmol) and cesium carbonate (0.163 g, 0.50 mmol) were weight in another flask and flushed with nitrogen. The Pd-BINAP mixture was joined and the reaction mixture was warmed to 120 C and stirred over night. The reaction was monitored using LCMS. No product could " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=C(N=C(C=C2)Cl)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/10/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "203" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[K+].[K+]" - } - amount { - moles { - value: 8e-06 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.001 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)N" - } - amount { - moles { - value: 0.00012 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=NC(=C1I)Cl)Cl" - } - amount { - moles { - value: 0.0001 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 8e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Biphenyl-2-yldicyclohexylphosphine (2.80 mg, 8.00 mol) and diacetoxypalladium (0.898 mg, 4.00 mol) were dilutet in dioxane (1 ml) and flushed with nitrogen. 2,6-dichloro-3-iodopyridine (0.027 g, 0.1 mmol), aniline (10.96 l, 0.12 mmol) and potassium carbonate (0.276 g, 2.00 mmol) were weight in another flask and flushed with nitrogen. The ligand-Pd mixture was joined and the reaction mixture was stirred at 120C over night. The reaction was monitored by LCMS and TLC. No desired product could be obtained and the starting materi" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=C(N=C(C=C2)Cl)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/14/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "206" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0015 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)N" - } - amount { - moles { - value: 0.005 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=NC(=C1I)Cl)Cl" - } - amount { - moles { - value: 0.001 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 7.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "The reaction was carried out under nitrogen. Two runs using the same amount of starting material (2,6-dichloro-3-iodopyridine (274 mg, 1 mmol)) and the same conditions were started and carried out as described in the following.BINAP (46.7 mg, 0.08 mmol) and Pd2(dba)3 (22.89 mg, 0.03 mmol)nbsp;were given into a nitrogen charged reaction vessel and dissolved in dioxane (10ml). 2,6-dichloro-3-iodopyridine (274 mg, 1 mmol), aniline (0.457 ml, 5.00 mmol) and sodium tert-butoxide (144 mg, 1.50 mmol) were weight in another flask and flushed with nitrogen. The prepared ligand-Pd mixture was added and the reaction mixture was heated at 100C over night. The reaction was monitored using TLC and LCMS. After the reaction was completed,nbsp;the dioxane was evapurated and both reaction vessels containing the same reaction-mixture were combined. The crude was solved in DCM, filtered through a silica plug and it followed a water work up using sodium bicarbonate (5 %), brine and water. The organic p was dried over sodium sulfate and concentrated to yield a dark brown oil. NMR showed the desired product, as well as the bis-addition of aniline.The crude product was purified by reverse-phase preparative HPLC. Column: Kromasil C8. Eluent: A: MeCN, B: H2OMeCNCH3COOH, 9550.2. Gradient: The A fraction was increased from 30 % to 70 % over 40 minutes. Flow: 70 mLmin.The relevant fractions (6-9) were concentrated and freeze dried to yield 220.3 mg (46%) a brown oil." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=C(N=C(C=C2)Cl)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 92.14 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/01/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "207" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.007 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC1CCNCC1" - } - amount { - moles { - value: 0.005 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC(=CC=C1)Br" - } - amount { - moles { - value: 0.005 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.0005 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.0005 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "All chemicals were mixed in a 50 mL round bottom flask. The solids were degassed and placed under nitrogen. Toluene was added and the mixture was stirred at 100C for 24 h. Cooled and filtered. The filtrate was concentrated under vacuum. Crude product was mainly starting material but some product had been formed. The product was purified by silica gel chromatography using 1-4% methanolDCM. Product was slightly more polar than starting material bromide. There was obtained 230 mg of the desired product as a solid. HNMR and LC MS ok." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC1CCN(CC1)C2=CC=CC(=C2)C(=O)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 13.76 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/28/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "208" - } - identifiers { - type: NAME - details: "reaction type" - value: "9.7.39 [Other functional group interconversion] Chloro to amino" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000912 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.028 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N" - } - amount { - moles { - value: 0.012 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1F)Cl" - } - amount { - moles { - value: 0.0114 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000912 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000456 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-chloro-4-fluoropyridine (1.5 g, 11.40 mmol), tert-butyl carbamate (1.403 g, 11.97 mmol), CESIUM CARBONATE (7.43 g, 22.81 mmol) ,TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (0.418 g, 0.46 mmol) and 9,9-DIMETHYL-4,5-BIS(DIPHENYLPHOSPHINO)XANTHENE (0.528 g, 0.91 mmol) were suspended in 1,4-dioxane (28 ml) ,degased with argon andnbsp;heated to 90 C for 4 hours.After cooling the reaction wasnbsp;quenched with waternbsp;and extracted with ethyl acetate ( x 2 ). The combined organic phasesnbsp;were washed with waternbsp;, a saturated aqueous solution of brine , dried over magnesium sulfate , concentrated thennbsp;purified bynbsp;preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The product was diluted in DCM (5 mL) and was added TFA (1.00 mL). After 15 minutes, the volatiles were evaporatehe residue was treated with aq NH3 30% and reevaporated." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1F)N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 25.34 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/21/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "211" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "[O-]P(=O)([O-])[O-].[K+].[K+].[K+]" - } - amount { - moles { - value: 9.96e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0045 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)CN(C)C1=CC(=C(C=C1)N)OC" - } - amount { - moles { - value: 0.0011 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN2C(=CN=C2C(=C1)F)C3=NC(=NC=C3Cl)Cl" - } - amount { - moles { - value: 0.000996 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 9.96e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.98e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A microwave tube was charged with diacetoxypalladium (11.18 mg, 0.05 mmol), potassium phosphate (529 mg, 2.49 mmol),2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (62.0 mg, 0.10 mmol), 3-(2,5-dichloropyrimidin-4-yl)-8-fluoroimidazo[1,2-a]pyridine (282 mg, 1.00 mmol) purged with nitrogen. Dioxane (4.5 ml) was added followed by tert-butyl 2-((4-amino-3-methoxyphenyl)(methyl)amino)acetate (292 mg, 1.10 mmol). The resulting suspension was purged again andnbsp;was heated at 100 C for 1h30.After cooling, the mixture was filtered through a pad of Dicalite speed plus and washed with dichloromethane. The solvent were evaporated. PBO-01970-51-01The crude product was purified by flash chromatography on silica gel (Merck cartridge SVF D26 - SI60 15-40m - 30g) eluting with 0 up to 50% EtOAc in petroleum ether. Collected fractions worated to afford tert-butyl 2-((4-(5-chloro-4-(8-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-ylamino)-3-methoxyphenyl)(methyl)amino)acetate (220 mg, 43.1 %) as a clear yellow solid. PBO-01970-51-02" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)CN(C)C1=CC(=C(C=C1)NC2=NC=C(C(=N2)C3=CN=C4N3C=CC=C4F)Cl)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 43.05 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/05/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "213" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00308 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=C(C=CC=C1OC)N" - } - amount { - moles { - value: 0.00265 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C(=CN=C1Cl)C(F)(F)F)I" - } - amount { - moles { - value: 0.00257 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000411 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000206 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-chloro-4-iodo-5-(trifluoromethyl)pyridine (790 mg, 2.57 mmol), 2-amino-6-methoxy-N-methylbenzamide (477 mg, 2.65 mmol), diacetoxypalladium (46.2 mg, 0.21 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (238 mg, 0.41 mmol) and cesium carbonate (1005 mg, 3.08 mmol) were mixed together in dioxane (15 mL). Reaction was degassed with argon and was stirred at 90 C overnight under argon.Reaction was filtered, washed with CH2Cl2 and filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford 2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-6-methoxy-N-methylbenzamide (590 mg, 63.8 %) as a white foam." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CNC(=O)C1=C(C=CC=C1OC)NC2=CC(=NC=C2C(F)(F)F)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 63.83 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/23/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "214" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00164 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.008 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=C(C=CC=C1OC)N" - } - amount { - moles { - value: 0.00137 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C(=CN=C1Cl)C(F)(F)F)I" - } - amount { - moles { - value: 0.00137 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000219 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000109 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-chloro-4-iodo-5-(trifluoromethyl)pyridine (420 mg, 1.37 mmol), 2-amino-6-methoxy-N-methylbenzamide (246 mg, 1.37 mmol), diacetoxypalladium (24.54 mg, 0.11 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (126 mg, 0.22 mmol) and cesium carbonate (534 mg, 1.64 mmol) were mixed together in dioxane (8 mL). Reaction was degassed with argon and was stirred at 90 C overnight (15 hours) under argon.Reaction was filtered, washed with CH2Cl2 and the filtrate was concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 10 to 30% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford 2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-6-methoxy-N-methylbenzamide (325 mg, 66.1 %) as a white solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CNC(=O)C1=C(C=CC=C1OC)NC2=CC(=NC=C2C(F)(F)F)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 66.13 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/08/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "215" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0273 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.075 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=C(C=CC=C1OC)N" - } - amount { - moles { - value: 0.0239 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C(=CN=C1Cl)C(F)(F)F)I" - } - amount { - moles { - value: 0.0228 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00364 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00182 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;2-chloro-4-iodo-5-(trifluoromethyl)pyridine (7 g, 22.77 mmol), 2-amino-6-methoxy-N-methylbenzamide (4.31 g, 23.91 mmol), diacetoxypalladium (0.409 g, 1.82 mmol) (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.108 g, 3.64 mmol) and cesium carbonate (8.90 g, 27.32 mmol) were suspended in dioxane (75 ml). Argon was let to bubble into the dark purple blurred solution and the reaction mixture was heated to at 90 C for 24h. (yellow suspension when temperature reached 70C).The reaction mixture was allowed to cool to room temperature, diluted with DCM (some drop of MeOH) and filtered. Silica gel was added and solents were evaporated to afford the crude, which was purified twice* by flash chromatography on silica gel eluting with 10 to 60% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford 2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-6-methoxy-N-methylbenzamide (7.00 g, 85 %) as an yellow f" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CNC(=O)C1=C(C=CC=C1OC)NC2=CC(=NC=C2C(F)(F)F)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 85.46 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/05/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "216" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00125 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.00312 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC1=CC(=CN=C1)I" - } - amount { - moles { - value: 0.000625 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.12e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "morpholine (0.272 mL, 3.12 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (43.4 mg, 0.07 mmol), tert-butyl 5-iodopyridin-3-ylcarbamate (200 mg, 0.62 mmol), diacetoxypalladium (7.01 mg, 0.03 mmol) andnbsp;cesium carbonate (407 mg, 1.25 mmol) were suspended in 1,4-dioxane (4 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness to afford the boc protected product.nbsp;HCl in dioxane (4M, 5mL) was added to the product . The resulting suspension was stirred at room temperature for 3 hours. The product was evaporated to dryness to afford crude product.nbsp;The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH plus 1% aqueous ammonia in DCM. Pure fractions were evaporated to drynes afford 5-morpholinopyridin-3-amine (31.0 mg, 27.7 %) as a cream solid. nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1COCCN1C2=CN=CC(=C2)N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 27.69 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/30/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "218" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00154 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(N=C1N)Cl" - } - amount { - moles { - value: 0.000772 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C=C1CO)Br)F" - } - amount { - moles { - value: 0.000772 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 9.26e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.86e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (8.67 mg, 0.04 mmol) was added to 2-chloropyrimidin-4-amine (100 mg, 0.77 mmol), (3-bromo-4-fluorophenyl)methanol (158 mg, 0.77 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (53.6 mg, 0.09 mmol) and cesium carbonate (503 mg, 1.54 mmol) in 1,4-dioxane (4 mL) . The resulting suspension was stirred at 150 C in the microwave for 30 minutes. None of the desired material was visible by LCMS. Reaction abandoned.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC(=C(C=C1CO)NC2=NC(=NC=C2)Cl)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/06/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "219" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CCC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000469 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)C(F)(F)F" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: " CC(C)(C(=O)OC)N" - } - amount { - moles { - value: 0.000427 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC=C(C=C1)Br" - } - amount { - moles { - value: 0.000469 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CCCCP(C12CC3CC(C1)CC(C3)C2)C45CC6CC(C4)CC(C6)C5" - } - amount { - moles { - value: 1.71e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.19e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 180.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "1-bromo-4-methoxybenzene (0.060 mL, 0.47 mmol), methyl 2-amino-2-methylpropanoate (0.05 g, 0.43 mmol), sodium 2-methylbutan-2-olate (0.052 g, 0.47 mmol), diacetoxypalladium (2.68 mg, 0.01 mmol) and methyl 2-(4-methoxyphenylamino)-2-methylpropanoate (0.00 g) was added to a microwave vial. (TRIFLUOROMETHYL)-BENZENE (0.5 mL) was used as solvent (1-1.2 mLmmol amine). The mixture was heated in microwave at 180 for 60min. No conversion of startingmaterial was obser" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C(=O)OC)NC1=CC=C(C=C1)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "12/19/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "220" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000854 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)C(F)(F)F" - } - amount { - volume { - value: 0.0004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: " CC(C)(C(=O)OC)N" - } - amount { - moles { - value: 0.000427 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1C(F)(F)F)Cl" - } - amount { - moles { - value: 0.000512 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CCCCP(C12CC3CC(C1)CC(C3)C2)C45CC6CC(C4)CC(C6)C5" - } - amount { - moles { - value: 4.27e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.13e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 180.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "1-chloro-4-(trifluoromethyl)benzene (0.068 mL, 0.51 mmol),nbsp;methyl 2-amino-2-methylpropanoate (0.05 g, 0.43 mmol),BUTYLDI-1-ADAMANTYLPHOSPHINE (0.015 g, 0.04 mmol), sodium 2-methylpropan-2-olate (0.082 g, 0.85 mmol) and diacetoxypalladium (4.79 mg, 0.02 mmol) was added to a microwave vial. (TRIFLUOROMETHYL)-BENZENE (0.5 mL) was used as solvent, before use the solvent was bubbled with nitrogen (1-1.2 mLmmol amine). The mixture was bubbled with nitrogen before the vial was sealed. The mixture was heated in microwave at 180 for 60min.. The mixture was heated in microwave at 180 for 60min. No conversion of startingmaterial was obser" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C(=O)OC)NC1=CC=C(C=C1)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/28/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "221" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00171 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: " CC(C)(C(=O)OC)N" - } - amount { - moles { - value: 0.00171 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=C(C=C1)Cl" - } - amount { - moles { - value: 0.00142 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CCCCP(C12CC3CC(C1)CC(C3)C2)C45CC6CC(C4)CC(C6)C5" - } - amount { - moles { - value: 5.69e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.85e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A flask was loaded with diacetoxypalladium (6.39 mg, 0.03 mmol), BUTYLDI-1-ADAMANTYLPHOSPHINE (0.020 g, 0.06 mmol), sodium 2-methylpropan-2-olate (0.164 g, 1.71 mmol) andnbsp;methyl 2-amino-2-methylpropanoate (0.2 g, 1.71 mmol). The flask was evacuated and backfilled and toluene (5ml) and 1-chloro-4-methylbenzene (0.168 ml, 1.42 mmol) was added.The mixture was stirred for 20h at 120. No conversion of startingmaterial was observed." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CC=C(C=C1)NC(C)(C)C(=O)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/28/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "222" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.024 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.075 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)N)C(C)C" - } - amount { - moles { - value: 0.0176 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" - } - amount { - moles { - value: 0.016 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00144 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000961 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (5 g, 16.02 mmol), 1-isopropyl-3-methyl-1H-pyrazol-5-amine (2.453 g, 17.62 mmol) and cesium carbonate (7.83 g, 24.03 mmol) were suspended in 1,4-dioxane (75 mL). Nitrogen was bubbled through mixture for 15 minutes. (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.834 g, 1.44 mmol) and diacetoxypalladium (0.216 g, 0.96 mmol) were added and flask was purged with nitrogen (x3). Mixture was stirred at reflux overnight.Reaction was allowed to cool to room temperature, filtered, washed with CH2Cl2MeOH (91, 60 mL). Silica (63-200 m) was added to the filtrate and mixture was concentrated to dryness. The crude product was purified by flash chromatography (dry loading) on silica gel eluting with 1 to 6% methanol in dichloromethane. The solvent was evaporated to dryness to afford 2-(5-chloro-2-(1-isopropyl-3-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-N-methoxybenzamide (3.35 g, 50.4 %) as a dark green foam =gt; icontains CH2Cl2 anOH.i EtOAc (10 mL) was added and mixture was stirred at room temperature for 5 hours. The resulting solid was filtered, washed with cold EtOAc and dried under high vacuum at 50C overnight to afford 2-(5-chloro-2-(1-isopropyl-3-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-N-methoxybenzamide (2.41 g, 36.3 %) as a pale yellow solid =gt; icrystalline powder under polarized light microscopyi" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)Cl)C(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 86.67 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/30/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "223" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.135 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.3 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)N)C(C)C" - } - amount { - moles { - value: 0.108 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" - } - amount { - moles { - value: 0.0897 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00807 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00538 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a stirred solution of 2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (28 g, 89.70 mmol) in 1,4-dioxane (300 mL) were added 1-isopropyl-3-methyl-1H-pyrazol-5-amine (14.98 g, 107.64 mmol), cesium carbonate (43.8 g, 134.55 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4.67 g, 8.07 mmol) and diacetoxypalladium (1.208 g, 5.38 mmol)Mixture was degassed 3 times with N2 and heated to reflux overnight: OK.Reaction was cooled down, then filtered, salts were washed with 500mL of a 9010 solution of CH2Cl2MeOH and the filtrate was concentrated.Residue was then dissolved in CH2Cl2MeOH, adsorbed on silica and purified by chromatography, eluting with 7% of MeOH in CH2Cl2.Solvent were concentrated and the solid obtained was stirred in 300mL of AcOEt for 3h.product was filtered, washed with AcOEt and dried on vacuum at 50C for the we.1H NMR indicates the presence of 7% of AcOEt...Need to dissolve the product in EtOH, then concentrato dryness and stirred with 500mL of water for 3h.Solid was filtered, washed with water and dried on vacuum overnight at 50C to afford 2-(5-chloro-2-(1-isopropyl-3-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-N-methoxybenzamide (21.50 g, 57.8 %) as a white powder.Purity-check OK." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)Cl)C(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 57.77 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/07/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "224" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000961 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)N)C(C)C" - } - amount { - moles { - value: 0.00128 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" - } - amount { - moles { - value: 0.000641 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000128 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" - } - amount { - moles { - value: 9.61e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (200 mg, 0.64 mmol), 1-isopropyl-3-methyl-1H-pyrazol-5-amine (178 mg, 1.28 mmol) and sodium 2-methylpropan-2-olate (92 mg, 0.96 mmol) were suspended in 1,4-dioxane (3 mL). Nitrogen was bubbled through mixture for 10 minutes. (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (74.1 mg, 0.13 mmol) and BIS(DIBENZYLIDENEACETONE)PALLADIUM(0) (55.3 mg, 0.10 mmol) were added and tube was sealed. Mixture was stirred at reflux overnight. Reaction was allowed to cool to room temperature, filtered, washed with CH2Cl2MeOH (91, 10 mL) and concentrated to dryness. The crude product was purified by flash chromatography (dry loading) on silica gel eluting with 1 to 5% methanol in dichloromethane. The solvent was evaporated to dryness to afford 2-(5-chloro-2-(1-isopropyl-3-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-N-methoxybenzamide (97 mg, 36.5 %) as a pink foam." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)Cl)C(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 36.49 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/25/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "225" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00192 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)N)C(C)C" - } - amount { - moles { - value: 0.00128 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" - } - amount { - moles { - value: 0.000641 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 6.41e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.2e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (200 mg, 0.64 mmol), 1-isopropyl-3-methyl-1H-pyrazol-5-amine (178 mg, 1.28 mmol) and cesium carbonate (626 mg, 1.92 mmol) were suspended in 1,4-dioxane (3 mL). Nitrogen was bubbled through mixture for 10 minutes. 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (39.9 mg, 0.06 mmol) and diacetoxypalladium (7.19 mg, 0.03 mmol) were added and tube was sealed. Mixture was stirred at reflux overnight. Reaction was allowed to cool to room temperature, filtered, washed with CH2Cl2MeOH (91, 10 mL) and concentrated to dryness. The crude product was purified by flash chromatography (dry loading) on silica gel eluting with 1 to 5% methanol in dichloromethane. The solvent was evaporated to dryness to afford 2-(5-chloro-2-(1-isopropyl-3-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-N-methoxybenzamide (125 mg, 47.0 %) as a pink foam =gt; icontaminated by a few BINAP or BINAP by-productsi" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)Cl)C(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 47.02 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/25/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "226" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00192 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)N)C(C)C" - } - amount { - moles { - value: 0.00128 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" - } - amount { - moles { - value: 0.000641 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000192 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 9.61e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (200 mg, 0.64 mmol), 1-isopropyl-3-methyl-1H-pyrazol-5-amine (178 mg, 1.28 mmol) and cesium carbonate (626 mg, 1.92 mmol) were suspended in 1,4-dioxane (3 mL). Nitrogen was bubbled through mixture for 10 minutes. 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (120 mg, 0.19 mmol) and diacetoxypalladium (21.58 mg, 0.10 mmol) were added and tube was sealed. Mixture was stirred at reflux overnight. Reaction was allowed to cool to room temperature, filtered, washed with CH2Cl2MeOH (91, 10 mL) and concentrated to dryness. The crude product was purified by flash chromatography (dry loading) on silica gel eluting with 1 to 5% methanol in dichloromethane. The solvent was evaporated to dryness to afford 2-(5-chloro-2-(1-isopropyl-3-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-N-methoxybenzamide (98 mg, 36.9 %) as a pink foam =gt; iimpure, contains BINAP or BINAP by-productsi" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)Cl)C(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 36.87 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/25/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "227" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000961 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)N)C(C)C" - } - amount { - moles { - value: 0.00128 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" - } - amount { - moles { - value: 0.000641 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 4.81e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.2e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (200 mg, 0.64 mmol), 1-isopropyl-3-methyl-1H-pyrazol-5-amine (178 mg, 1.28 mmol) and cesium carbonate (313 mg, 0.96 mmol) were suspended in 1,4-dioxane (3 mL). Nitrogen was bubbled through mixture for 10 minutes. (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (27.8 mg, 0.05 mmol) and diacetoxypalladium (7.19 mg, 0.03 mmol) were added and tube was sealed. Mixture was stirred at reflux overnight =gt; iincomplete reactioni. Reaction was heated for a further 7 hours =gt; ino evolutioni. More Pd(OAc)2 and Xantphos were added, mixture was degassed with nitrogen and heated at reflux overnight =gt; icompletei.Reaction was allowed to cool to room temperature, filtered, washed with CH2Cl2MeOH (91, 10 mL) and concentrated to dryness. The crude product was purified by flash chromatography (dry loading) on silica gel eluting with 1 to 5% methanol in dichloromethane. The solvent was evaporated to dryness to afford 2-(5-chloro-2-(1-isopropyl-3-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-N-methoxybenzamide (90 mg, 33.9 %) as a pink foam." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)Cl)C(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 33.86 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/25/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "228" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00192 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)N)C(C)C" - } - amount { - moles { - value: 0.000705 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" - } - amount { - moles { - value: 0.000641 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 6.41e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.2e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (200 mg, 0.64 mmol), 1-isopropyl-3-methyl-1H-pyrazol-5-amine (98 mg, 0.70 mmol) and cesium carbonate (626 mg, 1.92 mmol) were suspended in 1,4-dioxane (3 mL). Nitrogen was bubbled through mixture for 10 minutes. 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (39.9 mg, 0.06 mmol) and diacetoxypalladium (7.19 mg, 0.03 mmol) were added and tube was sealed. Mixture was stirred at reflux overnight. Reaction was allowed to cool to room temperature, filtered, washed with CH2Cl2MeOH (91, 10 mL). Silica (63-200 m) was added to the filtrate and mixture was concentrated to dryness. The crude product was purified by flash chromatography (dry loading) on silica gel eluting with 1 to 5% methanol in dichloromethane. The solvent was evaporated to dryness to afford 2-(5-chloro-2-(1-isopropyl-3-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-N-methoxybenzamide (120 mg, 45.1 %) as a pale beige foam =gt; icontaminated by a few BINAP or BINAP by-productsi" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)Cl)C(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 45.14 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/25/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "229" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00192 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)N)C(C)C" - } - amount { - moles { - value: 0.000961 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" - } - amount { - moles { - value: 0.000641 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 6.41e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.2e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (200 mg, 0.64 mmol), 1-isopropyl-3-methyl-1H-pyrazol-5-amine (134 mg, 0.96 mmol) and cesium carbonate (626 mg, 1.92 mmol) were suspended in 1,4-dioxane (3 mL). Nitrogen was bubbled through mixture for 10 minutes. 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (39.9 mg, 0.06 mmol) and diacetoxypalladium (7.19 mg, 0.03 mmol) were added and tube was sealed. Mixture was stirred at reflux overnight. Reaction was allowed to cool to room temperature, filtered, washed with CH2Cl2MeOH (91, 10 mL). Silica (63-200 m) was added to the filtrate and mixture was concentrated to dryness. The crude product was purified by flash chromatography (dry loading) on silica gel eluting with 1 to 5% methanol in dichloromethane. The solvent was evaporated to dryness to afford 2-(5-chloro-2-(1-isopropyl-3-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-N-methoxybenzamide (127 mg, 47.8 %) as a pale beige foam =gt; icontaminated by a few BINAP or BINAP by-productsi" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)Cl)C(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 47.78 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/25/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "231" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000682 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0043 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)N)C(C)C" - } - amount { - moles { - value: 0.00091 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2Cl)Cl" - } - amount { - moles { - value: 0.000455 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 9.1e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" - } - amount { - moles { - value: 6.82e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "dioxane (4.3 mL) was added to 2-(2,5-dichloropyridin-4-ylamino)-N-methoxybenzamide (142 mg, 0.45 mmol), 1-isopropyl-3-methyl-1H-pyrazol-5-amine (127 mg, 0.91 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (52.6 mg, 0.09 mmol), BIS(DIBENZYLIDENEACETONE)PALLADIUM (39.2 mg, 0.07 mmol) and sodium 2-methylpropan-2-olate (65.6 mg, 0.68 mmol) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT.nbsp;Reaction mixture from EN042315 was combined and filtered through a PTFE cup to remove insoluble precipitate, washed filter with dioxane and combined filtrates were purified by ion exchange chromatography, using an 25g SCX-2 column. The desired product was eluted from the column using 7M NH3MeOH and product fractions were evaporated to dryness to afford crude product (457 mg).nbsp;The crude product was purified by flash silica (40g grace) chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporateddryness to afford 2-(5-chloro-2-(1-isopropyl-3-methyl-1H-pyrazol-5-ylamino)pyridin-4-ylamino)-N-methoxybenzamide (175 mg, 93 %) as a beige solid. nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)Cl)C(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 92.72 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/28/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "233" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00475 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.3 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=C(N=C(C=N1)Cl)N" - } - amount { - moles { - value: 0.0791 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CS(=O)(=O)C1=CC=C(C=C1)Br" - } - amount { - moles { - value: 0.0791 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00475 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00237 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 85.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "1-bromo-4-(methylsulfonyl)benzene (18.6 g, 79.12 mmol) then cesium carbonate (33.5 g, 102.85 mmol) were successively added to a solution of 6-chloropyrazin-2-amine (10.25 g, 79.12 mmol) in 1,4-dioxane (300 ml). The mixture was purged with nitrogen, then (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.75 g, 4.75 mmol) and diacetoxypalladium (0.533 g, 2.37 mmol) were added, the mixture was purged with nitrogen then heated to 85C for 3 hours. After cooling the mixture was diluted with ethylacetate (300 mL), filtered, the solid washed with ethyl acetate (2x100 mL). Filtrate was washed with water (500 mL) =gt; iemulsion, 100 mL of brine were added to help separation of layers.i Organics were washed with brine and dried over MgSO4. Crude product (28g) was purified by flash chromatography on silica gel (solid deposit) eng with 1 to 4% methanolic ammonia (7 N) in dichloromethane =gt; ino separation !! crude was flushedi. The solvent was evaporated to dryness to afford crude product (22g). It was recrystallised from EtOAc (~450 mL) to afford 6-chloro-N-(4-(methylsulfonyl)phenyl)pyrazin-2-amine (14.00 g, 62.4 %, EN03787-21-01) as a white crystalline solid =gt; ipurity = 91%, contains 6.9% EtOAci. Silica (63-200 m) was added to filtrate and it was concentrated to dryness to be purified by flash chromatography on silica gel eluting with 1 to 4% methanolic ammonia (7 N) in dichloromethane =gt; iagain, no separation !! iFractions containing product were combined and concentrated to dryness. Residue (4.3g) was recrystallised from EtOAc (~70 mL) to afford 6-chloro-N-(4-(methylsulfonyl)phenyl)pyrazin-2-amine (1.80 g, 8.0 %, EN03787-21-02) as a white crystalline solid =gt; ipurity = 91%, contains 6.5% EtOAc.ibiHMS6ib" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CS(=O)(=O)C1=CC=C(C=C1)NC2=CN=CC(=N2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 70.39 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/10/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "234" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000758 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C(F)(F)F)Cl" - } - amount { - moles { - value: 0.000303 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C(=N1)C(F)(F)F)N.Cl" - } - amount { - moles { - value: 0.000607 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 4.85e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.43e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-N-methylbenzamide (100 mg, 0.30 mmol), 1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-amine hydrochloride (122 mg, 0.61 mmol), cesium carbonate (247 mg, 0.76 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (28.1 mg, 0.05 mmol) and diacetoxypalladium (5.45 mg, 0.02 mmol) were suspended in dioxane (1.5 mL) and sealed into a tube. The reaction was degased, purged with nitrogen and heated to 100 C for 18 hours. Reaction was filtered. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford N-methyl-2-(2-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)benzamide (84 mg, 60.4 %) as a yellow crystne solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C(F)(F)F)NC3=CN(N=C3C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 60.42 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/20/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "236" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000885 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN" - } - amount { - moles { - value: 0.000885 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=NC=C1Br)C(F)(F)F" - } - amount { - moles { - value: 0.000442 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 1.33e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C(Cl)(Cl)Cl.[Pd].[Pd]" - } - amount { - moles { - value: 8.85e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 130.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "3-bromo-5-(trifluoromethyl)pyridine (100 mg, 0.44 mmol), methylamine 2 M in THF (0.442 mL, 0.88 mmol), and cesium carbonate (202 mg, 0.62 mmol) were suspended in dioxane (3 mL) . The reaction was purged with nitrogen for 30 minutes then 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (7.68 mg, 0.01 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0)-CHLOROFORM ADDUCT (9.16 mg, 8.85 mol) were added. The reaction was heated at 130 c for 30mins. No REACTION ABANDONED" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CNC1=CN=CC(=C1)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/30/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "237" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000885 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN.Cl" - } - amount { - moles { - value: 0.000885 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=NC=C1Br)C(F)(F)F" - } - amount { - moles { - value: 0.000442 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 1.33e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C(Cl)(Cl)Cl.[Pd].[Pd]" - } - amount { - moles { - value: 8.85e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 130.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "3-bromo-5-(trifluoromethyl)pyridine (100 mg, 0.44 mmol), methylamine hydrochloride (59.8 mg, 0.88 mmol), and cesium carbonate (490 mg, 1.50 mmol) were suspended in dioxane (3 mL) . The reaction was purged with nitrogen for 30 minutes then 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (7.68 mg, 0.01 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0)-CHLOROFORM ADDUCT (9.16 mg, 8.85 mol) were added. The reaction was heated to 130 C in a CEM microwave for 1 hour. No Product formed.Aband" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CNC1=CN=CC(=C1)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/02/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "238" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 3e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.001 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNC(=O)C1" - } - amount { - moles { - value: 0.000499 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=CC(=C1)Cl)[N+](=O)[O-]" - } - amount { - moles { - value: 0.000499 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of tert-butyl 3-oxopiperazine-1-carboxylate (100 mg, 0.50 mmol), 4-chloro-2-methoxy-1-nitrobenzene (94 mg, 0.50 mmol), cesium carbonate (244 mg, 0.75 mmol),nbsp;(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (17.34 mg, 0.03 mmol) and diacetoxypalladium (4.48 mg, 0.02 mmol) was dried for 15 min under HV. Degassed dioxane (1,0-1,2 ml) was added and the resulting mixture was stirred at 90c for 16 hours under inert atmosphere. TLC showed consumption of both SM and new spot (UV active). Reaction combined with EN02378-08 (same TLC profile).LC-MS of crude: EN02378-07-01Extraction: AE2M Na2CO3 sol. Purification by chromatography: eluent AEhexane 2080 to 6040. bIsolated: m= 240 mgb; orange foam. FLA 02378-07-02: 1H NMR, LC-MS: OK. Estimated yield: 68%." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(C(=O)C1)C2=CC(=C(C=C2)[N+](=O)[O-])OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 68.39 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "12/02/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "240" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000337 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.017 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNC(=O)C1" - } - amount { - moles { - value: 0.00749 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=CC(=C1)Cl)[N+](=O)[O-]" - } - amount { - moles { - value: 0.00749 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000337 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.00019 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of tert-butyl 3-oxopiperazine-1-carboxylate (1500 mg, 7.49 mmol), 4-chloro-2-methoxy-1-nitrobenzene (1405 mg, 7.49 mmol),cesium carbonate (3417 mg, 10.49 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (195 mg, 0.34 mmol)nbsp;and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (174 mg, 0.19 mmol)was dried for 15 min under HV. Degassed dioxane (17 ml) was added and the resulting mixture was stirred at 90C for 16 hours under inert atmosphere. Work-up and purification: see EN02378-07-02. tert-butyl 4-(3-methoxy-4-nitrophenyl)-3-oxopiperazine-1-carboxylate (2640 mg, 100 %) was isolated as an orange foam. FLA 02378-10-01: 1H NMR, LC-MS: OK." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(C(=O)C1)C2=CC(=C(C=C2)[N+](=O)[O-])OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 100.3 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "12/04/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "241" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0157 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.1 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.0157 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COCCOC1=CC(=CC(=C1)[N+](=O)[O-])I" - } - amount { - moles { - value: 0.0121 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000362 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000604 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;diacetoxypalladium (0.136 g, 0.60 mmol)nbsp;was added to a stirred mixture ofnbsp;1-iodo-3-(2-methoxyethoxy)-5-nitrobenzene (3.9 g, 12.07 mmol), morpholine (1.373 mL, 15.69 mmol)nbsp;and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.225 g, 0.36 mmol) and cesium carbonate (11.80 g, 36.21 mmol)nbsp;dissolved in toluene (100 mL) over a period of 5 minutes, degased and under argon. The resulting mixture was heatednbsp;at 110 C for 4 hours.The toluene was evaporated , water ( 50ml) was added and the mixture was extracted with ethyle acetate, dried over MgSO4, filtered and asorbed on silica gel.The crude product was purified by flash chromatography on silica gel eluting with 1 to 4% methanol in dichloromethane. The solvent was evaporated to dryness to afford 4-(3-(2-methoxyethoxy)-5-nitrophenyl)morpholine (0.550 g, 16.14 %) as anbsp;orange solid.( starting material unreacted : 2 .5g)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "COCCOC1=CC(=CC(=C1)[N+](=O)[O-])N2CCOCC2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 16.14 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/01/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "242" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0101 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.08 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.0101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COCCOC1=CC(=CC(=C1)[N+](=O)[O-])I" - } - amount { - moles { - value: 0.00774 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000774 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000387 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (0.087 g, 0.39 mmol) was added to a stirred mixture ofnbsp;1-iodo-3-(2-methoxyethoxy)-5-nitrobenzene (2.5 g, 7.74 mmol), cesium carbonate (7.56 g, 23.21 mmol) and morpholine (0.880 mL, 10.06 mmol) and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.482 g, 0.77 mmol) dissolved in toluene (80 mL) and dioxane (20 mL) over a period of 10 minutes, degased and under argon. The resulting suspensionnbsp;was heated at 110 C for 15 hours.Solvents were evaporated and the mixture was adsorbed with ammoniamethanol 7N on silica gel.The crude product was purified by flash chromatography on silica gel eluting with 40 to 60% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford 4-(3-(2-methoxyethoxy)-5-nitrophenyl)morpholine (2.000 g, 92 %) as anbsp;orange solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COCCOC1=CC(=CC(=C1)[N+](=O)[O-])N2CCOCC2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 91.56 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/03/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "243" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0901 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.25 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.039 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COCCOC1=CC(=CC(=C1)[N+](=O)[O-])I" - } - amount { - moles { - value: 0.03 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.003 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.0015 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "The diacetoxypalladium (0.337 g, 1.50 mmol) was added to a stirred mixture ofnbsp;1-iodo-3-(2-methoxyethoxy)-5-nitrobenzene (9.7 g, 30.02 mmol), cesium carbonate (29.3 g, 90.07 mmol) and morpholine (3.41 mL, 39.03 mmol) and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (1.869 g, 3.00 mmol) dissolved in toluene (200 mL) and dioxane (50 mL) The reaction was degased, purged with argon and heated at 110 C for 15 hours. The mixture was diluted with dichloromethane (250ml) the salts were fitered, the filtrate was concentrated.The crude product was purified by flash chromatography on silica gel eluting with 0 to 15% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford 4-(3-(2-methoxyethoxy)-5-nitrophenyl)morpholine (4.50 g, 53.1 %) as anbsp;orange solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COCCOC1=CC(=CC(=C1)[N+](=O)[O-])N2CCOCC2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 53.1 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/23/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "244" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00148 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.006 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC" - } - amount { - moles { - value: 0.00148 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1C2=CC(=O)C3=C(O2)C(=CC=C3)C4=CC=CC5=C4SC6=C5C=C(C=C6)OS(=O)(=O)C(F)(F)F" - } - amount { - moles { - value: 0.000369 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 1.85e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 9.23e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 140.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "6-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thiophen-2-yl trifluoromethanesulfonate (207.4 mg, 0.37 mmol), tert-butyl methylcarbamate (194 mg, 1.48 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (10.69 mg, 0.02 mmol) and cesium carbonate (481 mg, 1.48 mmol) were suspended in dioxane (6 mL) and sealed into a microwave tube. The reaction was heated to 140 C for 1 hour in the microwave reactor and cooled to RT. The reaction mixture was filtered then silica gel (2 g) added.nbsp;The mixture was concentrated iin vacuoi to yield a white powder which was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford tert-butyl methyl(6-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thiophen-2-yl)carbamate (70.0 mg, 34.9 %) as a white solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N(C)C1=CC2=C(C=C1)SC3=C2C=CC=C3C4=CC=CC5=C4OC(=CC5=O)N6CCOCC6" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 34.93 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/16/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "246" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00694 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0173 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC" - } - amount { - moles { - value: 0.0026 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1C2=CC(=O)C3=C(O2)C(=CC=C3)C4=CC=CC5=C4SC6=C5C=C(C=C6)OS(=O)(=O)C(F)(F)F" - } - amount { - moles { - value: 0.00173 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 8.67e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 4.34e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A solution of tert-butyl methylcarbamate (341 mg, 2.60 mmol) in dioxane (17.300 ml) was added to a stirred mixture of 6-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thiophen-2-yl trifluoromethanesulfonate (974 mg, 1.73 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (39.7 mg, 0.04 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (50.2 mg, 0.09 mmol) and cesium carbonate (2261 mg, 6.94 mmol). The resulting mixture was stirred under nitrogen at 110 C for 18 hours. The reaction mixture was poured into water (100 mL) and EtOAc (100 mL). Methanol addition was required to aid separation of layers. b[would vac off dioxane in future]b. The aqueous was further extracted with EtOAc (2 x 50 mL) and DCM (50 mL), all with the aid of methanol for layer separation. The combined organics were washed with saturated brine solution (still formed emulsions), dried over MgSO4 and concentrated under reduced pressure.The crude product was purified by flash silica chromatography, elutgradient 0 to 4% 7M NH3MeOH in DCM. Pure fractions were evaporated to dryness to afford tert-butyl methyl(6-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thiophen-2-yl)carbamate (630 mg, 66.9 %) as a yellow solid. This was taken through to the next step at 85% pure, with no further purification.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N(C)C1=CC2=C(C=C1)SC3=C2C=CC=C3C4=CC=CC5=C4OC(=CC5=O)N6CCOCC6" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 66.94 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/31/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "247" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000712 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.00178 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC" - } - amount { - moles { - value: 0.000267 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1C2=CC(=O)C3=C(O2)C(=CC=C3)C4=CC=CC5=C4SC6=C5C=C(C=C6)OS(=O)(=O)C(F)(F)F" - } - amount { - moles { - value: 0.000178 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 8.9e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 4.45e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A solution of tert-butyl methylcarbamate (35.0 mg, 0.27 mmol) in dioxane (1.781 ml) was added to a stirred mixture of 6-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thiophen-2-yl trifluoromethanesulfonate (100 mg, 0.18 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (4.08 mg, 4.45 mol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (5.15 mg, 8.90 mol) and cesium carbonate (232 mg, 0.71 mmol). The resulting mixture was stirred under nitrogen at 110 C for 3 hours. The cooled reaction mixture was diluted with methanol and the residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH andnbsp;evaporated to dryness to afford tert-butyl methyl(6-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo[b,d]thiophen-2-yl)carbamate (97 mg, 100 %) as a orange residue. 100% assumed and this was progressed to the next stage with no further purification." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N(C)C1=CC2=C(C=C1)SC3=C2C=CC=C3C4=CC=CC5=C4OC(=CC5=O)N6CCOCC6" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 100.38 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/12/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "248" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000776 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00646 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)Br)[N+](=O)[O-]" - } - amount { - moles { - value: 0.00646 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000776 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000517 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;diacetoxypalladium (0.116 g, 0.52 mmol)nbsp;was added to a stirred mixture ofnbsp;4-bromo-1-methoxy-2-nitrobenzene (1.5 g, 6.46 mmol), 1-(piperazin-1-yl)ethanone (0.829 g, 6.46 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.449 g, 0.78 mmol) and cesium carbonate (4.21 g, 12.93 mmol) dissolved in dioxane (10 mL) , degased and under argon. The resulting suspensionnbsp;was stirred at 120 C for 2 hours.At 25C, the mixture was filtered and evaporated under reduce pressure.The mixture was adsorbed on silica gel.The crude product was purified by flash chromatography on silica gel eluting with 1 to 5% methanol in ethyle acetate. The solvent was evaporated to dryness to afford 1-(4-(4-methoxy-3-nitrophenyl)piperazin-1-yl)ethanone (1.400 g, 78 %) as anbsp;orange so" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)OC)[N+](=O)[O-]" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 77.54 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/07/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "249" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0155 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.3 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.129 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)Br)[N+](=O)[O-]" - } - amount { - moles { - value: 0.129 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.0155 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.0103 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;diacetoxypalladium (2.322 g, 10.34 mmol)nbsp;was added to a stirred suspension ofnbsp;4-bromo-1-methoxy-2-nitrobenzene (30 g, 129.29 mmol), 1-(piperazin-1-yl)ethanone (16.57 g, 129.29 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (8.98 g, 15.52 mmol) and cesium carbonate (84 g, 258.59 mmol) dissolved in dioxane (300 mL) , degasednbsp;and under argon. The resulting suspension was stirred at 120 C for 2 hours.At 25C, the mixture was filtered and adsorbed on silica gel .The crude product was purified by flash chromatography on silica gel eluting with 1 to 5% methanol in ethyle acetate. The solvent was evaporated to dryness to afford 1-(4-(4-methoxy-3-nitrophenyl)piperazin-1-yl)ethanone (31.0 g, 86 %) as anbsp;orange so" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)OC)[N+](=O)[O-]" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 85.85 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/08/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "250" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00314 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.13 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CONC(=O)C1=CC=CC=C1N" - } - amount { - moles { - value: 0.0534 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" - } - amount { - moles { - value: 0.0314 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00314 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00157 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.817 g, 3.14 mmol), diacetoxypalladium (0.353 g, 1.57 mmol), 2-amino-N-methoxybenzamide (8.87 g, 53.39 mmol), N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (12 g, 31.40 mmol) and cesium carbonate (20.46 g, 62.81 mmol) were weighed out in a round bottom flask. dioxane (130 mL) was added and argon was let to bubble in the mixture for 10 minutes. The suspension was stirred at 100 C overnight. The reaction mixture was allowed to cool to room temperature under stirring, diluted with ethyl acetate and the insolubles were removed by filtration, washed with EtOAc and the filtrate was concentrated. (Insolubles~19g).The crude product (30g) was purified by flash chromatography on silica gel eluting with 0 to 5% methanol in ethyl acetate. The solvent was evaporated to dryness, giving a gummy foam EN02972-52-01 (15 g, 35.7 mmol, 114 %): not pure. It was repurified by flash chromatography on silica gel eluting with 0 t methanol in ethyl acetate. The solvent was evaporated to dryness to give to batches: one pure EN02972-52-02 (12 g, 28.5 mmol, 91 %), one less pure EN02972-52-03 (0.8 g, 1.903 mmol, 6.06 %).The foam EN02972-52-02 (12 g, 28.5 mmol, 91 %) was dissolved in hot EtOH (12mL). Crystallisation occurred. The resulting crystalline solid was collected by filtration and dried to a constant weight to afford EN02972-52-04 (8.7 g, 19.04 mmol, 60.6 %) as a white crystalline solid. Its filtrate was combined with EN02972-52-03 (0.8 g, 1.903 mmol, 6.06 %) and vacced down. The solid was taken up into EtOH, collected by filtration to give a second crop as a white solid EN02972-52-05 (1.88 g, 4.47 mmol, 14.24 %)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 74.87 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/17/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "251" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000523 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.06 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CONC(=O)C1=CC=CC=C1N" - } - amount { - moles { - value: 0.0089 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" - } - amount { - moles { - value: 0.00523 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000523 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000262 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.303 g, 0.52 mmol), diacetoxypalladium (0.059 g, 0.26 mmol), 2-amino-N-methoxybenzamide (1.479 g, 8.90 mmol), N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (2 g, 5.23 mmol) and cesium carbonate (3.41 g, 10.47 mmol) were weighed out in a round bottom flask. dioxane (60 mL) was added and argon was let to bubble in the mixture for 10 minutes. The suspension was stirred at 100 C overnight. The reaction mixture was allowed to cool to room temperature under stirring, diluted with dichloromethane and methanol, silicagel was added and the mixture was concentrated. The crude product was purified by flash chromatography on silica gel (150g) eluting with 0 to 5% methanol in ethyl acetateDCM (11). The solvent was evaporated to dryness, giving a gummy foam. 35 mL of tBuOMe was added and the resulting solution was stirred at rt for 3 hours. The resulting precipitate was collected by filtration, washed with tBuOMe and dried tconstant weight to afford EN02430-89-01 (1.53 g, 3.64 mmol, 69.5 %) as a white solid, which was contained DCM and EtOAc. It was taken up into a minimum of MeCN, heated to 100C and MeCN was added until complete solubilisation. The solution was filtered and left to cool to rt overnight. The crystallized product was collected by filtration and dried to constant weight under high vacuum (7.10-2mbar) at 50C for 1h, to give EN02430-89-02 (1.2 g, 2.63 mmol, 50.2 %) as a crystalline white solid. The filtrate was concentrated, triturated in MeCN and the resulting solid was collected by filtration to give EN02430-89-03 (0.2 g, 0.476 mmol, 9.09 %) - a second crop - as a white solid.1g of EN02430-89-02 (1.2 g, 2.63 mmol, 50.2 %), EN02430-89-03 (0.2 g, 0.476 mmol, 9.09 %) amp; EN02430-89-04 (48 mg, 0.114 mmol, 2.182 %) were combined, stirred in boiling water (100 mL) for 10 minutes, cooled down, collected by filtration and dried under vacuum (7.10-2mbar) at 50C in presence give EN02430-89-05 (1.1 g, 2.56 mmol, 49.0 %)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 48.99 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/20/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "252" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 5.89e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC=CC(=C1C(=O)NOC)N" - } - amount { - moles { - value: 0.000667 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" - } - amount { - moles { - value: 0.000393 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 5.89e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.53e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (34.1 mg, 0.06 mmol), diacetoxypalladium (7.93 mg, 0.04 mmol), 2-amino-N,6-dimethoxybenzamide (131 mg, 0.67 mmol), N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (150 mg, 0.39 mmol) and cesium carbonate (256 mg, 0.79 mmol) were weighed out in a wave vial, sealed and dioxane (5 mL) was added. Argon was let to bubble in the mixture for 5 minutes. The reaction was stirred at 90 C overnight. The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane and MeOH, silica gel was added and the mixture was concentrated. The crude product was purified by flash chromatography on silica gel (25g) eluting with 0 to 5% methanol in ethyl acetateDCM (11). The solvent was evaporated to dryness. The residue was triturated in diethyl ether (gummy in tBuOMe) and the resulting precipitate was collected by filtration, washed with diethyl ether and dried to a constant weight to afford 2-(2-(1,3-dimethrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (131 mg, 74.1 %) as a off-white solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=C(C(=CC=C3)OC)C(=O)NOC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 74.09 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/20/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "253" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00327 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.13 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=C(C=CC=C1OC)N" - } - amount { - moles { - value: 0.0491 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)I)C(F)(F)F)C" - } - amount { - moles { - value: 0.0327 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00327 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00164 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A suspension of 2-amino-6-methoxy-N-methylbenzamide (8.84 g, 49.07 mmol), N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (12.5 g, 32.71 mmol), diacetoxypalladium (0.367 g, 1.64 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.893 g, 3.27 mmol) and cesium carbonate (19.18 g, 58.88 mmol) in dioxane (130 mL) was degassed with argon, which was also let to bubble for 10 minutes then stirred at reflux for 6h. The reaction mixture was allowed to cool to rt, the insolubles were removed by filtration, washed with EtOAc and the filtrate was concentrated. (Insolubles~23g).The crude product (20g) was purified by flash chromatography on silica gel eluting with 0 to 5% methanol in ethyl acetate. The solvent was evaporated to dryness to afford a foam (7.9g) which was taken up into dichloromethane (40ml) (no time to get dissolved, it crashed out very quickly) and sonicated for 5 minutes. The resulting precipitate was collected by filtration, washed with dichloromethane and dried under vacuum at 50C to a constant weight to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-6-methoxy-N-methylbenzamide (6.53 g, 46.0 %) as anbsp;white solid.The filtrate was concentrated to dryness (residue weight: 700mg), taken up into DCM and collected by filtration to give a second sample EN02972-51-02 (0.36 g, 0.829 mmol, 2.53 %)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=C(C(=CC=C3)OC)C(=O)NC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 45.95 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/15/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "254" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0072 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.3 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=C(C=CC=C1OC)N" - } - amount { - moles { - value: 0.108 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)I)C(F)(F)F)C" - } - amount { - moles { - value: 0.072 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.0072 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.0036 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 95.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-amino-6-methoxy-N-methylbenzamide (19.45 g, 107.95 mmol), N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (27.5 g, 71.97 mmol) (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4.16 g, 7.20 mmol) diacetoxypalladium (0.808 g, 3.60 mmol) and cesium carbonate (42.2 g, 129.54 mmol) were suspended in dioxane (300 mL). The reaction was degased, purged with argon sereval times and heated to 95 C overnight. The reaction mixture was allowed to cool to rt, the insolubles were removed by filtration, washed with EtOAc and the filtrate was concentrated.The resulting residue was triturated with dichloromethane (150 ml), filtered, washed with DCM to give EN03299-47-01 (8.5 g, 19.57 mmol, 27.2 %)The filtrate was purified by flash chromatography on silica gel eluting with AcOEt and 5% methanol in ethyl acetate. Solvent were evaporated. The resulting precipitate was collected by filtration, washed with dichloromethane and dried to afford EN03299-47-02 (4.5 g, 10.36l, 14.39 %).Not enought combined with uEN03299-49u" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=C(C(=CC=C3)OC)C(=O)NC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 41.58 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/30/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "255" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000724 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000483 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1C2=C(N=C(C=C2)Cl)OC(CN1C)C3CC3" - } - amount { - moles { - value: 0.000483 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 2.41e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.21e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "8-chloro-2-cyclopropyl-4,5-dimethyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (122 mg, 0.48 mmol), 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (99 mg, 0.48 mmol), Pd2dba3 (11.05 mg, 0.01 mmol), BINAP (15.03 mg, 0.02 mmol) and SODIUM TERT-BUTOXIDE (69.6 mg, 0.72 mmol) were weighed in to a microwave vial, the vial was capped and flushed with argon. toluene (4 mL) was added and the mixture was heated to 100C in a microwaver apparatus for 2 h. The cooled reaction mixture was diluted with dichloromethane and filtered. The mixture was concentrated and purified by column chromatography on Silica, using gradient elution with increasing concentration of methanol, from 0 to 8 %, in dichloromethane to give a mixture of the two diastereomers. This was then jected to diastereo and enantio separation to give 31 mg of isomer 1, 32.6 mg of isomer 2, 29 mg of isomer 3 and 29.7 mg of isomer 4 of 2-cyclopropyl-N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4,5-dimethyl-2,3,4,5-tetrahydropyrido[f][1,4]oxazepin-8-amine (Total Yield 122.3 mg, 60 %)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1C2=C(N=C(C=C2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)OC(CN1C)C5CC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 15.27 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/12/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "256" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0669 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.14 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCCN1" - } - amount { - moles { - value: 0.287 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" - } - amount { - moles { - value: 0.0478 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00478 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.00119 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "sodium 2-methylpropan-2-olate (6.43 g, 66.88 mmol) was added to 1-(benzyloxy)-4-bromo-2-fluorobenzene (13.43 g, 47.77 mmol) and piperazine (24.69 g, 286.64 mmol) in toluene (140 mL). The resulting mixture was bubbled with nitrogen for 10 minutes then 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (2.97 g, 4.78 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (1.094 g, 1.19 mmol) were added and the mixture was stirred at 110 C for 20 hours.nbsp;The reaction mixture was cooled to room temperature then fitered through celite and the filter cake washed with ethyl acetate (500 mL).nbsp;The filtrate was evaporated to give crude product.nbsp;The crude product was purified by flash silica chromatography, elution gradient 0 to 20% MeOH in DCM. Pure fractions were evaporated to dryness to afford 1-(4-(benzyloxy)-3-fluorophenyl)piperazine (9.80 g, 71.6 %) as a solid. nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CN(CCN1)C2=CC(=C(C=C2)OCC3=CC=CC=C3)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 71.64 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "12/05/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "258" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000712 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.001 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)CN1CCOCC1" - } - amount { - moles { - value: 0.000214 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1C2=CC(=O)N3C=CC=C(C3=N2)C4=CC=CC5=C4SC6=C5C=C(C=C6)OS(=O)(=O)C(F)(F)F" - } - amount { - moles { - value: 0.000178 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 8.9e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 4.45e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A solution of 6-(2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)dibenzo[b,d]thiophen-2-yl trifluoromethanesulfonate (100mg, 0.18 mmol) in dry dioxane (1 ml) was added to a stirred mixture of N-methyl-2-morpholinoacetamide (33.8 mg, 0.21 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (4.08 mg, 4.45 mol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (5.15 mg, 8.90 mol) and cesium carbonate (232 mg, 0.71 mmol) in dry dioxane (1 ml) . The resulting mixture was stirred under nitrogen at 110 C for 3 hours.nbsp;UPLC analysis showed no appreciable product only hydrolysis of the triflate - not isolated , reaction abandonned" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(C1=CC2=C(C=C1)SC3=C2C=CC=C3C4=CC=CN5C4=NC(=CC5=O)N6CCOCC6)C(=O)CN7CCOCC7" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/23/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "259" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "[O-]P(=O)([O-])[O-].[K+].[K+].[K+]" - } - amount { - moles { - value: 1.12e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.001 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)CN1CCOCC1" - } - amount { - moles { - value: 0.000224 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1C2=CC(=O)N3C=CC=C(C3=N2)C4=CC=CC5=C4SC6=C5C=C(C=C6)OS(=O)(=O)C(F)(F)F" - } - amount { - moles { - value: 0.000112 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 1.12e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.12e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a microwave vial, under nitrogen, at room temperature, a solution of 6-(2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)dibenzo[b,d]thiophen-2-yl trifluoromethanesulfonate (63 mg, 0.11 mmol) in dry toluene (1 mL) was added to a stirred mixture of N-methyl-2-morpholinoacetamide (35.5 mg, 0.22 mmol), Tripotassium phosphate (47.6 mg, 0.22 mmol), rac BINAP (6.99 mg, 0.01 mmol) and Palladium(II) acetate (2.52 mg, 0.01 mmol) in . The resulting mixture was heated in a Biotage Optimiser Microwave reactor under nitrogen at 100 C for 3 hours.nbsp;UPLC of the reaction showed no indication of the desired compound - not isolated - reaction abandonned.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(C1=CC2=C(C=C1)SC3=C2C=CC=C3C4=CC=CN5C4=NC(=CC5=O)N6CCOCC6)C(=O)CN7CCOCC7" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/31/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "260" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000955 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000597 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC(=NC2=C1CN(CC(O2)C3=NC(=CS3)C)C)Cl" - } - amount { - moles { - value: 0.000597 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 2.99e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.49e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "8-chloro-4,6-dimethyl-2-(4-methylthiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (185 mg, 0.60 mmol), 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (122 mg, 0.60 mmol), Pd2dba3 (13.67 mg, 0.01 mmol), BINAP (18.59 mg, 0.03 mmol) and SODIUM TERT-BUTOXIDE (92 mg, 0.96 mmol) were weighed into a microwave vial. toluene (5 mL) was added and the vial was capped and flushed with argon. The mixture was heated to 100C in a microwave apparatus for 2 h. The reaction mixture was diluted with dichloromethane and filtered. The solvents were evaporated and the residue was purified by column chromatography on Silica using a gradient of increasing concentration of methanol, from 0 to 8 %, in dichloromethane to give 163 mg og the title product . The enantiomers were separated by HPLC using a chiral stationary phase to give enantiomer 1 of N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4,6-dimethyl-2-(4-methylthiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (66.3 mg, 23.25 %d enantiomer 2 of N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4,6-dimethyl-2-(4-methylthiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (65.2 mg, 22.86 %)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CC(=NC2=C1CN(CC(O2)C3=NC(=CS3)C)C)NC4=NC(=C(C=C4)C5=CN(N=C5)C)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 22.86 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/10/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "263" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[K+]" - } - amount { - moles { - value: 0.00926 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C=O" - } - amount { - volume { - value: 0.00926 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCNCC1" - } - amount { - moles { - value: 0.0231 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)NC1=CN=C(C=N1)Br" - } - amount { - moles { - value: 0.00463 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" - } - amount { - moles { - value: 0.00926 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 9.26e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "1-methylpiperazine (2.318 g, 23.14 mmol), N-(5-bromopyrazin-2-yl)acetamide (1 g, 4.63 mmol), tri-tert-butylphosphine (1.873 g, 9.26 mmol), tris(dibenzylideneacetone)dipalladium (0.085 g, 0.09 mmol) and potassium 2-methylpropan-2-olate (1.039 g, 9.26 mmol) were suspended in DMF (9.26 ml) and sealed into a microwave tube. The reaction was heated to 120 C for 40 minutes in the microwave reactor and cooled to RT. The mixture was diluted with methanol and acidified with HCl, then the solution was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness to afford N-(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)acetamide (0.866 g, 80 %) as a dark oil. Used without further purification. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)NC1=CN=C(C=N1)N2CCN(CC2)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 79.51 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/24/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "264" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00203 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CN=C1)N" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000122 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000101 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;pyridin-3-amine (95 mg, 1.01 mmol), 2,4-dichloropyridine (0.151 mL, 1.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (70.4 mg, 0.12 mmol) and cesium carbonate (660 mg, 2.03 mmol) were stirred in dioxane (5 mL).nbsp;The mixture was purged with nitrogen for 10 minutes.nbsp;Palladium(II) acetate (22.76 mg, 0.10 mmol) was added and the mixture heated at 100 C for 2h.nbsp;The mixture was cooled, filtered and concentrated.nbsp;The crude product was purified by flash silica chromatography, eluting gradient 5-45% EtOAc in isohexane. Fractions were evaporated to dryness and purified by flash silica chromatography, eluting at 35% EtOAc in isohexanenbsp;to afford 4-chloro-N-(pyridin-3-yl)pyridin-2-amine (107 mg, 51.5 %) as a cream powder." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC(=CN=C1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 51.48 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/29/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "266" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00201 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.001 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC(=NC2=C1CN(CC(O2)C3CCCO3)C)Cl" - } - amount { - moles { - value: 0.001 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 5.02e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.51e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (205 mg, 1.00 mmol), Pd2(dba)3 (22.99 mg, 0.03 mmol), BINAP (31.3 mg, 0.05 mmol) and SODIUM TERT-BUTOXIDE (193 mg, 2.01 mmol) were placed in a round bottomed flask. The flask was stoppered with a septum and flushed with argon. To this was added a solution of 8-chloro-4,6-dimethyl-2-(tetrahydrofuran-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (284 mg, 1.00 mmol) in toluene (5 mL) and the resulting mixture was heated to 100C for 5 h. The reaction mixture was diluted with dichloromethane and filtered, and the solvent was evaporated. The residue was purified by column chromatography on Silica using gradient elution with increasing concentration of methanol, from 0 to 8 %, in dichloromethane to give a mixture of the two diastereoisomers. The major isomer was precipitated from methanol once and from ethanol twice to give 45 mg of Isomer 1 of N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4,6-dimethyl-2-(tetrahydrofuran-2-yl)-2,3,4,5-tetrropyrido[3,2-f][1,4]oxazepin-8-amine (45 mg, 10 %) as a single diastereoisomer of unknown stereochemistry. The rest of the material was purified by HPLC to give Isomer 1 (115.7 mg, 25.6 %) and Isomer 2 (39 mg, 8.6 %) of N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4,6-dimethyl-2-(tetrahydrofuran-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CC(=NC2=C1CN(CC(O2)C3CCCO3)C)NC4=NC(=C(C=C4)C5=CN(N=C5)C)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 35.51 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/28/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "267" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00856 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.06 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CN(CCN1)CC2=CC=CC=C2" - } - amount { - moles { - value: 0.00673 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC(=O)C2=C(O1)C(=CC(=C2)OC)Br" - } - amount { - moles { - value: 0.00611 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000734 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000306 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Tris(dibenzylideneacetone)dipalladium(0) (0.280 g, 0.31 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.457 g, 0.73 mmol), ethyl 8-bromo-6-methoxy-4-oxo-4H-chromene-2-carboxylate (2 g, 6.11 mmol), 1-benzylpiperazine (1.169 mL, 6.73 mmol) and cesium carbonate (2.79 g, 8.56 mmol) were heated under argon to 80 C in toluene (60 mL) overnight.nbsp;The reaction mixture was allowed to cool.nbsp;Ethylacetate was added and the organic mixture was filtered.nbsp;The filtrate was evaporated onto Silica gel.nbsp;The crude product was added to a silica gel column and was eluted with MeOHDCM 0-5%.1H NMR in CDCl3 is consistent with desired productMSnbsp;(m+1) = 423.HPLC Peak RT = 3.38 minutes is product.nbsp;Purity = 63%." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC(=O)C2=C(O1)C(=CC(=C2)OC)N3CCN(CC3)CC4=CC=CC=C4" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 48.39 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/24/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "268" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[K+]" - } - amount { - moles { - value: 0.00094 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.000805 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC(=CC(=C1NC(=O)CC(C)(C)C)C)Br" - } - amount { - moles { - value: 0.000671 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C1=CC=CC=C1C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 6.86e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 3.39e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Exemplar cmpd from H. Lundbeck WO2007090409, though employing slightly different Buchwald-Hartwig coupling conditions.Tris(dibenzylidenacetone)dipalladium(0) (31 mg, 0.03 mmol) and 2\'-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (27 mg, 0.07 mmol) were stirred in anhydrous toluene (3 mL) for 15 minutes under an argon (g) sparge. To the stirring soluntion was added the N-(4-bromo-2,6-dimethylphenyl)-3,3-dimethylbutanamide (200 mg, 0.67 mmol) and morpholine (0.070 mL, 0.80 mmol) neat, followed by the potassium tert-butoxide (1M in THF) (0.94 mL, 0.94 mmol) via syringe. The mixture was then heated in a sealed vessel to 80 C for 18hrs before cooling to ambint temperature. The mixture was filtered thru a 0.7uM GMF. The resultant crude solution was ject to flash chromatorgraphy (SiO2 - 12 g; gradient elution: 100% hexanes for 1 minute then 0% - 80% EtOAcHexane over 13 minutes at 30 mLmin) via detection with UV light at 254nm. The appropriate fractions were then stirred overolorizing carbon (Norit neutral), filtered thru Celite and concentrated to afford the N-(2,6-dimethyl-4-morpholinophenyl)-3,3-dimethylbutanamide (130 mg, 63.7 %) as a off-white solid that appears to benbsp;~90% purity by 1H NMR (CDCl3), though TLC and LCMS reveal one peak. The resultant solid was ject to flash chromatorgraphy (basic alumina - 24 g; gradient elution: 5% EtOAcHexane for 1.5 minutes then 5% - 100% EtOAcHexane over 11 minutes at 30 mLmin) via detection with UV light at 254nm to afford the N-(2,6-dimethyl-4-morpholinophenyl)-3,3-dimethylbutanamide (130 mg, 63.7 %) again what appears to be ~90% purity by 1H NMR (CDCl3), though TLC and LCMS reveal one peak. Aliqout was provided to X. Ye for SFC analysis wherein all conditions examined reveal only one peak (attached). 1H NMR analysis in DMSO reveals one clean cmpd. Forming rotamers in CDCl3 with difference exagerated in the morpholino -CH2-N-CH2- protons." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CC(=CC(=C1NC(=O)CC(C)(C)C)C)N2CCOCC2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 63.67 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/14/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "269" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[K+]" - } - amount { - moles { - value: 0.00094 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.000804 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC(=CC(=C1NC(=O)CC2CCCC2)C)Br" - } - amount { - moles { - value: 0.00067 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C1=CC=CC=C1C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 6.86e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 3.39e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Exemplar cmpd from H. Lundbeck WO2007090409, though employing slightly different Buchwald-Hartwig coupling conditions.Tris(dibenzylidenacetone)dipalladium(0) (31 mg, 0.03 mmol) and 2\'-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (27 mg, 0.07 mmol) were stirred in anhydrous toluene (3 mL) for 15 minutes under an argon (g) sparge. To the stirring soluntion was added the N-(4-bromo-2,6-dimethylphenyl)-2-cyclopentylacetamide (208 mg, 0.67 mmol) and morpholine (0.070 mL, 0.80 mmol) neat, followed by the potassium tert-butoxide (1M in THF) (0.94 mL, 0.94 mmol) via syringe. he mixture was then heated in a sealed vessel to 80 C for 18hrs before cooling to ambint temperature. The mixture was filtered thru a 0.7uM GMF. The resultant crude solution was ject to flash chromatorgraphy (SiO2 - 12 g; gradient elution: 100% hexanes for 1 minute then 0% - 85% EtOAcHexane over 14 minutes at 30 mLmin) via detection with UV light at 254nm. The appropriate fractions were then stirred over lorizing carbon (Norit neutral), filtered thru Celite and concentrated to afford the 2-cyclopentyl-N-(2,6-dimethyl-4-morpholinophenyl)acetamide (47.0 mg, 22.17 %) as a white solid in 90% purity by 1H NMR (CDCl3), though TLC and LCMS reveal one peak. The resultant solid was ject to flash chromatorgraphy (basic alumina - 24 g; gradient elution: 5% EtOAcHexane for 1.5 minutes then 5% - 100% EtOAcHexane over 11 minutes at 30 mLmin) via detection with UV light at 254nm to afford 2-cyclopentyl-N-(2,6-dimethyl-4-morpholinophenyl)acetamide (28.0 mg, 13.21 %) again what appears to be ~80% purity by 1H NMR (CDCl3), though TLC and LCMS reveal one peak. Aliqout was provided to X. Ye for SFC analysis wherein all conditions examined reveal only one peak (attached). 1H NMR analysis in DMSO reveals one cmpd. Forming rotamers in CDCl3 with difference exagerated in the morpholino -CH2-N-CH2- protons." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CC(=CC(=C1NC(=O)CC2CCCC2)C)N3CCOCC3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 13.21 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/14/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "270" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00478 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.025 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@@H]1CNCCN1C(=O)OC(C)(C)C" - } - amount { - moles { - value: 0.00358 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=CC(=C1)Br)OCC2=CC=CC=C2" - } - amount { - moles { - value: 0.00341 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000136 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000102 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Tonbsp;(R)-tert-butyl 2-methylpiperazine-1-carboxylate (0.717 g, 3.58 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.094 g, 0.10 mmol) and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.085 g, 0.14 mmol) andnbsp;Sodium tert-butoxide (0.459 g, 4.78 mmol) was added a solution of 1-(benzyloxy)-4-bromo-2-methoxybenzene (1 g, 3.41 mmol) in Toluene (25 mL).nbsp;The reaction was heated to 80 C for 18 hours. the reaction was allowed to cool to room temperature and diluted with dcm (50 ml). This was washed with water (2 x 50 ml), dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The crude product was dissolved in hydrochloric acid solution in methanol (4N, 20 ml) and stirred at room temprature overnight. The solvent was removed under reduced pressure.The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness to afford (R)-1-(4-(benzylo3-methoxyphenyl)-3-methylpiperazine (0.429 g, 40.3 %) as a yellow gum. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@@H]1CN(CCN1)C2=CC(=C(C=C2)OCC3=CC=CC=C3)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 40.26 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/11/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "271" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 3.93e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCONC(=O)C1=CC=CC=C1N" - } - amount { - moles { - value: 0.000667 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)I)C(F)(F)F)C" - } - amount { - moles { - value: 0.000393 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.93e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.96e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (22.71 mg, 0.04 mmol), diacetoxypalladium (4.41 mg, 0.02 mmol), 2-amino-N-ethoxybenzamide (120 mg, 0.67 mmol), N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (150 mg, 0.39 mmol) and cesium carbonate (256 mg, 0.79 mmol) were weighed out in a wave vial, sealed and dioxane (4 mL) was added. Reaction was degassed with nitrogen. The reaction was stirred at 90 C for 12 hours =gt; iincomplete (~90% conversion)i. A few Pd(OAc)2, Xantphos and Cs2CO3 were added. Reaction was degassed with nitrogen and stirred at 90C for 2 hours =gt; icomplete.i The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane and MeOH and silica (40-63 m) was added. Mixture was concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 0 to 4% methanol in dichloromethane. Solvent was evaporated to afford product as a pale yellow foam. This wEt2O, petroleum ether was added and the resulting precipitate was sonicated for 10 minutes. Solid was filtered and dried under high vacuum to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N-ethoxybenzamide (127 mg, 74.5 %) as a white solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCONC(=O)C1=CC=CC=C1NC2=CC(=NC=C2C(F)(F)F)NC3=CC(=NN3C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 74.48 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/13/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "272" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 3.93e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C(=C1)C(=O)NOCCO)N" - } - amount { - moles { - value: 0.000667 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)I)C(F)(F)F)C" - } - amount { - moles { - value: 0.000393 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.93e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.96e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (22.71 mg, 0.04 mmol), diacetoxypalladium (4.41 mg, 0.02 mmol), 2-amino-N-(2-hydroxyethoxy)benzamide (131 mg, 0.67 mmol), N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (150 mg, 0.39 mmol) and cesium carbonate (256 mg, 0.79 mmol) were weighed out in a wave vial, sealed and dioxane (4 mL) was added. Reaction was degassed with nitrogen. The reaction was stirred at 90 C for 12 hours =gt; iincomplete (~85% conversion)i. A few Pd(OAc)2, Xantphos and Cs2CO3 were added. Reaction was degassed with nitrogen and stirred at 90C for 2 hours =gt; ialmost complete.i The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane and MeOH and silica (40-63 m) was added. Mixture was concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 0 to 12% methanol in ethyl acetate. Solvent was evaporated to afford product as a yellow riturated in Et2O and petroleum ether and the resulting precipitate was sonicated for 10 minutes. Solid was filtered and dried under high vacuum to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N-(2-hydroxyethoxy)benzamide (86 mg, 48.6 %) as a yellow solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOCCO)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 48.64 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/13/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "273" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 9.1e-06 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=N1)C2=CC=C(C=C2)N" - } - amount { - moles { - value: 1.82e-05 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 1.82e-05 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 1.82e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.82e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A solution of (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (5.00 mg, 0.02 mmol) and 4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (3.17 mg, 0.02 mmol) in DME (.5 mL) was added via a syringe to a capped microwave vial containing PALLADIUM(II) ACETATE (0.409 mg, 1.82 mol), 2-(DICYCLOHEXYLPHOSPHINO)BIPHENYL (0.638 mg, 1.82 mol), CESIUM CARBONATE (8.89 mg, 0.03 mmol) and KI (1.511 mg, 9.10 mol) under an argon atmosphere. The resulting mixture was heated to 100C in a microwavwe apparatus for 1 h and analyzed by LCMS." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=N1)C2=CC=C(C=C2)NC3=NC4=C(CN(C[C@H](O4)C5=CC=CC=C5)C)C=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/16/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "275" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 2.73e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=N1)C2=CC=C(C=C2)N" - } - amount { - moles { - value: 1.82e-05 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 1.82e-05 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 1.82e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.82e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A solution of (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (5.00 mg, 0.02 mmol) and 4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (3.17 mg, 0.02 mmol) in DME (.5 mL) was added via a syringe to a capped microwave vial containing PALLADIUM(II) ACETATE (0.409 mg, 1.82 mol), 2-(DICYCLOHEXYLPHOSPHINO)BIPHENYL (0.638 mg, 1.82 mol) and CESIUM CARBONATE (8.89 mg, 0.03 mmol) under an argon atmosphere. The resulting mixture was heated to 100C in a microwave apparatus for 1 h and analyzed by LCMS. No " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=N1)C2=CC=C(C=C2)NC3=NC4=C(CN(C[C@H](O4)C5=CC=CC=C5)C)C=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/16/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "276" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[K+]" - } - amount { - moles { - value: 2.73e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=N1)C2=CC=C(C=C2)N" - } - amount { - moles { - value: 1.82e-05 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 1.82e-05 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 1.82e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.82e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A solution of (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (5.00 mg, 0.02 mmol) and 4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (3.17 mg, 0.02 mmol) in DME (0.5 mL) was added via a syringe to a capped microwave vial containing PALLADIUM(II) ACETATE (0.409 mg, 1.82 mol), 2-(DICYCLOHEXYLPHOSPHINO)BIPHENYL (0.638 mg, 1.82 mol) and KOtBu (3.06 mg, 0.03 mmol) under an argon atmosphere. The resulting mixture was heated to 100C in a microwavwe apparatus for 1 h and analyzed by LCMS. No " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=N1)C2=CC=C(C=C2)NC3=NC4=C(CN(C[C@H](O4)C5=CC=CC=C5)C)C=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/16/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "277" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 2.73e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=N1)C2=CC=C(C=C2)N" - } - amount { - moles { - value: 1.82e-05 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 1.82e-05 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 1.82e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.82e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A solution of (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (5.00 mg, 0.02 mmol) and 4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (3.17 mg, 0.02 mmol) in DME (.5 mL) was added via a syringe to a capped microwave vial containing PALLADIUM(II) ACETATE (0.409 mg, 1.82 mol), XANTPHOS (1.053 mg, 1.82 mol) and CESIUM CARBONATE (8.89 mg, 0.03 mmol) under an argon atmosphere. The resulting mixture was heated to 100C in a microwavwe apparatus for 1 h and analyzed by LCMS. No " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=N1)C2=CC=C(C=C2)NC3=NC4=C(CN(C[C@H](O4)C5=CC=CC=C5)C)C=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/16/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "278" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 2.73e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=N1)C2=CC=C(C=C2)N" - } - amount { - moles { - value: 1.82e-05 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 1.82e-05 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 1.82e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 9.1e-07 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A solution of (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (5.00 mg, 0.02 mmol) and 4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (3.17 mg, 0.02 mmol) in DME (.5 mL) was added via a syringe to a capped microwave vial containing Pd2(dba)3 (0.833 mg, 0.91 mol), 2-(DICYCLOHEXYLPHOSPHINO)BIPHENYL (0.638 mg, 1.82 mol) and Cs2CO3 (8.89 mg, 0.03 mmol) under an argon atmosphere. The resulting mixture was heated to 100C in a microwavwe apparatus for 1 h and analyzed by LCMS. No " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=N1)C2=CC=C(C=C2)NC3=NC4=C(CN(C[C@H](O4)C5=CC=CC=C5)C)C=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/16/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "279" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.005 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1CCOC1" - } - amount { - volume { - value: 0.036 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCCN1" - } - amount { - moles { - value: 0.0125 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC2=C(C=C(O2)C(=O)N)C(=C1)Br" - } - amount { - moles { - value: 0.0025 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00025 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000125 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 70.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "The crude product from EN03731-54-001, 4-bromobenzofuran-2-carboxamide (0.600 g, 2.5 mmol), was dissolved in THF (18 mL) and water (18.00 mL). To this mixture were added piperazine (1.077 g, 12.50 mmol), Cesium carbonate (1.629 g, 5.00 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.114 g, 0.13 mmol) and rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.156 g, 0.25 mmol) and the reaction was heated at 70 C over night.2010-04-13 No product was detected. The reaction mixture was filtered and solvents were removed in vacuo. The residue was partitioned between methylene chloride and water. The organic layer was washed with 1M HCl(aq), dired with sodium sulfate, filtered, concentrated and purified by flash chromatography(Isolute Si 70g, methylene chloride: methanol; 97:3). No product could be detectedisolated." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CN(CCN1)C2=C3C=C(OC3=CC=C2)C(=O)N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/12/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "280" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00204 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.000926 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C(=CC=C1)Br)[N+](=O)[O-]" - } - amount { - moles { - value: 0.000926 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000185 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 9.26e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "tert-butyl piperazine-1-carboxylate (172 mg, 0.93 mmol) and 1-bromo-3-methyl-2-nitrobenzene (0.124 mL, 0.93 mmol), were added to a stirred solution of diacetoxypalladium (20.78 mg, 0.09 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (107 mg, 0.19 mmol) and cesium carbonate (664 mg, 2.04 mmol) dissolved in dioxane (3 mL). The resulting solution was stirred at 80 C under nitrogen overnight.The reaction mixture was filtered, dried under vaccum.nbsp;The crude product was purified by flash chromatography on silica gel eluting with 5 to 15% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-(3-methyl-2-nitrophenyl)piperazine-1-carboxylate (50.0 mg, 16.81 %) as anbsp;orange oil." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C(=CC=C1)N2CCN(CC2)C(=O)OC(C)(C)C)[N+](=O)[O-]" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 16.81 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/29/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "281" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00469 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N" - } - amount { - moles { - value: 0.00396 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C=C1Br)F)C=O" - } - amount { - moles { - value: 0.0033 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000264 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" - } - amount { - moles { - value: 0.000132 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A solution of 4-bromo-2-fluorobenzaldehyde (0.670 g, 3.30 mmol) dissolved in toluene (10 mL) was treated with tert-butyl carbamate (0.464 g, 3.96 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.164 g, 0.26 mmol), Bis(dibenzylideneacetone)palladium (0.076 g, 0.13 mmol) and cesium carbonate (1.527 g, 4.69 mmol)nbsp;under nitrogen. The mixture was degassed under vacuum several times before heating at 100 C for 24 hours. Reaction incomplete so heated for further 10 hours. The reaction mixture was diluted with water (250 mL), and extracted with ethyl acetate (250 mL X 2).nbsp;The organic was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution 10% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 3-fluoro-4-formylphenylcarbamate (0.660 g, 84 %) as a yellow solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC1=CC(=C(C=C1)C=O)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 83.59 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/20/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "282" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0216 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.04 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N" - } - amount { - moles { - value: 0.0183 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C=C1Br)F)C=O" - } - amount { - moles { - value: 0.0152 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00122 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" - } - amount { - moles { - value: 0.000609 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A solution of 4-bromo-2-fluorobenzaldehyde (3.09 g, 15.22 mmol) dissolved in toluene (40 mL) was treated with tert-butyl carbamate (2.140 g, 18.27 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.758 g, 1.22 mmol), Bis(dibenzylideneacetone)palladium (0.350 g, 0.61 mmol) and cesium carbonate (7.04 g, 21.62 mmol)nbsp;under nitrogen. The mixture was degassed under vacuum several times before heating at 100 C for 30 hours. The reaction mixture was diluted with water (250 mL), and extracted with ethyl acetate (250 mL X 2).nbsp;The organic was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution 10% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 3-fluoro-4-formylphenylcarbamate (3.55 g, 97 %) as a yellow solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC1=CC(=C(C=C1)C=O)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 97.47 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/24/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "283" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "[O-]P(=O)([O-])[O-].[K+].[K+].[K+]" - } - amount { - moles { - value: 0.003 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NCCC1CCNCC1" - } - amount { - moles { - value: 0.0015 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)I" - } - amount { - moles { - value: 0.00218 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" - } - amount { - moles { - value: 0.00015 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C.[Pd]" - } - amount { - moles { - value: 0.00015 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a solution of tert-butyl 2-(piperidin-4-yl)ethylcarbamate (0.342 g, 1.5 mmol) in anhydrous DME were added iodobenzene (0.444 g, 2.18 mmol), bis(tri-t-butylphosphine)palladium(0) (0.077 g, 0.15 mmol) and potassium phosphate (0.245 mL, 3.00 mmol). The reaction was heated to 100C overnight. This reaction did not work." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NCCC1CCN(CC1)C2=CC=CC=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/08/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "284" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00679 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CN(CCN1)CC2=CC=CC=C2" - } - amount { - moles { - value: 0.0063 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(O1)C(=CC=C2)Br" - } - amount { - moles { - value: 0.00485 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.000485 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000242 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 95.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "The mixture ofnbsp;Tris(dibenzylideneacetone)dipalladium(0) (0.222 g, 0.24 mmol) and 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (0.231 g, 0.48 mmol) in dioxane (10 mL) (degassed with argon for 5 min) was heated at 95 C under argon for 5 min . This was transferred to a flask containing 7-bromo-N,N-dimethylbenzofuran-2-carboxamide (1.3 g, 4.85 mmol), 1-benzylpiperazine (1.111 g, 6.30 mmol) and Cesium carbonate (2.212 g, 6.79 mmol) in dioxane (10 mL) (degassed with argon for 5 min). The resulting mixture was heated at 95 C over night.nbsp;After cooling, the reaction mixture was filtered, the solid washed with DCM and concentrated. The product was purified by isco (DCM:MeOH; 0-3%). A small portion was also purified by prepLC giving EN02745-79-" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(O1)C(=CC=C2)N3CCN(CC3)CC4=CC=CC=C4" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 52.15 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/26/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "285" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000191 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0022 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NCCC1CCNCC1" - } - amount { - moles { - value: 0.0015 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)Br" - } - amount { - moles { - value: 0.000955 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000191 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 9.55e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 50.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "palladium(II) acetate (21.45 mg, 0.10 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (111 mg, 0.19 mmol) were placed in a round-bottomed vessel that was filled with nitrogen. Toluene (0.8 mL) was added and the mixture was heated to 50C for 30 min.sodium tert-butoxide (138 mg, 1.43 mmol) was added to a second vessel and inerted with nitrogen. tert-butyl 2-(piperidin-4-yl)ethylcarbamate (342 mg, 1.5 mmol) and bromobenzene (150mg, 0.96 mmol) and toluene (1.4 mL) were added. 1404 2009 13:57:24 +0200 The catalyst solution was added to the reagent mixture and the combined mixture was heated to reflux for several hours. The reaction did not work." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NCCC1CCN(CC1)C2=CC=CC=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/09/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "287" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000355 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CN(CCN1)CCC2=CC=CC=C2" - } - amount { - moles { - value: 0.000254 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC2=C(C(=C1)Br)OC=C2" - } - amount { - moles { - value: 0.000254 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 1.02e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 5.08e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A dried Radley tube was charged with rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (6.32 mg, 10.15 mol), Tris(dibenzylideneacetone)dipalladium(0) (4.65 mg, 5.08 mol) and Sodium tert-butoxide (34.1 mg, 0.36 mmol). Argon atmosphere was introduced andnbsp;toluene (3ml) was added followed by 7-bromobenzofuran (50mg, 0.25 mmol) and 1-phenethylpiperazine (48.3 mg, 0.25 mmol). The reaction mixture was heated at reflux over night.2010-03-25 The reaction mixture was filtered, concentrated and purified by flash chromatography (Isolute Si 10g, heptane: ethyl acetate; 4:1) to give 1-(benzofuran-7-yl)-4-phenethylpiperazine (48.3 mg, 62." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CN(CCN1CCC2=CC=CC=C2)C3=CC=CC4=C3OC=C4" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 62.12 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/24/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "288" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00097 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@@H]1CNC[C@@H](N1)C" - } - amount { - moles { - value: 0.00194 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)Br)[N+](=O)[O-]" - } - amount { - moles { - value: 0.000646 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 9.05e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 6.46e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a solution of 4-bromo-1-methoxy-2-nitrobenzene (150 mg, 0.65 mmol) in dioxane (4 mL) was added (2R,6S)-2,6-dimethylpiperazine (221 mg, 1.94 mmol) followed by cesium carbonate (316 mg, 0.97 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (56.4 mg, 0.09 mmol) and diacetoxypalladium (14.51 mg, 0.06 mmol). The resulting mixture was heated at 100 C under argon over night (black). LCMS Ok. The solids were filtered through celite and washed with ethyl acetate. The ethyl acetate was evaporated under reduced pressure and the crude product was purified by flash-chromatograpy eluated with dichloromethane Methanol + 0.2% Et3Nnbsp;1000 =gt;9010 over 20 min. The pure fractions was collected and concentrated to give (3R,5S)-1-(4-methoxy-3-nitrophenyl)-3,5-dimethylpiperazine (96 mg, 56.0 %) as red solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@@H]1CN(C[C@@H](N1)C)C2=CC(=C(C=C2)OC)[N+](=O)[O-]" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 55.97 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/05/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "290" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0097 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.04 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@@H]1CNC[C@@H](N1)C" - } - amount { - moles { - value: 0.0194 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)Br)[N+](=O)[O-]" - } - amount { - moles { - value: 0.00646 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000905 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000646 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a solution of 4-bromo-1-methoxy-2-nitrobenzene (1500 mg, 6.46 mmol) in dioxane (40 mL) was added (2R,6S)-2,6-dimethylpiperazine (2215 mg, 19.39 mmol) followed by cesium carbonate (3159 mg, 9.70 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (564 mg, 0.91 mmol) and diacetoxypalladium (145 mg, 0.65 mmol). The resulting mixture was heated at 100 C under argon over night (black). LCMS Ok. The solids were filtered through celite and washed with ethyl acetate. The ethyl acetate was evaporated under reduced pressure and the crude product was purified by flash-chromatograpy eluated with Dichloromethane 2 M NH3 in Methanolnbsp;1000 =gt;8020 over 20 min. The pure fractions was collected and concentrated to give (3R,5S)-1-(4-methoxy-3-nitrophenyl)-3,5-dimethylpiperazine (1540 mg, 90 %) as red solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@@H]1CN(C[C@@H](N1)C)C2=CC(=C(C=C2)OC)[N+](=O)[O-]" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 89.79 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/18/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "291" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00554 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.03 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)N)C" - } - amount { - moles { - value: 0.00471 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=C(C=CC=C1OC)NC2=CC(=NC=C2C(F)(F)F)Cl" - } - amount { - moles { - value: 0.00461 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000738 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000369 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "i2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-6-methoxy-N-methylbenzamide (1.66 g, 4.61 mmol)ii, ii1,3-dimethyl-1H-pyrazol-5-amine (0.523 g, 4.71 mmol)ii, iidiacetoxypalladium (0.083 g, 0.37 mmol)ii, ii(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.427 g, 0.74 mmol)ii and iicesium carbonate (1.804 g, 5.54 mmol)ii were mixed together in iidioxane (30 mL)ii. Reaction was degassed with argon and was stirred at ii90 Cii for 3 hours under argon.The mixture was filtered ,the filtrate was concentrated andnbsp;purified by flash chromatography on silica gel 15-40m eluting with ii0ii to ii4ii% methanol in CH2Cl2AcOEt (6040).The product obtained was not enough purenbsp;so the product was repurifiednbsp;by flash chromatography on silica gel 15-40m eluting with 0 to 4% methanol in CH2Cl2AcOEt (6040).The solvent was evaporated to dryness to afford i2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)omethyl)pyridin-4-ylamino)-6-methoxy-N-methylbenzamide (0.882 g, 44.0 %)i as anbsp;ibeigei isolidi.iiEN 02814-27-01i" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=C(C(=CC=C3)OC)C(=O)NC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 44.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/17/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "292" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00174 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" - } - amount { - moles { - value: 0.00058 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OCC1CN(CC2=C(O1)N=C(C=C2)Cl)C" - } - amount { - moles { - value: 0.00058 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 5.8e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 5.8e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "8-chloro-2-(isopropoxymethyl)-4-methyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.157 g, 0.58 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.118 g, 0.58 mmol), Palladium acetate (0.013 g, 0.06 mmol), 2-(Dicyclohexylphosphino)biphenyl (0.020 g, 0.06 mmol) and Cesium carbonate (0.567 g, 1.74 mmol) were placed in a microwave vial. The mixture was capped and flushed with argon.nbsp;1,2-dimethoxyethane (5 mL) was added and the mixture was run in a microwave for 60 minutes at 100C. Very little product. Added 0.1 eq ligand and palladium acetate, flushed with argon and run in the microwave at 100C for 60 min. Still have a lot of startingmaterial (oxazepine) left. Added 0.1 eq ligand and palladium acetate, flushed with argon and run in the microwave at 100C for 60 min. The reaction mixturenbsp;was filtrated through Celite and washed with dichloromethane. The filtrate was concentrated and the crude product was purified by preparative chromatography. The productcontaining fractions, concentrated and the residue was partitioned between sat. NaHCO3 (aq) and dichloromethane. The organic layer was separated by a Phase Separator and concentrated giving 2-(isopropoxymethyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-4-methyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (0.013 g, 5.28 %)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(CN(CC(O4)COC(C)C)C)C=C3)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 5.28 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/02/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "294" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00197 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CCO" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=N1)C2=C(C=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000655 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.000655 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 6.55e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 6.55e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (180 mg, 0,66 mmol), 3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (134 mg, 0,66 mmol), Palladium acetate (14,71 mg, 0,07 mmol), 2-(Dicyclohexylphosphino)biphenyl (22,96 mg, 0,07 mmol) and Cesium carbonate (640 mg, 1,97 mmol) were mixed in DME (3 mL) in a microwave vial. EtOH (0,3 mL) was added and the mixture was run for 1 hour at 100C in a microwave reactor. the reaction had to be run for an additional 2 hours with more catalyst and ligand added. the mixture was filtered and purified using flash chromatography 0-10% MeOH in DCM." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(CN(C[C@H](O4)C5=CC=CC=C5)C)C=C3)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 18.97 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "12/02/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "297" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00383 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CONC(=O)C1=CC=CC=C1N" - } - amount { - moles { - value: 0.00326 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C(=NN1C)C)NC2=NC=C(C(=C2)I)C(F)(F)F" - } - amount { - moles { - value: 0.00192 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000287 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000172 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-amino-N-methoxybenzamide (541 mg, 3.26 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (166 mg, 0.29 mmol), cesium carbonate (1249 mg, 3.83 mmol) and diacetoxypalladium (38.7 mg, 0.17 mmol) were added to a stirred solution of 4-iodo-5-(trifluoromethyl)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridin-2-amine (759 mg, 1.92 mmol) dissolved in dioxane (20 mL) in a wave vial at RT.nbsp;Argon was let to bubble in the mixture for 5 minutes and the resulting slurry was then stirred at 90 C for 15 hours. Lcms showed complete reaction.The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane, filtered, silica gel was added and the mixture was concentrated. The crude product was purified by flash chromatography on silica gel eluting with 30 to 100% ethyl acetate in petroleum ether. The solvent was evaporated to dryness, the remainning gum was taken up in DCM and concentrated in the cold. The precipitate was collected by filtration, washed with diethyand dried to a constant weight to afford N-methoxy-2-(5-(trifluoromethyl)-2-(1,3,5-trimethyl-1H-pyrazol-4-ylamino)pyridin-4-ylamino)benzamide (742 mg, 89 %) (batch EN03692-99-01) as a off-white solid. NMR showed the presence of solvents (ethyl acetate and diethyl ether). The solid was then dried several days under vacuum at 55C to removed these solvents (--gt; batch EN03692-99-02 (723 mg, 1.664 mmol, 87 %)) : unsuccessfully!bAnalysis: - NMR (CDE) --gt; strenght = 95%, bbethyl acetatebb= 0.06 molemole and diethyl ether = 0.11 molemolebbnbsp;- analytical lcms (DDO) --gt; purity = 99%b" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C(=NN1C)C)NC2=NC=C(C(=C2)NC3=CC=CC=C3C(=O)NOC)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 89.15 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/12/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "298" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0121 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.03 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CN(CCN1)CC2=CC=CC=C2" - } - amount { - moles { - value: 0.0102 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(O1)C=CC=C2Br" - } - amount { - moles { - value: 0.00929 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.000929 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000465 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 95.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2010 2009 10:10:14 +0200To ethyl 4-bromobenzofuran-2-carboxylate (2.50 g, 9.29 mmol) and 1-benzylpiperazine (1.776 mL, 10.22 mmol) in dry degassed dioxane (30 mL) were added Cesium carbonate (3.94 g, 12.08 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-triisopropylbiphenyl (0.443 g, 0.93 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (0.425 g, 0.46 mmol) under argon and the reaction heated at 95C on. All starting material consumed.nbsp;The crude solution was pooled with the corresponding solution in EN03307-46Water and DCM were added and the layers separated. The aq phase was extracted with DCM (3x). The combined org phases were washed with water, dried (MgSO4), filtered and evaporated. The crude was purified by flash chrom. (SiO2; HeptaneEtOAc 7030) to give 3.05 g (50%) of the product as a yellow solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(C=CC=C2O1)N3CCN(CC3)CC4=CC=CC=C4" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 90.08 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/20/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "300" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00446 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CN(CCN1)CC2=CC=CC=C2" - } - amount { - moles { - value: 0.00483 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(O1)C=CC=C2Br" - } - amount { - moles { - value: 0.00372 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C1=CC=CC=C1C2=CC=CC=C2)C(C)(C)C" - } - amount { - moles { - value: 0.000223 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 7.43e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "bPurpose:b Buchwald-Hartwig coupling using unpurified ethyl 4-bromobenzofuran-2-carboxylate. The analysis on crude 4-bromobenzofuran-2-carboxylate shows traces of non cyclized and non aromoatized by-products.2010-03-1016:38:11: To a 25 mL rounbottomed flask was added ethyl 4-bromobenzofuran-2-carboxylate (1 g; 3.72 mmol) and toluene (10 mLg-bulk-LR; 10 mL). The mixture was concentrated under reduced pressure to remove traces of water. The procedure was repeated once more. and finally toluene (10 mLg-bulk-LR; 10 mL). The system was inerted three times and stirred under nitrogen gas.17:03:56: To the homogenous mixture was added 1-benzylpiperazine (1.3 eq; 0.852 g; 0.84 mL; 4.83 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.02 eq; 68 mg; 0.07 mmol), 2-(DI-T-BUTYLPHOSPHINO)BIPHENYL (0.06 eq; 67 mg; 0.22 mmol) and CESIUM CARBONATE (1.2 eq; 1.453 g; 4.46 mmol). The system was inerted three times and stirred under nitrogen gas.17:07:37: The Tj was set to Tj=100 C. mixture was stirred under nitrogen gas over night.2010-03-1108:42:44: IPC1 (15 h) sample was gathered and diluted with methanol. The analysis (EN03690-35-001-A) showed only 16 % conversion.bResults and conclusion: bThe experiment was discarded due to poor conversion.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(C=CC=C2O1)N3CCN(CC3)CC4=CC=CC=C4" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/10/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "301" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00483 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CN(CCN1)CC2=CC=CC=C2" - } - amount { - moles { - value: 0.00334 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(O1)C=CC=C2Br" - } - amount { - moles { - value: 0.00372 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.000372 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000186 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 95.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "ethyl 4-bromobenzofuran-2-carboxylate (1 g, 3.72 mmol), 1-Benzylpiperazine (0.580 mL, 3.34 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.170 g, 0.19 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (0.177 g, 0.37 mmol) and CESIUM CARBONATE (1.574 g, 4.83 mmol) in dioxane (5 mL) were heated under argon to 95 C overnight.nbsp;The mixture was allowed to cool. The mixture was diluted with EtOAc and the mixture was filtered through a pad of Celite.nbsp;The filterate was collected and the solvent was removed by rotary evaporation.nbsp;The crude product was added to a silica gel column and was eluted withnbsp;0-50% EtOAc in heptane.nbsp;The collected fractions were combined and the solvent was removed to yield ethyl 4-(4-benzylpiperazin-1-yl)benzofuran-2-carboxylate (0.360 g, 26.6 %).MSnbsp;(m+1) = 365.6.HPLC Peak RT = 3.33 minutes is product.nbsp;Purity = 96%." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(C=CC=C2O1)N3CCN(CC3)CC4=CC=CC=C4" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 26.58 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/08/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "302" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[K+]" - } - amount { - moles { - value: 0.0052 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.007 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CN(CCN1)CC2=CC=CC=C2" - } - amount { - moles { - value: 0.00483 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(O1)C=CC=C2Br" - } - amount { - moles { - value: 0.00372 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000149 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 7.43e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 50.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "bPurpose:b Buchwald-Hartwig coupling using unpurified ethyl 4-bromobenzofuran-2-carboxylate. The analysis on crude 4-bromobenzofuran-2-carboxylate shows traces of non cyclized and non aromoatized by-products.2010-03-0215:25:22: To a 25 mL roundbottomed flask was added ethyl 4-bromobenzofuran-2-carboxylate (LR; 1 g; 3.72 mmol) and toluene (7 mLg-bulk-LR; 7 mL). The mixture was concentrated under reduced pressure. To the mixture was added toluene (7 mLg-bulk-LR; 7 mL) and the mixture was concentrated a second time under reduced pressure. To the mixture was added toluene (7 mLg-bulk-LR; 7 mL) followed by 1-benzylpiperazine (1.3 eq; 0.852 g; 0.84 mL), BINAP (0.04 eq; 93 mg) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.02 eq; 68 mg). The mixture was stirred for 5 minutes followed by addition of POTASSIUM TERT-BUTOXIDE (1.4 eq; 0.58 g). The mixture is stirred at Tm=50 C.15:45:57: IPC1 (15 min) sample was gathered. The sample was quenched with a mixture consisting of 700 metic acid buffer pH=2 and methanol. The sample was filtered and analyzed by means of HPLC-UV (EN03690-30-001-F) which indicated 44 % conversion17:09:21: IPC2 (100 min) sample was gathered. The sample was quenched with a mixture consisting of 700 mM acetic acid buffer pH=2 and methanol. The sample was filtered and analyzed by means of HPLC-UV (EN03690-30-001-H) which indicated 95 % conversion.17:20:00: The temperature was allowed to reach rt and the mixture was stirred over night. 2010-03-0309:51:29: IPC3 (18 h) sample was gathered. The sample was quenched with a mixture consisting of 700 mM acetic acid buffer pH=2 and methanol. The sample was filtered and analyzed by means of HPLC-UV (EN03690-30-001-J) which indicated +99 % conversion.10:10:32: The mixture was transfered to a mixture consisting of 700 mM acetate buffer pH=2 (12.5 mLg-bulk-LR; 12.5 mL) and isopropyl acetate (6.2 mLg-bulk-LR; 6.2 mL) to give pH=5.65. To the mixture was added 4 M aqueous sulfuric acid (1.77 mLg-bulk-LR; 1.77 mL) to give pH=2. The mixture was stirred for 15 minutes. The phases were separated and analyzed by means of HPLC-UVnbsp;12:32:57: To the water phase was added dichloromethane (10 mLg-bulk-LR; 10 mL). The mixture was stirred and 50 % aqueous sodium hydroxide (1 mL) was added to give pH=12. The phases were separated and analyzed by means of HPLC-UV. The organic phase was concentrated under reduced pressure to give yellow oil. The crude product was purified by means of column chromatography (40 g SiO2; 4 % MeOH, 1 NH3 in MeOH in DCM; Rf=0.2). Yellow solid was obtained (250 mg). 1H NMR showed not correct product. bResult:b Correct product was not isolated.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(C=CC=C2O1)N3CCN(CC3)CC4=CC=CC=C4" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/01/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "303" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0242 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.025 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CN(CCN1)CC2=CC=CC=C2" - } - amount { - moles { - value: 0.0186 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(O1)C=CC=C2Br" - } - amount { - moles { - value: 0.0186 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.00186 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000929 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 95.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "ethyl 4-bromobenzofuran-2-carboxylate (5 g, 18.58 mmol), 1-benzylpiperazine (3.22 mL, 18.58 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (0.886 g, 1.86 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.851 g, 0.93 mmol) and CESIUM CARBONATE (7.87 g, 24.16 mmol) were heated under argon to 95 C overnight.nbsp;The mixture was allowed to cool. The mixture was diluted with EtOAc and the mixture was filtered through a pad of Celite.nbsp;The filterate was collected and the solvent was removed by rotary evaporation.nbsp;The crude product was added to a silica gel column and was eluted withnbsp;0-50% EtOAc in heptane.nbsp;The collected fractions were combined and the solvent was removed to yield ethyl 4-(4-benzylpiperazin-1-yl)benzofuran-2-carboxylate (2.160 g, 31.9 %).MSnbsp;(m+1) = 365.6.HPLC Peak RT = 3.30 minutes is product.nbsp;Purity = 94%." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(C=CC=C2O1)N3CCN(CC3)CC4=CC=CC=C4" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 31.9 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/13/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "305" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0524 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCCC12OCCO2" - } - amount { - moles { - value: 0.0349 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=NC(=C1)Br" - } - amount { - moles { - value: 0.0349 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.0015 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.0015 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: nan - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "The same procrdure as EN03653-93-01. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CN(CCC12OCCO2)C3=CC=CC=N3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 66.56 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/09/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "306" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00268 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)S(=O)(=O)N)N" - } - amount { - moles { - value: 0.00134 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(N=C1Cl)Cl" - } - amount { - moles { - value: 0.00134 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000161 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 6.71e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2,4-dichloropyrimidine (200 mg, 1.34 mmol), 3-aminobenzenesulfonamide (231 mg, 1.34 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (93 mg, 0.16 mmol), cesium carbonate (875 mg, 2.68 mmol) and diacetoxypalladium (15.07 mg, 0.07 mmol) were suspended in dioxane (5 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT. The reaction mixture was diluted with EtOAc (150 mL) and washed with water (150 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 4% (10:1 MeOHNH3 (aq)) in DCM. NMR analysis showed a trace amount of product." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)S(=O)(=O)N)NC2=NC=CC(=N2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/23/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "307" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 4.35e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.000956 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC(=CN=C1)Br" - } - amount { - moles { - value: 0.000869 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C1=CC=CC=C1C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 4.35e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.17e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "ethyl 5-bromonicotinate (200 mg, 0.87 mmol), morpholine (0.083 mL, 0.96 mmol), sodium 2-methylpropan-2-olate (167 mg, 1.74 mmol), 2\'-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (17.11 mg, 0.04 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (19.90 mg, 0.02 mmol) were suspended in dioxane (5 mL) and sealed into a microwave tube. The reaction was heated to 100 C for 1 hour in the microwave reactor and cooled to RT. LCMS analysis appeared to indicate addition of 2 morpholine rings and the reaction was abandoned." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC(=CN=C1)N2CCOCC2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/01/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "308" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 4.35e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.000956 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC(=CN=C1)Br" - } - amount { - moles { - value: 0.000869 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C1=CC=CC=C1C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 4.35e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.17e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "ethyl 5-bromonicotinate (200 mg, 0.87 mmol), morpholine (0.083 mL, 0.96 mmol), sodium 2-methylpropan-2-olate (167 mg, 1.74 mmol) and 2\'-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (17.11 mg, 0.04 mmol) were suspended in dioxane (5 mL). The reaction flask was purged with nitrogen and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (19.90 mg, 0.02 mmol) was added. The reaction was stirred at 80 C for 90 minutes. LCMS analysis appeared to indicate addition of 2 morpholine rings and the reaction was abandoned." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC(=CN=C1)N2CCOCC2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/05/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "309" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0108 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.00678 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)C1=CC(=CN=C1)Br" - } - amount { - moles { - value: 0.00542 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000814 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000271 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "tert-butyl 5-bromonicotinate (1.4 g, 5.42 mmol), morpholine (0.591 ml, 6.78 mmol), cesium carbonate (3.53 g, 10.85 mmol) and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.507 g, 0.81 mmol) were dissolved in toluene (20 ml). The reaction flask was purged with nitrogen and diacetoxypalladium (0.061 g, 0.27 mmol) was added. The resulting suspension was stirred at 80 C for 5 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 5-morpholinonicotinate (0.381 g, 26.6 %) as a yellow oil which solidified on standing. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)C1=CC(=CN=C1)N2CCOCC2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 26.56 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/11/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "310" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0305 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.05 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C(=C1)N)Cl" - } - amount { - moles { - value: 0.0167 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC2=C(C=C1Br)NN=C2" - } - amount { - moles { - value: 0.0152 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00228 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00152 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium(II) acetate (0.342 g, 1.52 mmol) and rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (1.422 g, 2.28 mmol) were added to a stirred slurry of 2-chloroaniline (1.763 mL, 16.75 mmol), 6-bromo-1H-indazole (3 g, 15.23 mmol) and cesium carbonate (9.92 g, 30.45 mmol) in toluene (50 mL) at 23C under nitrogen. The resulting slurry was stirred at 80 C for 2 hours. The reaction was incomplete (both SM left) so the temperature was increased to 100C and the reaction mixture was stirred for a further 2 hours. Mainly 2 SM detected. problem of solubility of bromoindazole?The reaction was incomplete and further Palladium(II) acetate (30mg), rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (200mg) and cesium carbonate (1g) were added as well as dioxane and the slurry was stirred at 110 C for a further 3 hours. Only SMs detected.No further work on this sample.Perform coupling with reverse coupling partners using Boc 6-aminoindazole. Known to work as used" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C(=C1)NC2=CC3=C(C=C2)C=NN3)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/19/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "311" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000655 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000284 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CC(OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.000218 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 2.18e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.18e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (60.0 mg, 0.22 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (57.7 mg, 0.28 mmol), palladium(II) acetate (4.90 mg, 0.02 mmol), 2-(Dicyclohexylphosphino)biphenyl (7.65 mg, 0.02 mmol) and CS2CO3 (213 mg, 0.66 mmol) were weighed into a microwave vial. The vial was capped and flushed with argon. DME (4 mL) was added and the mixture was heated to 100C in a microwave apparatus for 1 h. The cooled reaction mixture was diluted with dichloromethane and methanol, filtered through a plug of Celite and the solvents were evaporated. The residue was purified by HPLC to give 36 mg (37 % Yield) of the title product." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(CN(CC(O4)C5=CC=CC=C5)C)C=C3)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 37.23 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/25/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "312" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "[Li+].C[Si](C)(C)[N-][Si](C)(C)C" - } - amount { - moles { - value: 0.0399 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.087 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCNCC1" - } - amount { - moles { - value: 0.0208 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1O)Br" - } - amount { - moles { - value: 0.0173 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)CN1CCN2CCN(P1N(CC2)CC(C)C)CC(C)C" - } - amount { - moles { - value: 0.000347 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000173 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (0.039 g, 0.17 mmol) was added in one portion to 4-bromophenol (3 g, 17.34 mmol) and 1-methylpiperazine (2.308 mL, 20.81 mmol) in toluene (87 mL) at 25C under nitrogen. To this was added toluene (87 mL) then a solution of 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (0.123 mL, 0.35 mmol) in Toluene (1 mL) and finally 1M LITHIUM BIS(TRIMETHYLSILYL)AMIDE (39.9 mL, 39.88 mmol) in THF was added dropwise over 1 minute.nbsp;The resulting mixture was stirred at 80 C for 18 hours.nbsp;The reaction was allowed to cool to room temperature, SiO2 (23g) was added and evaporated to dryness.nbsp;The crude product was purified by flash silica chromatography (120g), elution gradient 0 to 10% MeOH in EtOAc. Pure fractions were evaporated to dryness to afford 4-(4-methylpiperazin-1-yl)phenol (1.700 g, 51.0 %) as a beige solid. n" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CCN(CC1)C2=CC=C(C=C2)O" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 50.99 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/13/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "313" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.191 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.2 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CC1C(=O)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.0763 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1OC2=C(C(=CN=C2O1)Cl)N" - } - amount { - moles { - value: 0.0763 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00839 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.0061 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a stirred solution of N-(4-chloropyridin-2-yl)cyclopropanecarboxamide (15 g, 76.28 mmol) in dioxane (200 mL) was added 6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-amine (13.16 g, 76.28 mmol), cesium carbonate (62.1 g, 190.71 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4.86 g, 8.39 mmol) and diacetoxypalladium (1.370 g, 6.10 mmol).Mixture was degassed 3 times with N2 and heated at reflux (110C) for 4h: OK.Reaction was cooled down, diluted with 200mL of CH2Cl2 and filtered. The filtrate was concentrated and the residue purified on silica, eluting with 2% of MeOH in CH2Cl2.Solvent were evaporated, diluted with a little CH2Cl2 until crystallisation occurs and diethyl ether was added. Solid was filtered, washed with diethyl ether and dried to afford N-(4-(6-chloro-[1,3]dioxolo[4,5-b]pyridin-7-ylamino)pyridin-2-yl)cyclopropanecarboxamide (15.00 g, 59.1 %) as a white powder.1H NMR OK." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CC1C(=O)NC2=NC=CC(=C2)NC3=C4C(=NC=C3Cl)OCO4" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 59.09 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/25/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "316" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[K+]" - } - amount { - moles { - value: 0.000221 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C=O" - } - amount { - volume { - value: 0.000198 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CN" - } - amount { - moles { - value: 0.000885 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CNC(=O)C2=C1C=C(C=C2)Br" - } - amount { - moles { - value: 0.000221 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 1.11e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.11e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 130.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "buRef:ub Synthesis, 2002, No. 11, p 1597, M. AltermanIn a 5 mL sealed MW* test tube was 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (50 mg, 0.22 mmol), phenylmethanamine (97 l, 0.88 mmol), BINAP (6.89 mg, 0.01 mmol) and palladium(II) acetate (2.483 mg, 0.01 mmol) in DMF (500 mL) combined to give a tan suspension.nbsp;potassium tert-butoxide (24.82 mg, 0.22 mmol) was then added last.nbsp;Placed test tube onto Smith MW* platform.nbsp;Heated reaction to 130C for 4 minutes.nbsp;Reaction know has a heavy black ppt present.nbsp;Took LCMS - there is some product (~15%) beginning to form.nbsp;Placed sealed test tube in heated (130C) oil bath overnight. Took LCMS - all SM is consumed with a moderate product peak in evidence.nbsp;Transferred reaction to separatory funnel.nbsp;Partitioned reaction with EtOAc (40 ml) and water (25 ml). Separated off aq layer.nbsp;Washed with sat NaCl.nbsp;The organic was dried MgSO4, filt and conc - pale yellow syrup, 02915-84-0.nbsp;Dissolv 100% MeOH, added 2 drops NH4OH to adjust pH of sample and filtered off insolubles.nbsp;The residue was purified via Agilent prep HPLC: Gradient run of 20-95% MeOHH2O with 10 mmol NH4CO3 buffer (pH 10) over 25 mins.nbsp;Flow rate 40 mlmin at wavelength 220 nM collection.nbsp;250 X 21.2 mm Gemini Axia pakC18 10 micron column.nbsp;Collected like fractions which were concentrated under pump vacuum.nbsp;Yield is low but see a mixture of products by NMR.nbsp;Spectra shows desired material plus dialkylation product.nbsp;Will reset and scale up reaction but lower amount of benzylamine and try the MW* only.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CNC(=O)C2=C1C=C(C=C2)NCC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/06/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "317" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C[O-].[Na+]" - } - amount { - moles { - value: 2.21e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.00219 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CN" - } - amount { - moles { - value: 0.000221 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CNC(=O)C2=C1C=C(C=C2)Br" - } - amount { - moles { - value: 0.000221 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(CCP(C2=CC=CC=C2)C3=CC=CC=C3)C4=CC=CC=C4" - } - amount { - moles { - value: 2.21e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.11e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a small MW* sealed test tube was 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (50 mg, 0.22 mmol), phenylmethanamine (24.16 l, 0.22 mmol), palladium(II) acetate (2.483 mg, 0.01 mmol), Ethylenebis(diphenylphosphine) (8.81 mg, 0.02 mmol) and sodium methoxide (13.14 mg, 0.24 mmol) in toluene (2188 l) combined to give a orange suspension.nbsp;Heated reaction to 100C overnight.nbsp;Took LCMS - No reaction, only see unreacted SM.nbsp;Discarded r" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CNC(=O)C2=C1C=C(C=C2)NCC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/06/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "318" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[K+]" - } - amount { - moles { - value: 0.000442 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C=O" - } - amount { - volume { - value: 0.000493 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CN" - } - amount { - moles { - value: 0.000885 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CNC(=O)C2=C1C=C(C=C2)Br" - } - amount { - moles { - value: 0.000442 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 2.21e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.21e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 130.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "bRepeat 02915-84 but use MW* only.nbsp;Reduce benzylamine from 4 to 2 eqs.bIn a 10 mL sealed MW* test tube was 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (100 mg, 0.44 mmol), phenylmethanamine (97 l, 0.88 mmol), BINAP (13.77 mg, 0.02 mmol) and palladium(II) acetate (4.97 mg, 0.02 mmol) in DMF (500 mL) combined to give a tan suspension.nbsp;potassium tert-butoxide (49.6 mg, 0.44 mmol) was then added last.nbsp;Placed test tube onto Smith MW* platform.nbsp;Heated reaction to 130C for 15 minutes.nbsp;Reaction know a cloudy pale amber.nbsp;Took LCMS - there is NO product present, ALL SM!!!nbsp;Placed sealed test tube in heated (130C) oil bath over weekend.nbsp;Took LCMS - all SM is consumed but NO desired product is seen!!!nbsp;Discarded r" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CNC(=O)C2=C1C=C(C=C2)NCC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/08/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "319" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[K+]" - } - amount { - moles { - value: 0.000221 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CN" - } - amount { - moles { - value: 0.000885 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CNC(=O)C2=C1C=C(C=C2)Br" - } - amount { - moles { - value: 0.000221 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 1.11e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.11e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 130.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "bRepeat 02915-84 but use NO solventbIn a 5 mL sealed MW* test tube was 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (50 mg, 0.22 mmol), phenylmethanamine (97 l, 0.88 mmol), BINAP (6.89 mg, 0.01 mmol) and palladium(II) acetate (2.483 mg, 0.01 mmol) combined to give a tan suspension.nbsp;potassium tert-butoxide (24.82 mg, 0.22 mmol) was then added last.nbsp;Placed test tube onto Smith MW* platform.nbsp;Heated reaction to 70C for 5 minutes.nbsp;NO reaction!!!nbsp;Added DMF (0.5 ml) and reheated reaction to 130C for 15 mins.nbsp;Took LCMS - no reaction, only unreacted SM!!nbsp;Discarded r" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CNC(=O)C2=C1C=C(C=C2)NCC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/12/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "320" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0017 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000566 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OCC1CN(CC2=C(O1)N=C(C=C2)Cl)C(=O)C" - } - amount { - moles { - value: 0.000566 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 5.66e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 5.66e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "1-(8-chloro-2-(isopropoxymethyl)-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)ethanone (0.169 g, 0.57 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.115 g, 0.57 mmol), Palladium acetate (0.013 g, 0.06 mmol), 2-(Dicyclohexylphosphino)biphenyl (0.020 g, 0.06 mmol) and Cesium carbonate (0.553 g, 1.70 mmol) were placed in a microwave vial. The mixture was capped and flushed with argon.nbsp;1,2-dimethoxyethane (5 mL) was added and the mixture was run in a microwave for 60 minutes at 100C. No product. Added 0.1 eq ligand and palladium acetate, flushed with argon and run in the microwave at 100C for 60 min. Reaction still not complete. Added 0.1 eq ligand and palladium aceate, flushed with argon and run in the microwave at 100C for 60 min. The reaction mixture was filtrated through Celite and washed with dichloromethane. The filtrate was concentrated and the crude product was purified by preparative chromatography. The productcontaining fractions were pooled, concentrated and the rertitioned between sat. NaHCO3 (aq) and dichloromethane. The organic layer was separated by a Phase Separator and concentrated giving 1-(2-(isopropoxymethyl)-8-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)ethanone (0.039 g, 14.66 %)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(CN(CC(O4)COC(C)C)C(=O)C)C=C3)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 14.66 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/02/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "323" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.18 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C(=C1)N)Cl" - } - amount { - moles { - value: 0.025 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C=C1Br)F)C#N" - } - amount { - moles { - value: 0.025 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00375 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.0025 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium(II) acetate (0.561 g, 2.50 mmol) and rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (2.335 g, 3.75 mmol) was added to a stirred slurry of 2-chloroaniline (2.63 mL, 25.00 mmol), 4-bromo-2-fluorobenzonitrile (5 g, 25.00 mmol) and cesium carbonate (16.29 g, 50.00 mmol) in toluene (180 mL) at 23Cunder nitrogen. The resulting slurry was stirred at 80 C for 2 hours. The reaction was incomplete (both SM left) so the temperature was increased to 100C and the reaction mixture was stirred for a further 2 hours. The reaction was incomplete and further Palladium(II) acetate (100mg), rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (400mg) and cesium carbonate (3g) were added and the slurry was stirred at 100 C for a further 3 hours. Only small amount of 2 SM left and more product being formed. So further Palladium(II) acetate (100mg), rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (400mg) and cesium carbonate (3g) were added and the slurry was stirred at 100 e 6 hours. traces of SM leftThe reaction mixture was filtered through PTFE,nbsp;diluted with DCM (100 mL), and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford productnbsp;as a pale yellow solid. LCMS showed 97% pure and 3% aniline.It was resuspended in DCM and the precipitate was collected by filtration, washed with DCM (10 mL) and dried under vacuum to afford 4-(2-chlorophenylamino)-2-fluorobenzonitrile (5.15 g, 84 %) as a white solid. EN03289-99-01 (2.75 g, 11.15 mmol, 44.6 %)Filtrate repurified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 4-(2-chlorophenylamino)-2-fluorobenzonitrile (5.15 g, 84 %) as a pale yellow solid. (pic 2) EN03289-99-02 (0.760 g, 3.08 mmol, 12.32 %)Pic 1 from column gave compound not 100% pure. Therefore it was triturated with isohexane to give a solid which was collected by filtration and dried under vacuum to give 4-(2-chlorophenylamino)-2-fluorobenzonitrile (5.15 g, 84 %) as a pale yellow solid. EN03289-99-03 (1.64 g, 6.65 mmol, 26.6 %)mixed fractions not kept as small amount.1H NMR (400 MHz, DMSO) d 6.63 - 6.77 (2H, m), 7.21 - 7.30 (1H, m), 7.39 (1H, m), 7.46 (1H, m), 7.54 - 7.69 (2H, m), 8.99 (1H, s).mz (ES-), (M-H)- = 245-247; HPLC tR =nbsp;2.62 min (acid and basic)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C(=C1)NC2=CC(=C(C=C2)C#N)F)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 83.52 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/09/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "324" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00233 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.007 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N1CCC2=CC(=C(C=C21)N)OC" - } - amount { - moles { - value: 0.00155 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN=C(N=C1C2=C3C=CC=CN3N=C2)Cl" - } - amount { - moles { - value: 0.00155 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000155 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000155 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of 3-(2-chloro-5-methylpyrimidin-4-yl)pyrazolo[1,5-a]pyridine (400 mg, 1.55 mmol), 1-(6-amino-5-methoxyindolin-1-yl)ethanone (341 mg, 1.55 mmol) and diacetoxypalladium (34.9 mg, 0.16 mmol) 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (97 mg, 0.16 mmol) cesium carbonate (759 mg, 2.33 mmol) were degassednbsp;with nitrogen then dioxane (7 mL)nbsp;was added to mixture and the solution was degassed under vacuum and placed under nitrogen. The resulting suspension was stirred at 90 C for 5hours.Control uplcms OKControl t.l.c : 100%EtOAc and 5%MeOHCH2Cl2After cooling, the mixture was filtered and the filtrate evaporated to dryness after addition of silica gelThe crude product was purified by flash chromatography on silica gel 45g Merck column solid injectioneluting with 0 to 10%MeOHEtOAc. The solvent was evaporated to dryness to afford 1-(5-methoxy-6-(5-methyl-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-ylamino)indolin-1-yl)ethanone (301 mg, 46.8 %) as anbsp;oranolid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN=C(N=C1C2=C3C=CC=CN3N=C2)NC4=C(C=C5CCN(C5=C4)C(=O)C)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 46.76 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/12/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "325" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000337 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)C2CN(CC3=C(O2)N=C(C=C3)Cl)CC#N)C" - } - amount { - moles { - value: 0.000337 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 3.37e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.37e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.068 g, 0.34 mmol),2-(8-chloro-2-(1,3-dimethyl-1H-pyrazol-5-yl)-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)acetonitrile (0.107 g, 0.34 mmol)nbsp;Palladium acetate (7.56 mg, 0.03 mmol) and Cesium carbonate (0.329 g, 1.01 mmol) were added in a microwave vial. The mixture was capped and flushed with argon.1,2-dimethoxyethane (5 mL) was added, the reaction mixture was flushed with argon and the mixture was run in a microwave for 60 minutes at 100C. Reaction complete. The reaction mixture was filtrated through Celite and washed with dichloromethane. The filtrate was concentrated and the crude product was purified by preparative chromatography. The productcontaining fractions were pooled, concentrated and the residue was partitioned between sat. NaHCO3 (aq) and dichloromethane. The organic layer was separated by a Phase Separator and concentrated giving 2-(2-(1,3-dimethyl-1H-pyrazol-5-yl)-8-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylo)-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)acetonitrile (0.027 g, 16.55 %). " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)C2CN(CC3=C(O2)N=C(C=C3)NC4=CC(=C(C=C4)N5C=C(N=C5)C)OC)CC#N)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 16.55 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/25/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "326" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00196 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0103 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CONC(=O)C1=C(C=CC(=C1)F)N" - } - amount { - moles { - value: 0.00168 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C(=CN=C1Cl)C(F)(F)F)I" - } - amount { - moles { - value: 0.00163 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000261 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000131 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-chloro-4-iodo-5-(trifluoromethyl)pyridine (0.502 g, 1.63 mmol), 2-amino-5-fluoro-N-methoxybenzamide (0.344 g, 1.68 mmol), diacetoxypalladium (0.029 g, 0.13 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.151 g, 0.26 mmol) and cesium carbonate (0.638 g, 1.96 mmol) were weighed out in a microwave vial and sealed. dioxane (10.31 ml) was added and argon was let to bubble through the reaction mixture then it was stirred at 90 C for 5 hours. The reaction mixture was allowed to cool to room temperature, silca gel was added and the mixture was concentrated to afford the crude, which was purified by flash chromatography on silica gel eluting with 20 to 50% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford 2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-5-fluoro-N-methoxybenzamide (0.240 g, 40.4 %) as an yellow oil which crystallised on standing." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CONC(=O)C1=C(C=CC(=C1)F)NC2=CC(=NC=C2C(F)(F)F)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 40.43 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/14/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "327" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 4.32e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CONC(=O)C1=C(C=C(C=C1)F)N" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" - } - amount { - moles { - value: 0.000288 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 4.32e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.59e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 95.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (24.98 mg, 0.04 mmol), diacetoxypalladium (5.82 mg, 0.03 mmol), 2-amino-4-fluoro-N-methoxybenzamide (90 mg, 0.49 mmol), N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (110 mg, 0.29 mmol) and cesium carbonate (188 mg, 0.58 mmol) were weighed out in a wave vial, sealed and dioxane (3 mL) was added. Argon was let to bubble in the mixture for 5 minutes. The reaction was stirred at 95 C for 6h. The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane, silica gel was added and the mixture was concentrated. The crude product was purified by flash chromatography on silica gel (25g) eluting with 0 to 5% methanol in ethyl acetateDCM (11). The solvent was evaporated to dryness. The residue was triturated in tBuOMe (a bit soluble and soluble in diethyl ether) and the resulting precipitate was collected by filtration and dried to a constant weight to afford 2-(2-(1,3-dimethyl-1H-pyrazol-o)-5-(trifluoromethyl)pyridin-4-ylamino)-4-fluoro-N-methoxybenzamide (50.0 mg, 39.6 %) as a white solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=C(C=CC(=C3)F)C(=O)NOC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 39.62 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/11/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "328" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00288 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" - } - amount { - moles { - value: 0.00096 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1[C@H](OC2=C(CN1CC#N)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.00096 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 9.6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 9.6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (195 mg, 0.96 mmol), (R)-2-(8-chloro-2-phenyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)acetonitrile (288 mg, 0.96 mmol)nbsp;Palladium acetate (21.55 mg, 0.10 mmol) and Cesium carbonate (938 mg, 2.88 mmol) were added in a microwave vial. The mixture was capped and flushed with argon. 1,2-dimethoxyethane (5 mL) was added, the reaction mixture was flushed with argon and the mixture was run in a microwave for 60 minutes at 100C. Only after two additional additions of catalyst and ligand with 3h extra runtime was the reaction complete. The reaction mixture was filtrated through Celite and washed with dichloromethane. The filtrate was concentrated and the crude product was purified by preparative chromatography 3 times yielding (R)-2-(8-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-2-phenyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)acetonitrile (35.0 mg, 7.81 %). " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(CN(C[C@H](O4)C5=CC=CC=C5)CC#N)C=C3)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 7.81 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/28/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "329" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000984 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=N1)C2=C(C=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000328 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1[C@H](OC2=C(CN1CCO)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.000328 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 3.28e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.28e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (67.0 mg, 0.33 mmol), (R)-2-(8-chloro-2-phenyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)ethanol (100 mg, 0.33 mmol), Palladium acetate (7.37 mg, 0.03 mmol), 2-(Dicyclohexylphosphino)biphenyl (11.50 mg, 0.03 mmol) and Cesium carbonate (321 mg, 0.98 mmol) were added to a microwave vial. 1,2-dimethoxyethane (2 mL) was added. The reaction mixture was flushed with argon and the mixture was run in a microwave for 60 minutes at 100C. No product was observed. Additional catalyst and ligand were added and the reaction was run 1h @ 100C. Still no reaction occurred. EtOH (0.500 mL) was added and another h @ 100C was executed. Full conversion into product was observed. The solids were filtered off and the solvent was concentrated. The crude product was purified twice on Si. 20-80% MeOH in DCM. Yield: (R)-2-(8-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-2-phenyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)ethanol (33.0 ." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(CN(C[C@H](O4)C5=CC=CC=C5)CCO)C=C3)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 21.28 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/28/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "330" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00148 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000492 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(N=C1)Cl" - } - amount { - moles { - value: 0.000492 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 4.92e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.92e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-Chloropyrimidine (0.056 g, 0.49 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.100 g, 0.49 mmol), Palladium acetate (0.011 g, 0.05 mmol), 2-(Dicyclohexylphosphino)biphenyl (0.017 g, 0.05 mmol) and Cesium carbonate (0.481 g, 1.48 mmol) were placed in a microwave vial. The mixture was capped and flushed with argon.nbsp;1,2-dimethoxyethane (5 mL) was added and the mixture was run in a microwave for 60 minutes at 100C. Very little product. Added 0.1 eq ligand and palladium acetate, flushed with argon and run in the microwave at 100C for 60 min. No change. Seems as if the 2-chloropyrimidine is not very soluble in DME. Added 1.5 mL DMF and the reaction was run again in the microwave for 60 minutes.nbsp;The reaction mixture was filtrated through Celite and washed with dichloromethane. The filtrate was concentrated and the crude product was purified by preparative chromatography. The productcontaining fractions were pooled, concentrated and the residue was partitioned between sat.ub3 (aq) and dichloromethane. The organic layer was separated by a Phase Separator and concentrated giving N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)pyrimidin-2-amine (0.026 g, 18.78 %)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC=CC=N3)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 18.78 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/28/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "332" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[K+]" - } - amount { - moles { - value: 0.00288 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.006 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC1=CC=C(C=C1)F" - } - amount { - moles { - value: 0.000766 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1CO)Cl" - } - amount { - moles { - value: 0.000697 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 6.97e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 3.48e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 105.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 50 mL round-bottomed flask (t=g) was (2-chloropyridin-4-yl)methanol (.1 g, 0.70 mmol), Pd2dba3 (0.032 g, 0.03 mmol), and biphenyl-2-yldicyclohexylphosphine (0.024 g, 0.07 mmol) in toluene (6 mL) to give a dark red solution. 4-fluoro-N-methylaniline (0.096 g, 0.77 mmol) and KOtBu (.323 g, 2.88 mmol) were added.Mixture was degassed by bubbling N2 for 20 minutes, then placed in oil bath at 105 C. Reaction went for 3 hours, at which point LCMS was taken. No product was observed. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(C1=CC=C(C=C1)F)C2=NC=CC(=C2)CO" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/15/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "333" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000599 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.016 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC1=CC=C(C=C1)F" - } - amount { - moles { - value: 0.0004 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=NC=C1Br)Br" - } - amount { - moles { - value: 0.000479 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 5.99e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 50 mL round-bottomed flask (t=g) was 4-fluoro-N-methylaniline (.05 g, 0.40 mmol), 3,5-dibromopyridine (0.114 g, 0.48 mmol), and Pd2(dba)3 (0.018 g, 0.02 mmol) in toluene (16 mL) ([VOLUME]) to give a purple suspension. biphenyl-2-yldicyclohexylphosphine (0.021 g, 0.06 mmol) and CS2CO3 (0.195 g, 0.60 mmol) were added. After LCMS indicated no reaction had taken place at room temp, the temperature was gradually rasied to up to 110 degrees. LCMS indicated that the reaction was not progressing.Reaction was discarded." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(C1=CC=C(C=C1)F)C2=CC(=CN=C2)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/25/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "336" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[K+]" - } - amount { - moles { - value: 0.0104 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.016 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC1=CC=C(C=C1)F" - } - amount { - moles { - value: 0.00799 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=NC=C1Br)Br" - } - amount { - moles { - value: 0.00959 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 0.0012 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.0004 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 50 mL round-bottomed flask (t=g) was 4-fluoro-N-methylaniline (1 g, 7.99 mmol), 3,5-dibromopyridine (2.272 g, 9.59 mmol), and Pd2(dba)3 (0.366 g, 0.40 mmol) in toluene (16 mL) ([VOLUME]) to give a purple suspension. biphenyl-2-yldicyclohexylphosphine (0.420 g, 1.20 mmol) and KOtBu (1.166 g, 10.39 mmol) were added. Reaction was allowed to stir for 1.5 hours at which point LCMS was taken which indicated that all the dibromopyridine had been consumed. Reaction was quenched by addition of excess ammonium chloride. Mixture was filtered though a plug of celite, extracted with ethyl acetate. The organic fractions were collected and washed with water, then dried over NaSO4, rotovapped down to an oil, redissolved in DCM then purified over a 120g column using 5 minutes of pure hexane, followed by a 0-50% EtOAc gradient (product comes off at around 35%). The relevant fractions were collected and rotovapped down yielding the product as an oil." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(C1=CC=C(C=C1)F)C2=CC(=CN=C2)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 12.46 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/24/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "338" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00048 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=C(N=C(C=N1)Cl)N" - } - amount { - moles { - value: 0.006 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CS(=O)(=O)C1=CC=C(C=C1)Br" - } - amount { - moles { - value: 0.006 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00048 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00024 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "i1-bromo-4-(methylsulfonyl)benzene (1410 mg, 6.00 mmol)ii then iicesium carbonate (2540 mg, 7.80 mmol)iinbsp;were successively added to a solution of ii6-chloropyrazin-2-amine (777 mg, 6.00 mmol)iinbsp;ii1,4-dioxane (20 ml)ii into a microwave reactor.ii The mixture was purged by bubbling nitrogen for 5 minutes, thenii ii(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (278 mg, 0.48 mmol)ii and iidiacetoxypalladium (53.9 mg, 0.24 mmol)ii were added ,nbsp;the mixture was degassed by vacuumnitrogen three times, then heatednbsp;tonbsp;ii75 Cii in an heating block( internal temperature )for 1 hr then at ii85 Ciinbsp;and finally at ii90 Cii for 30 minioling the mixture was diluted with ethylacetate , filtered , the solid washed with ethyl acetate, and the organic solution washed with water, pre-dried with brine and dried over MgSO4 , filtratednbsp;and concentrated in vacuo.The solid was taken up with ethylacetatenbsp;( 20 ml) stirred 15 min , and diluted with diethylether until some trouble occured; the solid was filterednbsp;and the procedure was repeated.The solid was dried under vacuum ( 1 mmHg1 hr 50C ) to afford 6-chloro-N-(4-(methylsulfonyl)phenyl)pyrazin-2-amine (1000 mg, 58.8%)ii. The filtrate was concentrated and the abovenbsp;purification procedure was repeated three times to afford a second batch ii6-chloro-N-(4-(methylsulfonyl)phenyl)pyrazin-2-amine (0.200 mg, 11.75 %) of the same purity . The 2nbsp;batches were combined to affordnbsp;ii6-chloro-N-(4-(methylsulfonyl)phenyl)pyrazin-2-amine (1200 mg, 70.5 %)ii as a beige solidi" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CS(=O)(=O)C1=CC=C(C=C1)NC2=CN=CC(=N2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 70.51 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/03/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "340" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00088 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.075 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=C(N=C(C=N1)Cl)N" - } - amount { - moles { - value: 0.02 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CS(=O)(=O)C1=CC=C(C=C1)Br" - } - amount { - moles { - value: 0.02 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00088 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00044 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "i1-bromo-4-(methylsulfonyl)benzene (4.70 g, 19.99 mmol)ii then iicesium carbonate (8.47 g, 25.99 mmol)iinbsp;were successively added to a solution of ii6-chloropyrazin-2-amine (2.59 g, 19.99 mmol)iinbsp;ii1,4-dioxane (75 ml)ii into a microwave reactor.ii The mixture was purged by bubbling nitrogen for 5 minutes, thenii ii(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.509 g, 0.88 mmol)ii and iidiacetoxypalladium (0.099 g, 0.44 mmol)ii were added , the mixture was degassed by vacuumnitrogen three times, then heatednbsp;tonbsp;ii80 Cii in an heating block fornbsp;2 hours then at ii90 Cii for 30 minnbsp;and a further 1 hour heatingnbsp;at ii85 Cii. iing the mixture was diluted with ethylacetate , filtered , the solid washed with ethyl acetate, the organic solution was washed with water,nbsp;pre-dried with brine and dried over MgSO4 , filtratednbsp;and concentrated in vacuo.The solid was taken up with ethylacetatenbsp;( 50 ml) stirred 15 min , and diluted with diethylether until some trouble occured; the solid was filterednbsp;and the procedure was repeated twice The solid was dried under vacuum ( 1 mmHg1 hr 50C ) to afford 6-chloro-N-(4-(methylsulfonyl)phenyl)pyrazin-2-amine (3. 15g, 55.5% , purity uv 98.6% ). The filtrate was concentrated and purified by flash chromatography on silica gel eluting with 0 to 3% methanol in dichloromethane. The solvent was evaporated to dryness to afford 6-chloro-N-(4-(methylsulfonyl)phenyl)pyrazin-2-amine (1.95 g,34.4% uv purity 94.6%) as a white solid.nbsp;Nevertheless the 2nbsp;batches were combined to affordnbsp;6-chloro-N-(4-(methylsulfonyl)phenyl)pyrazin-2-amine (5.10 g, 90 %)nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CS(=O)(=O)C1=CC=C(C=C1)NC2=CN=CC(=N2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 89.91 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/04/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "341" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[K+]" - } - amount { - moles { - value: 0.000468 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C=O" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.000936 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C(=CC=C1)C)C(=O)NC(C2=CC=C(C=C2)Br)C34CCC(N3C)CC4" - } - amount { - moles { - value: 0.000234 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 2.34e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.34e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 130.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a CEM microwave vial was N-((4-bromophenyl)(7-methyl-7-azabicyclo[2.2.1]heptan-1-yl)methyl)-2,6-dimethylbenzamide (100 mg, 0.23 mmol), morpholine (0.082 mL, 0.94 mmol), palladium(II) acetate (5.25 mg, 0.02 mmol), BINAP (14.57 mg, 0.02 mmol), and potassium tert-butoxide (52.5 mg, 0.47 mmol) solid and DMF (2 mL) was added. The vial was capped and placed into the microwave at 300 watts, 130 C for 4 minutes.nbsp;After reaction completion, the the mixture was concentrated and crude taken up in CH2Cl2 and washed with water and dried (Na2SO4).nbsp;The material was purified on anbsp;12 gram Isco silica cartridge and eluted with 0% to 5% MeOH 2M NH3CH2Cl2 to give a light yellowish solid 2,6-dimethyl-N-((7-methyl-7-azabicyclo[2.2.1]heptan-1-yl)(4-morpholinophenyl)methyl)benzamide (30.0 mg, 29.6 %)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C(=CC=C1)C)C(=O)NC(C2=CC=C(C=C2)N3CCOCC3)C45CCC(N4C)CC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 29.57 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/16/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "342" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00122 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" - } - amount { - moles { - value: 0.00122 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CC(OC2=C(C1)C=CC(=N2)Cl)C3CC3" - } - amount { - moles { - value: 0.00122 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 0.000122 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000122 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.249 g, 1.22 mmol), 8-chloro-2-cyclopropyl-4-methyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.292 g, 1.22 mmol), Palladium acetate (0.027 g, 0.12 mmol), 2-(Dicyclohexylphosphino)biphenyl (0.043 g, 0.12 mmol) and Cesium carbonate (0.399 g, 1.22 mmol) were added in a microwave vial. The mixture was capped and flushed with argon. 1,2-dimethoxyethane (4 mL) was added and the mixture was run in a microwave for 60 minutes at 100C. No product, only unreacted startingmaterial. Added 1 eq CsCO3, and 0.1 eq ligand and palladium acetate, flushed with argon and run in the microwave at 100C for 60 min. 9% product according to LCMS. Added 0.1 eq ligand and palladium acetate, flushed with argon and run in the microwave at 100C for 60 min. No change.nbsp;Added 0.1 eq ligand and palladium acetate, flushed with argon and run in the microwave at 100C for 60 min. No change. Decided to isolate the intermediate and eventual product. The was filtrated through celite and concentrated. The crude was purified by preparative chromatography. The little product-containing fractions were collected but HPLC showed that they were not pure. The solvent was evaporated and the crude was partitioned between dichloromethane and sat. NaHCO3 (aq). The organic layer was separated with a phase separator and concentrated. Have 3 mg which is not pure. Discarded. Fractions with the intermediate 8-chloro-2-cyclopropyl-4-methyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine was collected, concentrated and the residue was partitioned with dichloromethane and sat. NaHCO3 (aq). The organic layer was separated, dried (Na2SO4) and concentrated giving 0.036 g of 8-chloro-2-cyclopropyl-4-methyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(CN(CC(O4)C5CC5)C)C=C3)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/10/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "343" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000151 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000151 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CC(OC2=C(C1)C=CC(=N2)Cl)C3CC3" - } - amount { - moles { - value: 0.000151 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 1.51e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.51e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.031 g, 0.15 mmol), 8-chloro-2-cyclopropyl-4-methyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.036 g, 0.15 mmol), Palladium acetate (3.39 mg, 0.02 mmol), 2-(Dicyclohexylphosphino)biphenyl (5.29 mg, 0.02 mmol) and Cesium carbonate (0.049 g, 0.15 mmol) were added in a microwave vial. The mixture was capped and flushed with argon. 1,2-dimethoxyethane (2 mL) was added and the mixture was run in a microwave for 60 minutes at 100C. Extremely little product was formed according to LCMS and all oxazepinestartingmaterial was consumed. Did not isolate, discarded." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(CN(CC(O4)C5CC5)C)C=C3)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/12/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "344" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00093 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" - } - amount { - moles { - value: 0.00093 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CC(OC2=C(C1)C=CC(=N2)Cl)C3CC3" - } - amount { - moles { - value: 0.00093 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 9.3e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 9.3e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.189 g, 0.93 mmol), 8-chloro-2-cyclopropyl-4-methyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.222 g, 0.93 mmol), Palladium acetate (0.021 g, 0.09 mmol), 2-(Dicyclohexylphosphino)biphenyl (0.033 g, 0.09 mmol) and Cesium carbonate (0.303 g, 0.93 mmol) were added in a microwave vial. The mixture was capped and flushed with argon. 1,2-dimethoxyethane (2 mL) was added and the mixture was run in a microwave for 60 minutes at 100C. Extremely little product was formed according to LCMS. Added 0.1 eq of Palladium acetate and 2-(Dicyclohexylphosphino)biphenyl and 1 eq Cesium carbonate and let run for another 60 min at 100C in the microwave. According to LCMS ther is 13% startingmaterial oxazepine left. Added a small spatula of acetoxy(2\'-(di-tert-butylphosphino)biphenyl-2-yl)palladium and 0.3 mL ethanol and let run for 30 minutes at 100C. The reaction mixture was filtrated through celite and concentrated. The crude product was purified by siliomatography using a gradient of metanol (+ 10%7M ammonia) in dichloromethane. Unreacted starting material 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline came out together with the product. Obtained 0.203 mg of impure product (at 254 nm 18% pure, at 220 nm 28% pure, at 290 nm 60% pure). Combined this with EN03597-98-001 and EN03597-99-001 at EN03597-97-001." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(CN(CC(O4)C5CC5)C)C=C3)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/18/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "345" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00148 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=CC(=C1)N)C#N" - } - amount { - moles { - value: 0.000492 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1[C@H](OC2=C(CN1CCO)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.000492 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 4.92e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.92e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;4-amino-2-methoxybenzonitrile (72.9 mg, 0.49 mmol), (R)-2-(8-chloro-2-phenyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)ethanol (150 mg, 0.49 mmol),nbsp;Palladium acetate (11.05 mg, 0.05 mmol), 2-(Dicyclohexylphosphino)biphenyl (17.25 mg, 0.05 mmol)and Cesium carbonate (481 mg, 1.48 mmol) were added to a microwave vial. 1,2-dimethoxyethane (2 mL) and EtOH (0.500 mL) were added. The reaction mixture was flushed with argon and the mixture was run in a microwave for 60 minutes at 100C. The solvent was decanted and the solids were washed with 5ml DCM. The solvent was evaporated and the crude product was purified on Si, 0-6% MeOH in DCM, yielding (R)-4-(4-(2-hydroxyethyl)-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-ylamino)-2-methoxybenzonitrile (27.0 mg, 13.17 %)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=C(C=CC(=C1)NC2=NC3=C(CN(C[C@H](O3)C4=CC=CC=C4)CCO)C=C2)C#N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 13.17 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/10/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "347" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[K+].[K+]" - } - amount { - moles { - value: 0.00518 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" - } - amount { - moles { - value: 0.00345 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=NC(=NC=C2C1)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.00363 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000173 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000104 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Purpose:nbsp;to examine scale-up of microwave conditions established in a previous experiment.Charged a round-bottom flask with a mixture of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.702 g, 3.45 mmol), (R)-2-chloro-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine (1.0 g, 3.63 mmol), palladium (II) acetate (0.023 g, 0.10 mmol), rac-BINAP (0.108 g, 0.17 mmol), potassium carbonate (0.716 g, 5.18 mmol), and toluene (20 mL).nbsp;The atmosphere s inerted through nitrogen purge cycles, then heated at 120 C or 16 hours.HPLC-UV shows the reaction is not as clean as in the microwave, and conversion is very poor.nbsp;The contents were allowed to continue heating over the weekend, but although conversion improved, the mixture contained many impurities.nbsp;Not progressed.autotext key=quot;0C636C73quot; name=quot;[Samples]quot; index=quot;0quot; field=quot;Samplesquot; type=quot;fieldquot; length=quot;9quot;gt;ber-coloured foam." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC=C4CN(C[C@H](OC4=N3)C5=CC=CC=C5)C)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/16/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "348" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000218 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.001 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000181 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=NC(=NC=C2C1)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.000181 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" - } - amount { - moles { - value: 1.4e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 5.44e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(R)-2-chloro-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine (0.05 g, 0.18 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.037 g, 0.18 mmol) (0.65), PALLADIUM(II) ACETATE (1.221 mg, 5.44 mol), CESIUM CARBONATE (0.071 g, 0.22 mmol) and Tri-tert- butylphosphonium tetrafluoriborate (0.0043 g, 0.014 mmol, 6 mol%) in 1 ml of dioxane was degaset over argone and heated in MW 120C 30 min. 002 - 4.8% of conversionmixture was heated more in MW 140C 30 min.003 - 15% of conversionmixture was heated more in MW 160C 30 min.Experiment was not" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC=C4CN(C[C@H](OC4=N3)C5=CC=CC=C5)C)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/20/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "349" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CCC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0002 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.001 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000181 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=NC(=NC=C2C1)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.000181 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" - } - amount { - moles { - value: 1.4e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 5.44e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(R)-2-chloro-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine (0.05 g, 0.18 mmol), PALLADIUM(II) ACETATE (1.221 mg, 5.44 mol) (1.6), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.037 g, 0.18 mmol) (0.64), Tri-tert- butylphosphonium tetrafluoriborate (0.0043 g, 0.014 mmol, 6 mol%) and Na-t-amilate (0.022 g, 1.1 equ, 0.2 mmol)nbsp;in 1 ml of dioxane was degaset over argone and heated in MW 120C 30 min. No reaction.Experiment was not progres" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC=C4CN(C[C@H](OC4=N3)C5=CC=CC=C5)C)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/20/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "351" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00029 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.018 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" - } - amount { - moles { - value: 0.00131 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=NC(=NC=C2C1)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.00145 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00029 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000145 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 130.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(R)-2-chloro-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine (400 mg, 1.45 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (265 mg, 1.31 mmol), Cesium carbonate (709 mg, 2.18 mmol), Palladium(II) acetate (32.6 mg, 0.15 mmol) and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (168 mg, 0.29 mmol) were added to a microwave vial then dioxane (18 mL) was added. The reaction mixture was flushed with argon and then heated at 140C for 60 min in a MW. The reaction mixture was filtered through celite and concentrated. The crude product was purified by silica flash chromatography using a gradient of methanol (0 to 5%) in dichloromethane. Not pure enough. The product was purified further with preparative chromatography. The productcontainng product was collected and the methanol was evaporated off. The wather phase was extracted three times with dichloromethane, dried (Na2SO4) and concentrated giving (R)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-6-methnyl-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepin-2-amine (195 mg, 30.4 %) as a dry film.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC=C4CN(C[C@H](OC4=N3)C5=CC=CC=C5)C)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 30.38 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/27/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "352" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 1.47e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.001 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000105 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=NC(=NC=C2C1)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.000105 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 1.47e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 7.36e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "The aim is optimization.(R)-2-chloro-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine (29 mg, 0.11 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (21.38 mg, 0.11 mmol), Sodium tert-butoxide (15.16 mg, 0.16 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (9.17 mg, 0.01 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (6.74 mg, 7.36 mol) were added to a microwave vial then toluene (1 mL) was added. The reaction mixture was flushed with nitrogen and the mixture was heated to 120C for 45 min. Small amount of product was formed. Abando" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC=C4CN(C[C@H](OC4=N3)C5=CC=CC=C5)C)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/27/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "353" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00119 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000357 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=NC(=NC=C2C1)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.000297 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 2.97e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.97e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium(II) acetate (6.68 mg, 0.03 mmol), 2-(Dicyclohexylphosphino)biphenyl (10.42 mg, 0.03 mmol) and Cesium carbonate (0.388 g, 1.19 mmol) were put in a 5 mL microwave vial and sealed. The vial was flushed with argon. (R)-2-chloro-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine (0.082 g, 0.30 mmol) in DME (5 mL) was added to the vial. The reaction mixture was run in the microwave at 100C for 60 minutes. Forgot the aniline! Added 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.086 g, 0.36 mmol) and a small spatula of Palladium(II) acetate and 2-(Dicyclohexylphosphino)biphenyl and the reaction mixture was run in the microwave for 60 minutes for 100C. The reaction mixture was filtrated through celite, concentrated and purified first by preparative chromatography. The productcontaining fractions were pooled, concentrated and partitioned between sat. NaHCO3 (aq) and dichloromethane. The organic layer was washed with sat. NaHCO3 (aq), dried (Na2) and concentrated giving (R)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepin-2-amine (9.00 mg, 6.84 %)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC=C4CN(C[C@H](OC4=N3)C5=CC=CC=C5)C)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 6.84 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/18/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "355" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 2.18e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.001 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000109 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=NC(=NC=C2C1)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.000109 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 2.18e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.09e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 130.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "The aim is optimization.(R)-2-chloro-6-methyl-8-phenyl-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine (30 mg, 0.11 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (22.11 mg, 0.11 mmol), Cesium carbonate (53.2 mg, 0.16 mmol), [Reactants] and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (12.59 mg, 0.02 mmol) were added to a microwave vial then dioxane (1 mL) was added. The reaction mixture was flushed with nitrogen and then heated at 130C for 45 min in a MW. Small amount of product, quite messy. Abandoned." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC=C4CN(C[C@H](OC4=N3)C5=CC=CC=C5)C)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/27/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "357" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000491 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1[C@H](OC2=NC(=NC=C2CN1CCF)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.000409 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 4.09e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.09e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.118 g, 0.49 mmol), Palladium(II) acetate (9.19 mg, 0.04 mmol), 2-(Dicyclohexylphosphino)biphenyl (0.014 g, 0.04 mmol) and Cesium carbonate (0.00 mol) were put in a 5 mL microwave vial and sealed and purged with argon.nbsp;(R)-2-chloro-6-(2-fluoroethyl)-8-phenyl-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepine (0.126 g, 0.41 mmol) in DME (5 mL) was added. The reaction mixture was run in the microwave at 100C for 60 minutes. Reaction still not complete. Additional palladium(II)acetate and 2-(dicyclohexylphosphino)biphenyl (small spatula) andnbsp;the reaction was run again in the microwave for 60 minutes. The reaction mixture was filtrated through celite, concentrated and purifiednbsp;by preparative chromatography. The productcontaining fractions were pooled, concentrated and partitioned between sat. NaHCO3 (aq) and dichloromethane. The organic layer was washed with brine, dried (NaSO4) and concentrated giving (R)-6-(2-fluorN-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-8-phenyl-5,6,7,8-tetrahydropyrimido[5,4-f][1,4]oxazepin-2-amine (0.029 g, 14.93 %) as the product. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC=C4CN(C[C@H](OC4=N3)C5=CC=CC=C5)CCF)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 14.93 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/18/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "358" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0019 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC=CN1C2=CC=C(C=C2)N" - } - amount { - moles { - value: 0.000696 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)C2CN(CC3=C(O2)N=C(C=C3)Cl)CC#N)C" - } - amount { - moles { - value: 0.000633 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 6.33e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 6.33e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;4-(2-methyl-1H-imidazol-1-yl)aniline (0.121 g, 0.70 mmol), Palladium acetate (0.014 g, 0.06 mmol) and Cesium carbonate (0.618 g, 1.90 mmol) were added in a microwave vial. The mixture was capped and flushed with argon. 2-(8-chloro-2-(1,3-dimethyl-1H-pyrazol-5-yl)-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)acetonitrile (0.201 g, 0.63 mmol) innbsp;1,2-dimethoxyethane (5 mL) was added, the reaction mixture was flushed with argon and the mixture was run in a microwave for 60 minutes at 100C. No product, only unreacted startingmaterial. Added 1 eq CsCO3, and 0.1 eq ligand and palladium acetate, flushed with argon and run in the microwave at 100C for 60 min. Reaction complete. The reaction mixture was filtrated through Celite and washed with dichloromethane. The filtrate was concentrated and the crude product was purified by preparative chromatography. The productcontaining fractions were pooled, concentrated and the residue was partitioned between sat. NaHCO3 (aq) anromethane. The organic layer was separated by a Phase Separator and concentrated giving 2-(2-(1,3-dimethyl-1H-pyrazol-5-yl)-8-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)acetonitrile (0.041 g, 14.26 %)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)C2CN(CC3=C(O2)N=C(C=C3)NC4=CC=C(C=C4)N5C=CN=C5C)CC#N)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 14.26 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/24/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "359" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00118 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.0025 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C=C1N)Cl)N2C=NC=N2" - } - amount { - moles { - value: 0.000394 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1[C@H](OC2=C(CN1CCO)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.000394 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 3.94e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.94e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;3-chloro-4-(1H-1,2,4-triazol-1-yl)aniline (77 mg, 0.39 mmol), (R)-2-(8-chloro-2-phenyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)ethanol (120 mg, 0.39 mmol),nbsp;Palladium acetate (8.84 mg, 0.04 mmol), 2-(Dicyclohexylphosphino)biphenyl (13.80 mg, 0.04 mmol)and Cesium carbonate (385 mg, 1.18 mmol) were added to a microwave vial. 1,2-dimethoxyethane (2 mL) and EtOH (0.500 mL) were added. The reaction mixture was flushed with argon and the mixture was run in a microwave for 60 minutes at 100C. The solvent was decanted and the solids were washed with DCM, 5ml. The solvent was then evaporated and the crude product was purified on prepHPLC yielding (R)-2-(8-(3-chloro-4-(1H-1,2,4-triazol-1-yl)phenylamino)-2-phenyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)ethanol (16.00 mg, 8.78 %)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1[C@H](OC2=C(CN1CCO)C=CC(=N2)NC3=CC(=C(C=C3)N4C=NC=N4)Cl)C5=CC=CC=C5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 8.78 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/04/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "360" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00232 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(N=C1N)Cl" - } - amount { - moles { - value: 0.00193 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=CC=C1I" - } - amount { - moles { - value: 0.00193 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 0.00019 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00015 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (0.035 g, 0.15 mmol) was added to a mixture of 2-chloropyrimidin-4-amine (0.250 g, 1.93 mmol), 4-iodopyridine (0.396 g, 1.93 mmol), cesium carbonate (0.755 g, 2.32 mmol) and (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (0.105 g, 0.19 mmol) in 1,4-dioxane (10 mL) and the reaction mixture stirred for 18 hours at 80 C under nitrogen. EtOAc (50ml) was added to the reaction mixture and then the organics washed with water (3 x 50ml), brine (50ml) and then dried over MgSO4. The organics were then evaporated in vacuo to give the crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 2-chloro-N-(pyridin-4-yl)pyrimidin-4-amine (0.181 g, 45.3 %) as an orange solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CN=CC=C1NC2=NC(=NC=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 45.34 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/29/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "361" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0105 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.005 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1O)Br" - } - amount { - moles { - value: 0.005 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.0005 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.00025 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "4-Bromophenol (865 mg, 5 mmol), Tris(dibenzylideneacetone)dipalladium(0) (229 mg, 0.25 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (238 mg, 0.50 mmol), Morpholine (0.437 mL, 5.00 mmol) and sodium tert-butoxide (1009 mg, 10.50 mmol) were stirred in toluene (5 mL) overnight at 100 C.nbsp;The mixture was allowed to cool to ambient temperature.nbsp;Ethylacetate was added and the mixture was washed with aqueous NaHCO3 (satd.) and water.nbsp;The organic phase was separated, dried over MgSO4, filtered and the solvent removed by rotary evaporation.nbsp;The crude product was added to a silica gel column and was eluted with 0-2 % MeOH in DCM.nbsp;The collected fraction were combined and the solvent was removed by rotary evaporation.1H NMR in CDCl3 is consistent with desired productMSnbsp;(m+1) = 180.HPLC Peak RT = 2.55 minutes is product.nbsp;Purity = 96%." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1COCCN1C2=CC=C(C=C2)O" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 31.25 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/04/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "362" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0213 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.0102 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC2=C(C(=C1)Br)OC=C2" - } - amount { - moles { - value: 0.0102 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.00102 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000508 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "7-bromobenzofuran (2 g, 10.15 mmol), tert-Butyl 1-piperazinecarboxylate (1.891 g, 10.15 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.465 g, 0.51 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (0.484 g, 1.02 mmol) and sodium t-butoxide (1.856 mL, 21.32 mmol) were heated to 100 C in toluene (10 mL) for 3h.nbsp;The mixture was allowed to cool to ambient temperature.nbsp;Ethylacetate was added and the mixture was filtered through Celite.nbsp;The filtrate was concentrated and redissolved in ethylacetate.nbsp;The organic mixture was washed with satd. aqueous Na2CO3 and brine.nbsp;The organic phase was separated, dried over Na2CO3, filtered and the solvent removed by rotary evaporation.nbsp;The crude product was redissolved in diethylether and loaded onto a silica gel column and eluted with 0-50% EtOAc in heptanes.nbsp;The collected fractions were combined and the solvent removed by rotary evaporation to yield tert-butyl enzofuran-7-yl)piperazine-1-carboxylate (2.58 g, 84 %).MSnbsp;(m+1) = 303.HPLC Peak RT = 5.97 minutes is product.nbsp;Purity = 94%." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC=CC3=C2OC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 84.06 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/21/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "363" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00533 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00254 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC2=C(C(=C1)Br)OC=C2" - } - amount { - moles { - value: 0.00254 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.000254 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000127 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "7-bromobenzofuran (500 mg, 2.54 mmol), tert-Butyl 1-piperazinecarboxylate (473 mg, 2.54 mmol), Tris(dibenzylideneacetone)dipalladium(0) (116 mg, 0.13 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (121 mg, 0.25 mmol) and sodium t-butoxide (0.464 mL, 5.33 mmol) were heated in toluene (2 mL) to 100 C for 2h.nbsp;The mixture was allowed to cool.nbsp;Ethylacetate was added and the mixture was filtered through Celite.nbsp;The filtrate was concentrated and redissolved in ethylacetate.nbsp;The organic mixture was washed with satd. aqueous Na2CO3 and brine.nbsp;The organic phase was separated, dried over Na2CO3, filtered and the solvent removed by rotary evaporation.nbsp;The crude product was added to a silica gel column and was eluted with 0-2% MeOH in DCM and to a second silica gel column eluted with 0-100% EtOAc in heptane.nbsp;The collected fractions were combined to yield tert-butyl 4-(benzofuran-7-yl)piperazine-1-carboxylate (560 73.0 %).1H NMR in CD3OD is consistent with desired productMSnbsp;(m+1) = 303.1.HPLC Peak RT = 5.99 minutes is product.nbsp;Purity = 98%." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC=CC3=C2OC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 72.98 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/25/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "364" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00118 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.0025 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CC2=NN=C(N2C1)C3=CC=C(C=C3)N" - } - amount { - moles { - value: 0.000394 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1[C@H](OC2=C(CN1CCO)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.000394 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 3.94e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.94e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;4-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)aniline (79 mg, 0.39 mmol), (R)-2-(8-chloro-2-phenyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)ethanol (120 mg, 0.39 mmol)nbsp;Palladium acetate (8.84 mg, 0.04 mmol), 2-(Dicyclohexylphosphino)biphenyl (13.80 mg, 0.04 mmol)and Cesium carbonate (385 mg, 1.18 mmol) were added to a microwave vial. 1,2-dimethoxyethane (2 mL) and EtOH (0.500 mL) were added. The reaction mixture was flushed with argon and the mixture was run in a microwave for 60 minutes at 100C. The crude product was taken up in DCM and the solids were thoroughly washed with DCM. The solvents were evaporated and the crude product was purified on Si. 0-20% MeOH in DCM with 2% triethylamine. Yield: (R)-2-(8-(4-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)phenylamino)-2-phenyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)ethanol (39.0 mg, 21.14 %)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CC2=NN=C(N2C1)C3=CC=C(C=C3)NC4=NC5=C(CN(C[C@H](O5)C6=CC=CC=C6)CCO)C=C4" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 21.14 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/02/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "365" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00755 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.018 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.0036 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=C(C=C(C=C1)I)O" - } - amount { - moles { - value: 0.0036 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00036 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.00018 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "tert-butyl piperazine-1-carboxylate (0.670 g, 3.60 mmol) and methyl 2-hydroxy-4-iodobenzoate (1 g, 3.60 mmol), BINAP (0.224 g, 0.36 mmol), cesium carbonate (2.461 g, 7.55 mmol) were put inDME (18 mL),nbsp;tris(dibenzylideneacetone)dipalladium(0) (0.165 g, 0.18 mmol) was added last.nbsp;Reaction wsa purged by nitrogen, and heated at90 C overnight.nbsp;No desired product was found. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC(=C(C=C2)C(=O)OC)O" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/17/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "366" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0382 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0764 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CONC(=O)C1=C(C=CC(=C1)F)N" - } - amount { - moles { - value: 0.0287 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" - } - amount { - moles { - value: 0.0191 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00191 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000955 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (7.3 g, 19.10 mmol), 2-amino-5-fluoro-N-methoxybenzamide (5.28 g, 28.66 mmol), diacetoxypalladium (0.214 g, 0.96 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.105 g, 1.91 mmol) and cesium carbonate (12.45 g, 38.21 mmol) were suspended in 1,4-dioxane (76 ml). The reaction was degased, purged with nitrogen and heated to 90C (internal temperature) overnighti. iReaction was concentrated to dryness. Residue was diluted with EtOAc (200 mL) and water (200 mL). Aqueous was extracted with EtOAc (100 mL) then with EtOAcMeOH 91 (100 mL) =gt; iaqueous still contained some expected product.i Aqueous was saturated with NaCl and extracted with EtOAcMeOH 91 (100 mL). Combined organic layers were dried over MgSO4 and concentrated to dryness. The crude product (12g) was dissolved in CH2Cl2 (80 mL) for liquid injection but product started to precipitate. Solid was filtered and washed twice with CH2Cl2 to aff2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-5-fluoro-N-methoxybenzamide (7.1 g) as an off-white solid. The filtrate was purified by flash chromatography on silica gel eluting with 10 to 100% ethyl acetate in dichloromethane (ielution of impuritiesi) then with 5%, 10% and 15% MeOH in ethyl acetate (iproduct elutes on TLC plate with 100% EtOAc but n MeOH to elute from the column probably due to poor solubility in EtOAci). The solvent was evaporated to dryness. Residual oil was triturated in CH2Cl2. Resulting solid was filtered nad dried to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (0.9 g) as an off-white solid.Both batches (8g) were combined and recrystallised from EtOH (70 mL) to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (3.6 g) as a white crystalline solid =gt;i less hot EtOH (lt;60 mL ?) could have been used to solubilise all.iFiltrate was concentrated to ~half the volume and then stirred at room temperature for 4 hours. The resulting solid was filtered to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (3.2 g) as a white solid.Both batches of solid (6.8 g) were combined and slurried in EtOAc (65 mL) at room temperature for 24 hours. The resulting solid was filtered and dried at 50C under high vacuum overnight to afford 2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-5-fluoro-N-methoxybenzamide (4.52g, 54%, EN03787-13-01) as a white solid.Filtrate was concentrated to ~20 mL and then stirred at room temperature 24 hours. The resulting solid was filtered and dried under high vacuum at 50C overnight to afford 2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-5-fluoro-N-methoxybenzamide (1.12g, 13.4%, EN03787-13-02) as a white so" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=C(C=C(C=C3)F)C(=O)NOC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 67.7 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/14/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "367" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000592 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CONC(=O)C1=C(C=CC(=C1)F)N" - } - amount { - moles { - value: 0.000326 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" - } - amount { - moles { - value: 0.000296 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 2.96e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.48e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 95.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (113 mg, 0.30 mmol), 2-amino-5-fluoro-N-methoxybenzamide (60 mg, 0.33 mmol) and Cesium carbonate (193 mg, 0.59 mmol) in degassed dioxane (4 mL) under nitrogen at room temperature were degassed (nitrogen) for a further 5 minutes before adding Palladium(II) acetate (3.32 mg, 0.01 mmol) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (17.14 mg, 0.03 mmol) the reaction mixture then being allowed to stir at 95 C for 6 hours and cooled to RT.nbsp;LCMS analysis showed a new peak for product (9%) but both SM\'s still remained (pyridine 71%, benzamide 13 %).nbsp;Another 1.1 eq of benzamide (60 mg in 2ml dioxane) was added and thenbsp;RMnbsp;was then heated at 95 C overnight. Lcms after this time showed no further progression with the reaction.nbsp;Therefore a further portion of palladium acetate (0.05 eq. 3.32 mg)nbsp;and the xanthene ligand (0.1 eq. 17.14 mg) were added and the RM stirred on at 95C.nbsp;An this time showed a majority peak for product and no pyridine SM remaining.nbsp;The RM was concentrated and dry loaded onto silica.nbsp;It was then purified on a 12g isco column using initially 0-100 % ethyl acetate in DCM followed by 0-10 % methanol in ethyl acetate to givenbsp;2-(2-(1,3-dimethyl-1H-pyrazol-4-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-5-fluoro-N-methoxybenzamide (60.0 mg, 46.2 %) which was not very pureTrituration with diethyl ether did not produce a purer product." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=C(C=C(C=C3)F)C(=O)NOC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 46.21 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/10/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "369" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000942 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.04 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CONC(=O)C1=C(C=CC(=C1)F)N" - } - amount { - moles { - value: 0.0141 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)I)C(F)(F)F)C" - } - amount { - moles { - value: 0.00942 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000942 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000471 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-amino-5-fluoro-N-methoxybenzamide (2.60 g, 14.13 mmol), N-(1,3-dimethyl-1H-pyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (3.6 g, 9.42 mmol) (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.545 g, 0.94 mmol) diacetoxypalladium (0.106 g, 0.47 mmol) and cesium carbonate (6.14 g, 18.84 mmol) were suspended in dioxane (40 mL). The reaction was degased, purged with argon (3 times) and heated to 100 C overnight.The reaction mixture was allowed to cool to room temperature under stirring, diluted with ethyl acetate and the insolubles were removed by filtration, washed with EtOAc and the filtrate was concentrated.The crude product was purified by flash chromatography on silica gel eluting with 0 to 15% methanol in ethyl acetateDCM (11). Fractions containing the most part of pure product were evaporated. This residue was re-purified by trituration with DCM (with 5% MeOH), to give after filtration EN03299-42-01 (3.5 g, 7.98 mmol, 85 %) which contains trace of AcOEt and 3l DCM.The resulting solid was recrystallised from ethanol (35 ml) and the resulting crystalline solid was collected by filtration, washed with ethanol and dried to a constant weight in a vacuum oven to afford EN03299-42-02 (2.7 g, 5.54 mmol, 58.8 %)nbsp;as anbsp;white crystalline solid.TSB 46.938" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C=C1NC2=NC=C(C(=C2)NC3=C(C=C(C=C3)F)C(=O)NOC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 58.84 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/23/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "370" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000916 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.04 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=C(C=C(C=C1)F)N" - } - amount { - moles { - value: 0.0137 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)I)C(F)(F)F)C" - } - amount { - moles { - value: 0.00916 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000916 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000458 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-amino-4-fluoro-N-methylbenzamide (2.310 g, 13.74 mmol), N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (3.5 g, 9.16 mmol) (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.530 g, 0.92 mmol) diacetoxypalladium (0.103 g, 0.46 mmol) and cesium carbonate (5.97 g, 18.32 mmol) were suspended in dioxane (40 mL). The reaction was degased, purged with argon (3 times) and heated to 100 C for 5 hours.The reaction mixture was allowed to cool to room temperature under stirring, diluted with ethyl acetate and the insolubles were removed by filtration, washed with EtOAc and the filtrate was concentrated.The crude product was purified by flash chromatography on silica gel eluting with 0 to 10% methanol in ethyl acetateDCM (11). Fractions containing pure product were evaporated to give a foam. This residue was triturated with DCM and filtered to afford EN03299-43-01 (1.4 g, 3.31 mmol, 36.2 %) as an off-white product.combined with APE-03299-487g of aniline was recovered" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=C(C=CC(=C3)F)C(=O)NC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 36.19 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/24/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "373" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000262 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.000436 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC=CC(=C1C(=O)NOC)N" - } - amount { - moles { - value: 0.000222 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)I)C(F)(F)F)C" - } - amount { - moles { - value: 0.000131 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 1.31e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 6.54e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (50 mg, 0.13 mmol), 2-amino-N,6-dimethoxybenzamide (43.6 mg, 0.22 mmol), diacetoxypalladium (1.469 mg, 6.54 mol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (8.15 mg, 0.01 mmol) and cesium carbonate (85 mg, 0.26 mmol) were suspended in 1,4-dioxane (436 l) and sealed into a microwave tube. The reaction was degased, purged with nitrogen and heated to 90 C overnight =gt; islow reaction, a few expected product formed, no des-iodo observed, both SM leftibiNOT ISOLATED" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=C(C(=CC=C3)OC)C(=O)NOC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/12/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "374" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[K+].[K+]" - } - amount { - moles { - value: 0.000262 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.000436 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC=CC(=C1C(=O)NOC)N" - } - amount { - moles { - value: 0.000222 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)I)C(F)(F)F)C" - } - amount { - moles { - value: 0.000131 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 1.31e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 6.54e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (50 mg, 0.13 mmol), 2-amino-N,6-dimethoxybenzamide (43.6 mg, 0.22 mmol), diacetoxypalladium (1.469 mg, 6.54 mol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (7.57 mg, 0.01 mmol) and potassium carbonate (36.2 mg, 0.26 mmol) were suspended in 1,4-dioxane (423 l) and sealed into a microwave tube. The reaction was degased, purged with nitrogen and heated to 90 C overnight =gt; inot complete but seemed to be clean, no des-iodo by-product formed, both SM leftiSame reaction was performed in toluene (423 l) =gt; ireaction complete, LCMS profile similar to the conception document referenceibiNOT ISOL" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=C(C(=CC=C3)OC)C(=O)NOC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/12/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "376" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00597 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.199 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC=CC(=C1C(=O)NOC)N" - } - amount { - moles { - value: 0.101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)I)C(F)(F)F)C" - } - amount { - moles { - value: 0.0597 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00597 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00298 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (22.8 g, 59.67 mmol), 2-amino-N,6-dimethoxybenzamide (19.90 g, 101.43 mmol), diacetoxypalladium (0.670 g, 2.98 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (3.45 g, 5.97 mmol) and cesium carbonate (23.33 g, 71.60 mmol) were suspended in 1,4-dioxane (199 ml). The reaction was degased, purged with nitrogen and heated to 90 C =gt; ireaction turned to dark brown and solidified after ~15 minutes.i1,4-dioxane (50 mL) was added and reaction was stirred at 90C (internal temperature) overnight =gt; istirring became easier and mixture turned to beigeyellow then to dark greengrey during the night. iReaction was concentrated to dryness. Residue was diluted with CH2Cl2 (300 mL) and water (300 mL). Aqueous was extracted with CH2Cl2 (100 mL) then with CH2Cl2MeOH 91 (100 mL) =gt; iaqueous still contained expected product.i Aqueous was saturated with NaCl and extracted with CH2Cl2MeOH 91 (100 bined organic layers were dried over MgSO4 and concentrated to dryness. The crude product (38.5g) was dissolved in CH2Cl2 (100 mL) for liquid injection but some product started to precipitate. Solid was filtered and washed twice with CH2Cl2 to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (5.2 g) as a white solid. The filtrate was purified by flash chromatography on silica gel eluting with 0 to 7% methanol in ethyl acetate. The solvent was evaporated to dryness to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (20.6 g) as a beige solid.Both batches of product (25.8 g) were combined and triturated in tBuOMe (50 mL) CH2Cl2 (20 mL). The resulting solid was filtered, washed with tBuOMe (50 mL) to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (23 g) as a white solid.It was suspended in H2O (350 mL) and stirred at room temperature overnight =gt; imixture solidified.i It was filtered and dried over P2O5 under high vacuum for 6 hours.The resulting solid was suspended in acetonitrile (460 mL) and stirred at room temperature over the weekend. It was filtered, washed with cold acetonitrile and dried under high vacuum at 50C overnight to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (8.4 g, 31.3%, EN03787-12-01) as a white solid =gt; iproduct is quite soluble in acetonitrile, volume of solvent was too important (ref from PARD : 50mg in 1mL)iFiltrate was concentrated to ~100 mL (= until preciptation occured on the rotavapor) and then stirred at room temperature for 4 hours. The resulting solid was filtered and dried under high vacuum at 50C overnight to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (9.3 g, 34.6%, EN03787-12-02) as a white solid.Filtratecentrated to dryness to afford another batch of impure product (2.8g) which was slurried in CH3CN (28 mL) at room temperature overnight. The resulting solid was filtered and dried under high vacuum at 50C to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (1.54 g, 5.73%, EN03787-12-03) as a white solid =gt; ithis batch is less pure than the 2 othersi" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=C(C(=CC=C3)OC)C(=O)NOC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 71.59 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/13/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "377" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00183 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.008 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC=CC(=C1C(=O)NOC)N" - } - amount { - moles { - value: 0.00138 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)I)C(F)(F)F)C" - } - amount { - moles { - value: 0.000917 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 9.17e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.59e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;N-(1,3-dimethyl-1H-pyrazol-5-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (351 mg, 0.92 mmol), 2-amino-N,6-dimethoxybenzamide (270 mg, 1.38 mmol) and Cesium carbonate (598 mg, 1.83 mmol) in degassed dioxane (8 mL) under nitrogen at room temperature were allowed to stir, degassing (nitrogen) for a further 5 minutes before adding Palladium(II) acetate (10.30 mg, 0.05 mmol) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (53.1 mg, 0.09 mmol).nbsp;The reaction mixture was then stirred at 90 C for 4 hours and cooled to RT.nbsp;LCMS analysis showed a new peak for product but both SM\'s still remained.nbsp;The RMnbsp;was then heated at 100 C for a further 4 hours, after this time LCMS analysis showed none of the pyridine SM remaining and a bigger peak for product.nbsp;The RM was concentrated and then dissolved in methanol and dry loaded onto silica.nbsp;The crude was purified on a 12g Si column eluting with 0-10 % methanol in DCM.nbsp;Fractions 3-8 and 18-28 contained product and wered.nbsp;LCMS analysisTLC showed that the product was still not pure.Diethyl ether trituration gave 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-N,6-dimethoxybenzamide (235 mg, 56.9 %) as a pure product." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=C(C(=CC=C3)OC)C(=O)NOC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 56.87 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/30/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "378" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0307 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.111 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)N)C" - } - amount { - moles { - value: 0.0307 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=C(C=C(C=C1)F)NC2=CC(=NC=C2C(F)(F)F)Cl" - } - amount { - moles { - value: 0.0256 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.0041 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00205 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-4-fluoro-N-methylbenzamide (8.9 g, 25.60 mmol), 1,3-dimethyl-1H-pyrazol-5-amine (3.41 g, 30.72 mmol), diacetoxypalladium (0.460 g, 2.05 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.370 g, 4.10 mmol) and cesium carbonate (10.01 g, 30.72 mmol) were suspended in 1,4-dioxane (111 ml). The reaction was degased, purged with nitrogen and heated to 90C (internal temperature) for 4 hoursi. iReaction was concentrated to dryness. Residue was diluted with CH2Cl2MeOH 91 (200 mL) and water (200 mL). Aqueous was extracted with CH2Cl2MeOH 91 (100 mL). Combined organic layers were dried over MgSO4 and concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 0 to 5% methanol in ethyl acetate. The solvent was evaporated to dryness to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-4-fluoro-N-methylbenzamide (7.6 g) as a yellow foam =gt; i1H NMR shothat it contained EtOAc and a vey small amount of an impurityi. This residue was triturated in CH2Cl2 (10 mL) =gt; icomplete solubilisation followed by precipitation. iThe resulting solid was filtered and washed with tBuOMe (10 mL) to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-4-fluoro-N-methylbenzamide (6.3 g) as a pale yellow solid =gt; i1H NMR showed that EtOAc and impurity has been removediThis solid was suspended in tBuOMe (20 mL) and stirred at 50C (heating block temperature) for 1 hour. Mixture was allowed to cool for 5 minutes then filtered, washed once with tBuOMe (10 mL) and dried overnight under high vacuum at 50C to afford 2-(2-(1,3-dimethyl-1H-pyrazol-5-ylamino)-5-(trifluoromethyl)pyridin-4-ylamino)-4-fluoro-N-methylbenzamide (6.00 g, 55.5 %) as a white so" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=C(C=CC(=C3)F)C(=O)NC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 55.5 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/21/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "379" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0069 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.025 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)N)C" - } - amount { - moles { - value: 0.0069 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=C(C=C(C=C1)F)NC2=CC(=NC=C2C(F)(F)F)Cl" - } - amount { - moles { - value: 0.00575 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00092 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00046 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;2-(2-chloro-5-(trifluoromethyl)pyridin-4-ylamino)-4-fluoro-N-methylbenzamide (2 g, 5.75 mmol), 1,3-dimethyl-1H-pyrazol-5-amine (0.767 g, 6.90 mmol) diacetoxypalladium (0.103 g, 0.46 mmol) (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.533 g, 0.92 mmol) and cesium carbonate (2.249 g, 6.90 mmol) were suspended in dioxane (25 ml). The reaction was degased, purged with argon (3 times) and heated to at 90 C for 4 hours.The reaction mixture was allowed to cool to room temperature, diluted with DCM (some drop of MeOH) and filtered. Silica gel was added and solvents were evaporated to afford the crude, which was purified by flash chromatography on silica gel eluting with 0 to 10% methanol in ethyl acetateDCM (11) . The solvent was evaporated to dryness to give a residue which was triturated with DCM, filtered and dried to afford EN03299-48-01 (1.5 g, 3.55 mmol, 61.7 %) as a off-white solid.This sample EN03299-48-01 (1.5 g, 3.55 mmol, 61.7 %) and uEN03299-43-01u werebined and triturated with hot tBuOMe, filtered and dried to afford EN03299-48-02 (2.1 g, 4.90 mmol, 85 %) as a white solid.Trituration filtrates were evaporated and the residue was taken with DCM, filtered and dried to afford EN03299-48-03 (0.5 g, 1.184 mmol, 20.58 %) as a white solidTSB 46.916" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NN(C(=C1)NC2=NC=C(C(=C2)NC3=C(C=CC(=C3)F)C(=O)NC)C(F)(F)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 61.74 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/01/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "380" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00212 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CS(=O)(=O)C1=CC=C(C=C1)N" - } - amount { - moles { - value: 0.00193 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(N=C(C=N1)Cl)Cl" - } - amount { - moles { - value: 0.00193 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000193 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000193 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2,6-dichloropyrazine (287 mg, 1.93 mmol), 4-(methylsulfonyl)aniline (330 mg, 1.93 mmol), diacetoxypalladium (43.3 mg, 0.19 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (120 mg, 0.19 mmol) and cesium carbonate (690 mg, 2.12 mmol) in 1,4-dioxane (2 mL) were degazed andnbsp;stirred at 90 C for 16 hours under nitrogen.The reaction mixture was evaporated to dryness and was purified by preparative HPLC using a Waters SunFire reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 6-chloro-N-(4-(methylsulfonyl)phenyl)pyrazin-2-amine (120 mg, 21.95 %)nbsp;as anbsp;yellow solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CS(=O)(=O)C1=CC=C(C=C1)NC2=CN=CC(=N2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 21.95 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/30/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "381" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "[Li+].C[Si](C)(C)[N-][Si](C)(C)C" - } - amount { - moles { - value: 0.123 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCCC1C#N" - } - amount { - moles { - value: 0.0642 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC(=CC=C1)Br" - } - amount { - moles { - value: 0.0535 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)CN1CCN2CCN(P1N(CC2)CC(C)C)CC(C)C" - } - amount { - moles { - value: 0.00214 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.0107 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Reaction carried out by Rolf Walker uEN03350-58u, work up and purification on this page.piperidine-4-carbonitrile (7.07 g, 64.16 mmol); 1-bromo-3-methoxybenzene (6.77 mL, 53.47 mmol) and diacetoxypalladium (2.401 g, 10.69 mmol) were thoroughly placed under an inert atmoshere. To this was added 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (0.732 g, 2.14 mmol); LITHIUM BIS(TRIMETHYLSILYL)AMIDE (123 mL, 122.97 mmol) and toluene (20 mL). The resultant mixture was stirred overnight at 100 C (suspect that it did not need overnight. The reaction mixture was poured onto DCM (200 mL), the mixture was filtered through celite and evaporated to afford a black residue. This was suspended in EtOAc (200 mL) and water (20 mL) and filtered through a pad of silica, washing through with EtOAc (300 mL) and water (20 mL). The filtrate was evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Pure tions were evaporated to dryness to afford 1-(3-methoxyphenyl)piperidine-4-carbonitrile (3.29 g, 28.5 %) as a yellow oil which solidified on standing." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=CC=CC(=C1)N2CCC(CC2)C#N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 28.45 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/03/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "382" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "[Li+].C[Si](C)(C)[N-][Si](C)(C)C" - } - amount { - moles { - value: 0.00615 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCCC1C#N" - } - amount { - moles { - value: 0.00321 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC(=CC=C1)Br" - } - amount { - moles { - value: 0.00267 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)CN1CCN2CCN(P1N(CC2)CC(C)C)CC(C)C" - } - amount { - moles { - value: 0.000107 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000535 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "piperidine-4-carbonitrile (0.353 g, 3.21 mmol); 1-bromo-3-methoxybenzene (0.339 mL, 2.67 mmol) and diacetoxypalladium (0.120 g, 0.53 mmol) were thoroughly placed under an inert atmoshere. To this was added 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (0.037 g, 0.11 mmol); LITHIUM BIS(TRIMETHYLSILYL)AMIDE (6.15 mL, 6.15 mmol) and toluene (10 mL). The resultant mixture was stirred overnight at 100 C (suspect that it did not need overnight.Equal vol of DCM was added and the reaction mixture filtered. Removal of the solvent under reduced pressure gave a dark brown gum.The crude product was purified by flash Silica chromatography {CombiFlash Companion - Presearch Ltd}, column size = 12 g , flow rate = 30 ml min, elution gradient 0 to 30% EtOAc in isohexane over 10 minutes {excluding lead in amp; wash etc.}. Pure fractions were evaporated to dryness to afford 1-(3-methoxyphenyl)piperidine-4-carbonitrile (0.315 g, 54.5 %) as a tan brown solid. nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=CC=CC(=C1)N2CCC(CC2)C#N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 54.48 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/21/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "385" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "[Li+].C[Si](C)(C)[N-][Si](C)(C)C" - } - amount { - moles { - value: 0.00615 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCCC1C(=O)N" - } - amount { - moles { - value: 0.00321 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC(=CC=C1)Br" - } - amount { - moles { - value: 0.00267 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)CN1CCN2CCN(P1N(CC2)CC(C)C)CC(C)C" - } - amount { - moles { - value: 0.000107 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000535 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "piperidine-4-carboxamide (0.411 g, 3.21 mmol); 1-bromo-3-methoxybenzene (0.339 mL, 2.67 mmol) and diacetoxypalladium (0.120 g, 0.53 mmol) were thoroughly placed under an inert atmoshere. To this was added 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (0.037 g, 0.11 mmol); LITHIUM BIS(TRIMETHYLSILYL)AMIDE (6.15 mL, 6.15 mmol) and toluene (10 mL). The resultant mixture was stirred at 100 C overnight.No sign of reaction by LCMS overnight.Abandonednbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=CC=CC(=C1)N2CCC(CC2)C(=O)N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/21/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "387" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000463 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.008 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN" - } - amount { - moles { - value: 0.0193 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC2=C(C=C1[N+](=O)[O-])SC(=N2)Br" - } - amount { - moles { - value: 0.00386 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000463 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000193 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;methanamine (0.793 mL, 19.30 mmol), 2-bromo-6-nitrobenzo[d]thiazole (1 g, 3.86 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.268 g, 0.46 mmol), cesium carbonate (1.886 g, 5.79 mmol) and diacetoxypalladium (0.043 g, 0.19 mmol) were suspended in 1,4-dioxane (8 mL) and sealed into a microwave tube. The reaction was heated to 150C for 30 minutes in the microwave reactor and cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness to afford a crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% DCM in EtOAc. Pure fractions were evaporated to dryness to afford N-methyl-6-nitrobenzo[d]thiazol-2-amine (0.050 g, 6.19 %) as a yellow solid. nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CNC1=NC2=C(S1)C=C(C=C2)[N+](=O)[O-]" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 6.19 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/23/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "388" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 4.54e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)[N+](=O)[O-])N" - } - amount { - moles { - value: 0.000379 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C2C(=C1)C(=CN2)C3=NC(=NC=C3Cl)Cl" - } - amount { - moles { - value: 0.000379 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 4.54e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.27e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a stirred solution of 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (100 mg, 0.38 mmol) in dioxane (10 mL) was added 2-methoxy-5-nitroaniline (63.7 mg, 0.38 mmol), cesium carbonate (247 mg, 0.76 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (26.3 mg, 0.05 mmol). The resulting suspension was purged with nitrogen for 5 minutes. diacetoxypalladium (5.10 mg, 0.02 mmol) was added and the mixture was purged with nitrogen for a further 5 minutes, and then heated at 80 C overnight. UPLC shows di-Cl SM almost completely consumed but no evidence of desired product.Reaction stopped" - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)[N+](=O)[O-])NC2=NC=C(C(=N2)C3=CNC4=CC=CC=C43)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/04/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "390" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 3.56e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.006 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000509 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC(=NC2=C1CN(CC(O2)CC(F)(F)F)C)Cl" - } - amount { - moles { - value: 0.000509 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 3.56e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 3.56e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (104 mg, 0.51 mmol), 8-chloro-4,6-dimethyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (150 mg, 0.51 mmol), Sodium tert-butoxide (73.4 mg, 0.76 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (22.19 mg, 0.04 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (32.6 mg, 0.04 mmol) were added to a radley tube followed by toluene (6 mL). The reaction mixture was flushed with argon and the mixture was heated to 100C and stirred overnight. The solids were filtered off and washed with DCM. The crude product was purified on prepHPLC yielding N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4,6-dimethyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (23.00 mg, 9.77 %)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CC(=NC2=C1CN(CC(O2)CC(F)(F)F)C)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 9.77 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/23/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "391" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00253 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCNCC1" - } - amount { - moles { - value: 0.00169 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=NC=C1Br)Br" - } - amount { - moles { - value: 0.00169 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000253 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000169 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 140.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Trial # 3:3,5-dibromopyridine (1000 mg, 4.22 mmol), 1-methylpiperazine (423 mg, 4.22 mmol), Pd2(dba)3 (387 mg, 0.42 mmol), XANTPHOS (366 mg, 0.63 mmol), SODIUM TERT-BUTOXIDE (609 mg, 6.33 mmol), PhCH3 (10 mL) as added to a 10 mL microwave vial. This was degassed and refilled with N2 and then heated at 140 C in microwave for 1h.LCMS showed reaction done with the peak at Rf0.52 showed a fragment mass of 256.Evaporated solvent. Residue purified by Gilson (CH3CNH2O 0-30%+TFA buffer )to get the desired product 1-(5-bromopyridin-3-yl)-4-methylpiperazine (107 mg, 9.90 %).Trial # 13,5-dibromopyridine (1000 mg, 4.22 mmol), 1-methylpiperazine (423 mg, 4.22 mmol), Pd2(dba)3 (387 mg, 0.42 mmol), XANTPHOS (366 mg, 0.63 mmol), [Reactants], PhCH3 (5 mL) as added to a 10 mL microwave vial. This was degassed and refilled with N2 and then heated at 140 C in microwave for 1h.LCMS showed reaction done with no desired peak formed.Trial # 2:3,5-dibromo (400 mg, 1.69 mmol), 1-methylpiperazine (169 mg, 1.69 mmol), Pd2(dba)3 (155 mg, 0.17 mmol), XANTPHOS (117 mg, 0.20 mmol), SODIUM TERT-BUTOXIDE (243 mg, 2.53 mmol), PhCH3 (5 mL) as added to a 10 mL microwave vial. This was degassed and refilled with N2 and then heated at 140 C in microwave for 1h.LCMS showed reaction done with the peak at Rf0.46 showed a fragment mass of 256.Evaporated solvent. Residue purified by Gilson (CH3CNH2O 0-30%+TFA buffer )to get the desired product 1-(5-bromopyridin-3-yl)-4-methylpiperazine (92 mg, 21.27 %)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CCN(CC1)C2=CC(=CN=C2)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 21.27 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/26/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "392" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CCN(CC)CC" - } - amount { - moles { - value: 0.00805 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C=O" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00268 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CSC(=C1)Cl" - } - amount { - moles { - value: 0.00268 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3" - } - amount { - moles { - value: 5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.[Pd]" - } - amount { - moles { - value: 5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 95.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a mixture of 2-chlorothiophene (0.248 mL, 2.68 mmol), tert-butyl piperazine-1-carboxylate (500 mg, 2.68 mmol), and TEA (1.123 mL, 8.05 mmol) in DMF (4 mL) was added Pd(Ph3P)4 (57.8 mg, .05 mmol). The reaction was allowed to heat at 95 C for overnight. LCMS and TLC showed the starting material peak as well as the triphenyl phosphene ionized M+1 peak. The tryphenyl phosphene showed up at the same retention time as 2-chlorothiophene. No new peak was observed following the reaction so no purification techniques were run.MSnbsp;(m+1) = not seen" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC=CS2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/19/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "394" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000677 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.001 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C(=C1)CN)C(F)(F)F" - } - amount { - moles { - value: 0.000677 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=NC=C1C(=O)N)Cl" - } - amount { - moles { - value: 0.000339 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 3.39e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.39e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a stirred solution of 6-chloronicotinamide (0.053 g, 0.34 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.021 g, 0.03 mmol), sodium 2-methylpropan-2-olate (0.065 g, 0.68 mmol) and diacetoxypalladium (7.60 mg, 0.03 mmol) in DME (1 mL) was added (2-(trifluoromethyl)phenyl)methanamine (0.095 mL, 0.68 mmol). The reaction mixture was jected to microwave irradiation for 4h at 120 C. Only traces of product was observed. The crude product was dissolved in DMSO (2 mL) and purified using Fractionlynx I, (Xbridge Prep C18 5m OBD 19x150 mm column), with 5 to 95% acetonitrile in 0.2% ammonia at pH 10.6-(2-(trifluoromethyl)benzylamino)nicotinamide: 1.45 mg (1.5 %)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C(=C1)CNC2=NC=C(C=C2)C(=O)N)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 1.45 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/21/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "395" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 3.39e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.001 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)C(F)(F)F)CN" - } - amount { - moles { - value: 0.000339 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=NC=C1C(=O)N)Cl" - } - amount { - moles { - value: 0.000339 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.39e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.39e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a stirred solution of 6-chloronicotinamide (0.053 g, 0.34 mmol), sodium 2-methylpropan-2-olate (0.065 g, 0.68 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.020 g, 0.03 mmol) and diacetoxypalladium (7.60 mg, 0.03 mmol) in DME (1 mL) was added (3-(trifluoromethyl)phenyl)methanamine (0.049 mL, 0.34 mmol). The reaction was run in microwave at 120 C for 4h. only traces of product observed. Reaction wasted." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)C(F)(F)F)CNC2=NC=C(C=C2)C(=O)N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/22/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "396" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000677 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.001 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1CN)C(F)(F)F" - } - amount { - moles { - value: 0.000677 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=NC=C1C(=O)N)Cl" - } - amount { - moles { - value: 0.000339 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 3.39e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.39e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a stirred solution of 6-chloronicotinamide (0.053 g, 0.34 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.021 g, 0.03 mmol), sodium 2-methylpropan-2-olate (0.065 g, 0.68 mmol) and diacetoxypalladium (7.60 mg, 0.03 mmol) in DME (1 mL) was added (4-(trifluoromethyl)phenyl)methanamine (0.097 mL, 0.68 mmol). The reaction was run in microwave at 100 C for 4h. The compound was purified by preparative HPLC on a Kromasil C8 column (10 m 250x20 ID mm) using a gradient of 51-55% acetonitrile in H2OACNFA 9550.2 buffer, over 25 minutes with a flow of 19 mLmin. The compounds were detected by UV at 270nm.6-(4-(trifluoromethyl)benzylamino)nicotinamide (7.40 mg, 7.40 %) was obtai" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1CNC2=NC=C(C=C2)C(=O)N)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 7.4 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/18/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "398" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00236 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.1 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" - } - amount { - moles { - value: 0.0283 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)Br)C#N" - } - amount { - moles { - value: 0.0236 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.00236 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00236 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "PdOAc2 (0.529 g, 2.36 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (1.124 g, 2.36 mmol) were added in one portion tonbsp;a degassed solution of 5-bromo-2-methoxybenzonitrile (5 g, 23.58 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (5.36 g, 28.30 mmol) and cesium carbonate (11.52 g, 35.37 mmol) in toluene (100 mL) at 20Cnbsp;under nitrogen. The resulting suspension was stirred at 120 C for 50 hours. The reaction mixture was diluted with EtOAc (150 mL)nbsp;and water (150 mL) and the biphasic mixture was filtered through celite. The organic layer was separated and washed sequentially with water (150 mL) and saturated brine (150 mL). The organic layer was evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-5-(2-(tert-butyldimethylsilyloxy)propylamino)-2-methoxybenzonitrile (3.60 g, 47.6 %) as a pale yellow o" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@H](CNC1=CC(=C(C=C1)OC)C#N)O[Si](C)(C)C(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 47.64 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/25/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "399" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0318 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.1 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" - } - amount { - moles { - value: 0.0255 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)Br)C#N" - } - amount { - moles { - value: 0.0212 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.00212 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00212 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Reaction carried out by Phill Walker in RSLPdOAc2 (0.476 g, 2.12 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (1.012 g, 2.12 mmol) were added in one portion to a degassed solution of 5-bromo-2-methoxybenzonitrile (4.50 g, 21.22 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (4.82 g, 25.47 mmol) and cesium carbonate (10.37 g, 31.83 mmol) in toluene (100 mL) at 20C in a microwave vial. The microwave vial was sealed and the reaction was heated to 120 C for 12 hours in the microwave reactor and cooled to RT.nbsp;The reaction mixture was diluted with EtOAc (100 mL) and water (100 mL). The biphasic mixture was filtered through celite. The organic layer was separated and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was filtered and dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was evaporated and was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohere fractions were evaporated to dryness to afford (R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)-3-fluoroaniline (0.851 g, 61.4 %) as a orange oil. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@H](CNC1=CC(=C(C=C1)OC)C#N)O[Si](C)(C)C(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 20.58 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/29/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "401" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 9.43e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" - } - amount { - moles { - value: 0.00113 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)Br)C#N" - } - amount { - moles { - value: 0.000943 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 9.43e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 9.43e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Trial reaction for Phil WalkerPdOAc2 (0.021 g, 0.09 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.045 g, 0.09 mmol) were added in one portion to a degassed solution of 5-bromo-2-methoxybenzonitrile (0.200 g, 0.94 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (0.214 g, 1.13 mmol) and cesium carbonate (0.461 g, 1.41 mmol) in toluene (10 mL) at 20C in a microwave vial. The reaction mixture was diluted with EtOAc (20 mL) and water (20 mL). The biphasic mixture was filtered through celite. The organic layer was separated and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was filtered and dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was evaporated and was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-5-(2-(tert-butyldimethylsilyloxy)propylamino)-2-methoxybenzonitrile (0.188 g, 62.2 %) as a ge oil. repated on a lager scale in RSL - See EN04063-90" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@H](CNC1=CC(=C(C=C1)OC)C#N)O[Si](C)(C)C(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 62.19 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/28/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "403" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00691 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N" - } - amount { - moles { - value: 0.00645 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=NC=C(C=N1)Br" - } - amount { - moles { - value: 0.00461 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000461 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00023 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "The methyl 5-bromopyrimidine-2-carboxylate (1 g, 4.61 mmol), tert-butyl carbamate (0.756 g, 6.45 mmol), diacetoxypalladium (0.052 g, 0.23 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.267 g, 0.46 mmol), cesium carbonate (2.252 g, 6.91 mmol) and dioxane (15 mL) were placed and sealed into a microwave tube. The reaction was degased, purged with argon and heated to 90 C (oil bath) over a period of 7 hours . The mixture was poured in water, extracted with ethyl acetate (x2). The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel 15-40m eluting with 5 to 50% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford methyl 5-(tert-butoxycarbonylamino)pyrimidine-2-carboxylate (0.710 g, 60.8 %) as a white so" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC1=CN=C(N=C1)C(=O)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 60.84 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/02/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "404" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0276 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.05 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N" - } - amount { - moles { - value: 0.0258 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=NC=C(C=N1)Br" - } - amount { - moles { - value: 0.0184 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00184 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000922 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "The methyl 5-bromopyrimidine-2-carboxylate (4 g, 18.43 mmol), tert-butyl carbamate (3.02 g, 25.80 mmol), diacetoxypalladium (0.207 g, 0.92 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.066 g, 1.84 mmol), cesium carbonate (9.01 g, 27.65 mmol) and dioxane (50 mL) were placed and sealed into a microwave tube. The reaction was degased, purged with argon and heated to 90 C (oil bath) over a period of 7 hours . The mixture was poured in water, extracted with ethyl acetate (x2). The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel 15-40m eluting with 5 to 50% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford methyl 5-(tert-butoxycarbonylamino)pyrimidine-2-carboxylate (3.00 g, 64.3 %) as a beige so" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC1=CN=C(N=C1)C(=O)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 64.27 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/09/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "406" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00105 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.0007 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CSC(=N1)C2CN(CC3=C(O2)N=C(C=C3)Cl)C" - } - amount { - moles { - value: 0.0007 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 7e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 7e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To 8-chloro-4-methyl-2-(4-methylthiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (207 mg, 0.70 mmol) in DME (3 mL) were 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (143 mg, 0.70 mmol), cesium carbonate (342 mg, 1.05 mmol), 2-(Dicyclohexylphosphino)biphenyl (24.53 mg, 0.07 mmol) and Palladium acetate (15.71 mg, 0.07 mmol) added. The reaction was heated to 110C for 60 min under N2 atmosphere. The solids were filtered off and washed with DCM, the solvents were evaporated and the crude product was purified by silica flash chromatography using DCM : [DCM:MeOH:NH3 = 90:10:1] = 100:0 to 35:65 as gradient. The title compound was obtained as yellow foam. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CSC(=N1)C2CN(CC3=C(O2)N=C(C=C3)NC4=NC(=C(C=C4)C5=CN(N=C5)C)OC)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 56.41 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/12/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "407" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.002 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(OC(=N1)N)C" - } - amount { - moles { - value: 0.001 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.001 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 140.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: Repeat of experiment EN04881-63 in an attempt to improve isolated yield using different normal phase eluent system (isolation was problematic for EN04881-63).Pd2(dba)3 (22.89 mg, 0.025 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (43.4 mg, 0.075 mmol), 2,4-dichloropyridine (148 mg, 1.00 mmol), cesium carbonate (652 mg, 2.00 mmol) and 4,5-dimethyloxazol-2-amine (112 mg, 1.00 mmol) were added to an oven dried microwave vial, the vial was capped and placed under an inert atmosphere, dioxane (4 mL) was added and the resulting mixture was heated to 140 C for 1 h by microwave irradiation under a nitrogen atmosphere.The crude product was purified by flash silica chromatography, elution gradient 0 to 3% methanolic ammmonia (7 M) in DCM. Pure fractions were evaporated to dryness to afford P1 as a brown solid. The product was further purified by crystallisation from hot DCMMeOH to afford N-(4-chloropyridin-2-yl)-4,5-dimethyloxazol-2-amine (34.0 mg, 15.20 %) as a besolid. Conclusion: A relatively low yield of the desired product was isolated here, it may be possible to increase the above yield at higher temperature or by using excess amine as electron rich oxazoles are prone to decomposition. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(OC(=N1)NC2=NC=CC(=C2)Cl)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 15.2 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/06/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "408" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.002 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(OC(=N1)N)C" - } - amount { - moles { - value: 0.001 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.001 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 140.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: To find out which strates are efficient coupling partners, is there a robust link between how electron poor the strate is and yield i.e. more electron poor aminooxazoles produce greater yields.Pd2(dba)3 (22.89 mg, 0.025 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (43.4 mg, 0.075 mmol), 2,4-dichloropyridine (148 mg, 1.00 mmol), cesium carbonate (652 mg, 2.00 mmol) and 4,5-dimethyloxazol-2-amine (112 mg, 1.00 mmol) were added to an oven dried microwave vial, the vial was capped and placed under an inert atmosphere, dioxane (4 mL) was added and the resulting mixture was heated to 140 C for 1 h by microwave irradiation under a nitrogen atmosphere.The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in heptane. Pure fractions were evaporated to dryness to afford N-(4-chloropyridin-2-yl)-4,5-dimethyloxazol-2-amine (34.0 mg, 15.20 %) as a pale yellow solid. Conclusion: The dimethyl stituted 2-aminooxazole (relaty electron rich) produces more coupled product than the unstituted 2-aminooxazole. Of the 2-aminooxazoles tested thus far the 4- and 5-ester stituted aminooxazoles are the most efficient coupling partners.Note: A run at T= 160 C may be beneficial, an increase in yield was seen for the ester stituted 2-aminooxazole under these more forcing conditions." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(OC(=N1)NC2=NC=CC(=C2)Cl)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 15.2 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/07/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "409" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000704 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=CN=C(C=C2)N" - } - amount { - moles { - value: 0.00047 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.00047 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 4.7e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.7e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (129 mg, 0.47 mmol), 5-(4-methyl-1H-imidazol-1-yl)pyridin-2-amine (82 mg, 0.47 mmol), PALLADIUM(II) ACETATE (10.54 mg, 0.05 mmol), 2-(DICYCLOHEXYLPHOSPHINO)BIPHENYL (16.46 mg, 0.05 mmol) and Cs2CO3 (229 mg, 0.70 mmol) were weighed into a microwave vial which was capped and flushed with argon. DME (5 mL) was added and the mixture was heated to 100C in a microwave apparatus for 2 h. The mixture was filtered and purified by column chromatography on Silica using gradient elution with increasing concentration of methanol, from 0 to 6 %, in dichloromethane to give(R)-4-methyl-N-(5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (69.5 mg, 35.9 %)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=CN=C(C=C2)NC3=NC4=C(CN(C[C@H](O4)C5=CC=CC=C5)C)C=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 35.89 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/08/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "410" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000763 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=CN=C(C=C2)N" - } - amount { - moles { - value: 0.000509 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC(=NC2=C1CN(CC(O2)CC(F)(F)F)C)Cl" - } - amount { - moles { - value: 0.000509 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 5.09e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 5.09e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To 8-chloro-4,6-dimethyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (300 mg, 0.51 mmol) in DME (4 mL) were 5-(4-methyl-1H-imidazol-1-yl)pyridin-2-amine (89 mg, 0.51 mmol), cesium carbonate (249 mg, 0.76 mmol), 2-(Dicyclohexylphosphino)biphenyl (17.84 mg, 0.05 mmol) and Palladium acetate (11.43 mg, 0.05 mmol) added. The reaction was heated to 110C for 3*90min. The solids were filtered of and washed with DCM and IPA and discarded. The solvents were evaporated and the crude product was purified using first flash chromatography, 0-7% MeOH in DCM and the prepHPLC yielding 4,6-dimethyl-N-(5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (34.0 mg, 15.45 %)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CC(=NC2=C1CN(CC(O2)CC(F)(F)F)C)NC3=NC=C(C=C3)N4C=C(N=C4)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 15.45 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/08/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "411" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0365 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.035 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.028 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(O1)C=CC=C2Cl" - } - amount { - moles { - value: 0.028 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.0028 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.0014 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 95.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "tert-butyl piperazine-1-carboxylate (5.22 g, 28.04 mmol), ethyl 4-chlorobenzofuran-2-carboxylate (6.3 g, 28.04 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (1.337 g, 2.80 mmol), Tris(dibenzylideneacetone)dipalladium(0) (1.284 g, 1.40 mmol) and CESIUM CARBONATE (11.88 g, 36.46 mmol) were heated under argon to 95 C 14:51:42 overnight, LC showed no s.m. EN03969-25-001. The mixture was allowed to cool to rt, diluted with EtOAc (35 mL) and filtered through a pad of Celite, washed with EtOAc (total of 100 mL). The filterate was collected and the solvent was removed by rotary evaporation.nbsp;The crude product was treated with diisopropylether under stirring at rt for 4 days, the mixture was filterered and washed with diisopropylether. The diisopropyletherphase was concentrated to give 3.6 g. The solid was treated with MeOH under stirring at rt for 4 h, filtrated, washed with MeOH, still not clear solution. The solid was vacuumdried at 40 C over night to give 7.6 g. The MeOH-mas filterered through a process K200 filter, the formed solution was concentrated to give 1.4 g.No pure product in any of the solids, were combined (12.6 g) and dissolved in CH2Cl2 and put on silica (200 g) using 1. CH2Cl2 (500 mL), 2. EtOAc (400 mL) as eluent. Fr. 5-6 were combined and concentrated to give EN03969-25-002 (10.6 g, 28.3 mmol, 101 %).To the brownish solid was added ether (40 mL) and the slurry was stirred at 35 C for 5-10 min. The now grey solid was filtered off, rinsed with 4x20 mL ether and dried under vacuum at 30 C o.n, yieldingnbsp;EN03969-25-003 (6.7 g, 17.89 mmol, 63.8 %).44 mg of EN03969-25-003 was sent to bStefan Elofsson bat Analytical Services and OA Support teamb bfor purity-assay (95 %), see report.EN03969-25-003 was delivered to CM Sdertlje in can: b3" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(C=CC=C2O1)N3CCN(CC3)C(=O)OC(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 63.8 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/29/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "412" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00142 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCCN1" - } - amount { - moles { - value: 0.00189 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C=C1Cl)Br)C#N" - } - amount { - moles { - value: 0.000947 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 9.47e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 4.74e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Tris(dibenzylideneacetone)dipalladium (0) (43.4 mg, 0.05 mmol) and rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (59.0 mg, 0.09 mmol) were added to a mixture of 2-bromo-4-chlorobenzonitrile (205 mg, 0.95 mmol), Cesium carbonate (463 mg, 1.42 mmol) and Piperazine (163 mg, 1.89 mmol) in dioxane (3 mL). Reaction vessel was placed in an oil bath set to 90 C 2.45pm.LCMS on shows large product peak (222).Cooled, filtered through a silica plug, washing with EtOAc until filtrate is clear. Crude NMR is very messy, target deprioritized. Discarded." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CN(CCN1)C2=C(C=CC(=C2)Cl)C#N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/14/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "413" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00187 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCCN1" - } - amount { - moles { - value: 0.0025 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C=C1F)Br)C#N" - } - amount { - moles { - value: 0.00125 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000125 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 6.25e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Tris(dibenzylideneacetone)dipalladium (0) (57.2 mg, 0.06 mmol) and rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (78 mg, 0.12 mmol) were added to a mixture of 2-bromo-4-fluorobenzonitrile (250 mg, 1.25 mmol), Cesium carbonate (611 mg, 1.87 mmol) and Piperazine (215 mg, 2.50 mmol) in dioxane (3 mL). Reaction vessel was placed in an oil bath at 90 C 4pm.LCMS on shows several peaks. Larger peak corresponding to displacement of F by piperazine (MW266) than for desired product (205).Discarded" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CN(CCN1)C2=C(C=CC(=C2)F)C#N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/15/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "414" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)[O-].[Na+]" - } - amount { - moles { - value: 3.05e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=COC(=N1)N" - } - amount { - moles { - value: 0.00112 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Br" - } - amount { - moles { - value: 0.00102 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.05e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.27e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 170.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: Improve yield of the desired product starting from the bromoaryl compound.To a flask containing 2-bromo-4-chloropyridine (196 mg, 1.02 mmol), sodium phenolate (177 mg, 1.52 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (11.63 mg, 0.01 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (17.64 mg, 0.03 mmol) (Xantphos), was added degassed dioxane (4 mL) and the mixture allowed to stir under nitrogen atmosphere for 5 min. To this solution was added oxazol-2-amine (94 mg, 1.12 mmol) and the reaction mixture was heated to 170 Cnbsp;for 2 h under microwave irradiation.Methanol was added to the crude reaction mixture together with silica (2 g), the solvent was removed under reduced pressure and the remaining residue was placed in dry load tube prior to chromatography. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to afford N-(4-chloropyridin-2-yl)oxazol-2-ami1.000 mg, 0.503 %) as a beige solid. Conclusion: Trace amount of the desired product isolated." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)NC2=NC=CO2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.5 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/11/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "415" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.002 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=COC(=N1)N" - } - amount { - moles { - value: 0.001 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Br" - } - amount { - moles { - value: 0.001 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 140.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: To find out if the 2-bromopyridine is a more efficient coupling partner than the chloro analogue.Pd2(dba)3 (22.89 mg, 0.025 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (43.4 mg, 0.075 mmol), 2-bromo-4-chloropyridine (192 mg, 1.00 mmol), cesium carbonate (652 mg, 2.00 mmol) and oxazol-2-amine (84 mg, 1.00 mmol) were added to an oven dried microwave vial, the vial was capped and placed under an inert atmosphere, dioxane (4 mL) was added and the resulting mixture was heated at 140 C for 1 h by microwave irradiation under a nitrogen atmosphere.The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in heptane. Pure fractions were evaporated to dryness to afford N-(4-chloropyridin-2-yl)oxazol-2-amine (15.00 mg, 7.67 %) as a white solid. Conclusion: A slightly improved yield of the desired product was formed with respect to the 2,4-dichloropyridine strate, however the difference could not be taken to be significant. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)NC2=NC=CO2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 7.67 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/05/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "416" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00203 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)[N+](=O)[O-])N" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000122 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000101 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;3-Nitroaniline (140 mg, 1.01 mmol), 2,4-dichloropyridine (150 mg, 1.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (70.4 mg, 0.12 mmol) and cesium carbonate (660 mg, 2.03 mmol) were stirred in dioxane (5 mL).nbsp;The mixture was purged with nitrogen for 10 minutes.nbsp;Palladium(II) acetate (22.76 mg, 0.10 mmol) was added and the mixture heated at 100 C for 1.5h.nbsp;The mixture was cooled, filtered and concentrated.nbsp;The crude product was purified by flash silica chromatography, eluting with 1% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-chloro-N-(3-nitrophenyl)pyridin-2-amine (121 mg, 47.8 %) as a yellow solid. nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)[N+](=O)[O-])NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 47.82 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/06/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "418" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00025 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N" - } - amount { - moles { - value: 0.000208 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CCN(CC1)C2=C(C=C(C(=C2)OC)N)Br" - } - amount { - moles { - value: 0.000167 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.33e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.67e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a suspension of 5-bromo-2-methoxy-4-(4-methylpiperazin-1-yl)aniline (50 mg, 0.17 mmol) in dioxane (4 mL) was added tert-butyl carbamate (24.39 mg, 0.21 mmol), cesium carbonate (81 mg, 0.25 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (19.27 mg, 0.03 mmol). The resulting suspension was degassed and Palladium(II) acetate (3.74 mg, 0.02 mmol) was added. The mixture was degassed and stirred at 120 C for 2 hours in the CEM microwave, then allowed to cool to ambient temperature. The reaction was incomplete so further cesium carbonate (81 mg, 0.25 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (19.27 mg, 0.03 mmol) and diacetoxyzinc (30.6 mg, 0.17 mmol) were added and the mixture was degassed. Further Palladium(II) acetate (3.74 mg, 0.02 mmol) was added, and the mixture was degassed and stirred at 130 C for 1 hour in the CEM microwave, then allowed to cool to amibient temperature. TLC (10% MeOH in DCM + 1% cNH3 (aq)) suggests bromo SM has been consumed but no evidence of desiret having been formed. UPLC shows only oxidised xantphos.Reaction stopped" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC1=C(C=C(C(=C1)N)OC)N2CCN(CC2)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/17/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "419" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000177 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCC(CC1)OC2=CC=CC(=C2)N" - } - amount { - moles { - value: 0.000177 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)NC(=O)C2=CC3=C(C=C2)OCCO3)NC(=O)C4=CN=C(C=C4)Cl" - } - amount { - moles { - value: 0.000118 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.08e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 3.54e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of 6-chloro-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)nicotinamide (50 mg, 0.12 mmol),3-(1-methylpiperidin-4-yloxy)aniline (36.5 mg, 0.18 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4.10 mg, 7.08 mol),TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (3.24 mg, 3.54 mol),sodium 2-methylpropan-2-olate (17.01 mg, 0.18 mmol) in toluene (2 mL)IPA (0.500 mL)was degassed with nitrogen and heated at reflux for 18 hours.The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with water (100 mL), The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% MeOH7MNH3 in EtOAc. lcms still showed 30% unreacted aniline. Fractions evaporated.The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (cont3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-(3-(1-methylpiperidin-4-yloxy)phenylamino)nicotinamide (23.00 mg, 32.8 %) as a cream solid. nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)NC(=O)C2=CC3=C(C=C2)OCCO3)NC(=O)C4=CN=C(C=C4)NC5=CC(=CC=C5)OC6CCN(CC6)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 32.84 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/13/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "420" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000177 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN(C)CC1=CC(=CC=C1)N" - } - amount { - moles { - value: 0.000177 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)NC(=O)C2=CC3=C(C=C2)OCCO3)NC(=O)C4=CN=C(C=C4)Cl" - } - amount { - moles { - value: 0.000118 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.08e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 3.54e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of 6-chloro-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)nicotinamide (50 mg, 0.12 mmol),3-((dimethylamino)methyl)aniline (26.6 mg, 0.18 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4.10 mg, 7.08 mol),TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (3.24 mg, 3.54 mol),sodium 2-methylpropan-2-olate (17.01 mg, 0.18 mmol) in toluene (2 mL)IPA (0.500 mL)was degassed with nitrogen and heated at reflux for 18 hours.The reaction mixture was filtered and filtered solid washed with ethyl acetate. The organic filtrate was washed with water (50ml), and organic layer dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-me6-(3-((dimethylamino)methyl)phenylamino)nicotinamide (24.60 mg, 38.8 %) as a cream solid. nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)NC(=O)C2=CC3=C(C=C2)OCCO3)NC(=O)C4=CN=C(C=C4)NC5=CC=CC(=C5)CN(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 38.79 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/21/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "421" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000248 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C1CCN(C1)C2=CC=CC(=C2)N" - } - amount { - moles { - value: 0.000248 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)NC(=O)C2=CC3=C(C=C2)OCCO3)NC(=O)C4=CN=C(C=C4)Cl" - } - amount { - moles { - value: 0.000165 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 9.91e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 4.95e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of 6-chloro-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)nicotinamide (70 mg, 0.17 mmol),[Reactants],(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (5.73 mg, 9.91 mol),TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (4.54 mg, 4.95 mol),sodium 2-methylpropan-2-olate (23.81 mg, 0.25 mmol) in toluene (4 mL)IPA (1.000 mL)was degassed with nitrogen and heated at reflux for 18 hours.The reaction mixture was filtered and filtered solid washed with ethyl acetate. The organic filtrate was washed with water (50ml), and organic layer dried over Na2SO4, filtered and evaporated.The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)-6-(3-(3-(dimethylamino)pyrrolidylamino)nicotinamide (10.00 mg, 10.22 %) as a cream solid. nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)NC(=O)C2=CC3=C(C=C2)OCCO3)NC(=O)C4=CN=C(C=C4)NC5=CC(=CC=C5)N6CCC(C6)N(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 10.22 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/22/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "422" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.002 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=COC(=N1)N" - } - amount { - moles { - value: 0.001 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.001 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 140.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: To find out which strates are efficient coupling partners, is there a robust link between how electron poor the strate is and yield i.e. more electron poor aminooxazoles produce greater yields.Pd2(dba)3 (22.89 mg, 0.025 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (43.4 mg, 0.075 mmol), 2,4-dichloropyridine (148 mg, 1.00 mmol), cesium carbonate (652 mg, 2.00 mmol) and 4-methyloxazol-2-amine (98 mg, 1.00 mmol) were added to an oven dried microwave vial, the vial was capped and placed under an inert atmosphere, dioxane (4 mL) was added and the resulting mixture was heated to 140 C for 1 h by microwave irradiation under a nitrogen atmosphere.Dichloromethane (10 mL) was added to the crude reaction mixture and the mixture was adsorbed onto silica gel. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in heptane. Pure fractions were evaporated to dryness to afford N-(4-chloropyridin-2-yl)-4-methyloxazol-2-amine (59.0 mg.1 %) as a cream solid. Note: a further 34 mg of impure product came off the column early and so the yield for this reaction is probably closer to 35% had the purification been efficient.Conclusion: Somewhat surprisingly the methyl stituted amino-oxazole gave significant amounts of coupled product. It appears that certain moderately elctron rich strates may also undergo relatively efficient coupling." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=COC(=N1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 28.14 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/24/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "423" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00371 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0075 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CO[C@@H]1CCNC1" - } - amount { - moles { - value: 0.00247 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=NC=C1Br)Br" - } - amount { - moles { - value: 0.00272 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000124 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 4.94e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of 3,5-dibromopyridine (0.644 g, 2.72 mmol), (R)-3-methoxypyrrolidine (0.25 g, 2.47 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (0.045 g, 0.05 mmol), sodium 2-methylpropan-2-olate (0.356 g, 3.71 mmol) and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.077 g, 0.12 mmol) in degassed toluene (7.5 ml) was sealed into a microwave tube and stirred for 16 hours at 90 C. The reaction was completed.After cooling, an aqueous solution of Na2CO3 was added. Extraction with DCM (twice). The organic layers were dried over MgSO4 and evaporated iin vacuoi to give the crude product as an orange oil. PBO-04062-54-01 It was purified by chromatography (Merck cartridge SVF D26 - SI60 15-40 m - 30 g) on silica gel eluting with EtOAc 0 to 25% in petroleum ether. Pure collected fractions were evaporated to afford (R)-3-bromo-5-(3-methoxypyrrolidin-1-yl)pyridine (0.325 g, 51.1 %) as a yellow oil. PBO-04062-5" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CO[C@@H]1CCN(C1)C2=CC(=CN=C2)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 51.14 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/05/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "424" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00534 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.15 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" - } - amount { - moles { - value: 0.0667 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" - } - amount { - moles { - value: 0.0534 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.00534 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00534 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "PdOAc2 (1.198 g, 5.34 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (2.54 g, 5.34 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (15.00 g, 53.36 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (12.63 g, 66.70 mmol) and cesium carbonate (26.1 g, 80.04 mmol) in toluene (150 mL) at 120C under nitrogen. The resulting suspension was stirred at 120 C for 16 hours. The reaction was incomplete so the reaction mixture was stirred for a further 24 hours at 120C. The reaction mixture was cooled and diluted with EtOAc (150 mL) and water (150 mL). The biphasic mixture was filtered through celite. The organic layer was separated and washed sequentially with water (150 mL) and saturated brine (150 mL). The organic layer was filtered and dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was evaporated and was purified by flash silica chromatography*, elution gradient 0 to 20% EtOAc in isohexre fractions were evaporated to dryness to affordnbsp;(R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)-3-fluoroaniline (11.7 g, 30.0 mmol, 56.3 %) as a orange oil. Fractions that contained small amounts of impurities were also combined and were evaporated to dryness to affordnbsp;(R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)-3-fluoroaniline (2.5 g, 6.42 mmol, 12.03 %) as a dark orange oil." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@H](CNC1=CC(=C(C=C1)OCC2=CC=CC=C2)F)O[Si](C)(C)C(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 68.31 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/04/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "425" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000356 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" - } - amount { - moles { - value: 0.00356 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" - } - amount { - moles { - value: 0.00356 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.000356 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000356 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "PdOAc2 (0.080 g, 0.36 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.170 g, 0.36 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (1 g, 3.56 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (0.674 g, 3.56 mmol) and cesium carbonate (1.739 g, 5.34 mmol) in toluene (20 mL) at 120C under nitrogen. The resulting suspension was stirred at 120 C for 16 hours. The reaction mixture was diluted with EtOAc (20 mL) and water (20 mL). The biphasic mixture was filtered through celite. The organic layer was separated and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was filtered and dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was evaporated and was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)-3-fluoro(0.851 g, 61.4 %) as a orange oil. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@H](CNC1=CC(=C(C=C1)OCC2=CC=CC=C2)F)O[Si](C)(C)C(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 61.41 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/13/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "427" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000356 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" - } - amount { - moles { - value: 0.00427 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" - } - amount { - moles { - value: 0.00356 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.000356 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000356 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "PdOAc2 (0.080 g, 0.36 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.170 g, 0.36 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (1 g, 3.56 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (0.808 g, 4.27 mmol) and cesium carbonate (1.739 g, 5.34 mmol) in anhydrous dioxane (20 mL) at 20C in a microwave vial. The microwave vial was sealed and the reaction was heated to 120 C for 10 hours in the microwave reactor and cooled to RT. LCMS indicates mainly starting material bbNo further action was ta" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@H](CNC1=CC(=C(C=C1)OCC2=CC=CC=C2)F)O[Si](C)(C)C(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/17/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "428" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00356 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.15 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" - } - amount { - moles { - value: 0.0427 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" - } - amount { - moles { - value: 0.0356 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.00356 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00356 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "PdOAc2 (0.799 g, 3.56 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (1.696 g, 3.56 mmol) were added in one portion tonbsp;a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (10.00 g, 35.57 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (8.08 g, 42.69 mmol) and cesium carbonate (17.39 g, 53.36 mmol) in toluene (150 mL) at 20Cnbsp;under nitrogen. The resulting suspension was stirred at 120 C for 35 hours. The reaction mixture was diluted with EtOAc (150 mL)nbsp;and water (150 mL) and the biphasic mixture was filtered through celite. The organic layer was separated and washed sequentially with water (150 mL) and saturated brine (150 mL). The organic layer was evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)-3-fluoroaniline (9.38 g, 67.7 %) as a orange b" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@H](CNC1=CC(=C(C=C1)OCC2=CC=CC=C2)F)O[Si](C)(C)C(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 67.69 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/20/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "429" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00534 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.2 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" - } - amount { - moles { - value: 0.0667 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" - } - amount { - moles { - value: 0.0534 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.00534 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00534 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "PdOAc2 (1.198 g, 5.34 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (2.54 g, 5.34 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (15.00 g, 53.36 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (12.63 g, 66.70 mmol) and cesium carbonate (26.1 g, 80.04 mmol) in toluene (200 mL) at 120C under nitrogen. The resulting suspension was stirred at 120 C for 16 hours under nitrogen. The reaction was incomplete so the reaction mixture was stirred for a further 24 hours at 120C. The reaction mixture was cooled and diluted with EtOAc (150 mL) and water (150 mL). The biphasic mixture was filtered through celite. The organic layer was separated and washed sequentially with water (150 mL) and saturated brine (150 mL). The organic layer was filtered and dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography*, elution gradient 0 to 20% EtOAc in isohexane.ons were evaporated to dryness to affordnbsp;(R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)-3-fluoroanilinenbsp;(12.2 g, 31.3 mmol, 58.7 %) as a orange oil. Fractions that contained small amounts of impurities were also combined and were evaporated to dryness to affordnbsp;(R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)-3-fluoroaniline (2.05 g, 5.26 mmol, 9.86 %) as a dark orange oil." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@H](CNC1=CC(=C(C=C1)OCC2=CC=CC=C2)F)O[Si](C)(C)C(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 68.55 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/04/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "430" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000178 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" - } - amount { - moles { - value: 0.00178 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" - } - amount { - moles { - value: 0.00178 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.000178 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000178 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "PdOAc2 (0.040 g, 0.18 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.085 g, 0.18 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (0.500 g, 1.78 mmol), [Reactants] and cesium carbonate (0.869 g, 2.67 mmol) in toluene (15 mL) at 20C in a microwave vial. The microwave vial was sealed and the reaction was heated to 120 C for 12 hours in the microwave reactor and cooled to RT. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was filtered and dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was taken up in DCM (20 mL) and an isoluble white solid EN04063-43-1 (401 mg)nbsp;was filtered off (not product). The filtrate was evaporated and was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-4-(benzyloxy)-N-(2-(tedimethylsilyloxy)propyl)-3-fluoroaniline (0.482 g, 69.6 %) as a yellow oil. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@H](CNC1=CC(=C(C=C1)OCC2=CC=CC=C2)F)O[Si](C)(C)C(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 69.56 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/11/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "431" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00356 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.15 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" - } - amount { - moles { - value: 0.0427 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" - } - amount { - moles { - value: 0.0356 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.00356 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00356 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "PdOAc2 (0.799 g, 3.56 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (1.696 g, 3.56 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (10.00 g, 35.57 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (8.08 g, 42.69 mmol) and cesium carbonate (17.39 g, 53.36 mmol) in toluene (150 mL) at 120C under nitrogen. The resulting suspension was stirred at 120 C for 16 hours. The reaction was incomplete so the reaction mixture was stirred for a further 24 hours at 120C. The reaction mixture was diluted with EtOAc (150 mL) and water (150 mL). The biphasic mixture was filtered through celite. The organic layer was separated and washed sequentially with water (150 mL) and saturated brine (150 mL). The organic layer was filtered and dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was evaporated and was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fe evaporated to dryness to afford (R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)-3-fluoroaniline (8.98 g, 64.8 %) as a orange oil. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@H](CNC1=CC(=C(C=C1)OCC2=CC=CC=C2)F)O[Si](C)(C)C(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 64.8 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/18/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "432" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00178 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.12 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" - } - amount { - moles { - value: 0.0178 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" - } - amount { - moles { - value: 0.0178 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.00178 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00178 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "PdOAc2 (0.399 g, 1.78 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.848 g, 1.78 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (5.00 g, 17.79 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (3.37 g, 17.79 mmol) and cesium carbonate (8.69 g, 26.68 mmol) in toluene (120 mL) at 20C in a microwave vial. The microwave vial was sealed and the reaction was heated to 120 C for 10 hours in the microwave reactor and cooled to RT.b bnbsp;Split into 5 x 20 ml mw vials such as in each was:PdOAc2 (0.080 g, 0.36 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.170 g, 0.36 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (1.000 g, 3.56 mmol), Reactant 2 (1.143 g, 3.56 mmol) and cesium carbonate (1.739 g, 5.34 mmol) in toluene (20 mL) at 20C in a microwave vial. The microwave vial was sealed and the reaction was heated to 120 furs in the microwave reactor and cooled to RT.b bThe reaction was incomplete so the reaction was heated to 120 C for 10 hours in the microwave reactor and cooled to RT.b bThe reaction mixtures were combined and diluted with EtOAc (100 mL), and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was filtered and dried over Na2SO4. The filtrate was washed sequentially with water (100 mL), and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)-3-fluoroaniline (5.10 g, 73.6 %) as a orange oil. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@H](CNC1=CC(=C(C=C1)OCC2=CC=CC=C2)F)O[Si](C)(C)C(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 73.6 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/14/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "433" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00356 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.1 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" - } - amount { - moles { - value: 0.0356 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" - } - amount { - moles { - value: 0.0356 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.00356 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00356 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "PdOAc2 (0.799 g, 3.56 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (1.696 g, 3.56 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (10.00 g, 35.57 mmol), 1-(benzyloxy)-4-bromo-2-fluorobenzene (10.00 g, 35.57 mmol) and cesium carbonate (17.39 g, 53.36 mmol) in toluene (100 mL) at 20C in a microwave vial. The microwave vial was sealed and the reaction was heated to 120 C for 10 hours in the microwave reactor and cooled to RT. nbsp;uSplit into 10 x 20 ml mw vials such as in each was:uPdOAc2 (0.080 g, 0.36 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.170 g, 0.36 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (1.000 g, 3.56 mmol), 2-(tert-butyldimethylsilyloxy)ethanamine (0.832 g, 3.56 mmol) and cesium carbonate (1.739 g, 5.34 mmol) in toluene (20 mL) at 20C in a microwave vial. The microwave vial was sealed and the reacted to 120 C for 10 hours in the microwave reactor and cooled to RT. The reaction mixtures were combined and diluted with EtOAc (150 mL) and water (150 mL). The biphasic mixture was filtered through celite. The organic layer was separated and washed sequentially with water (150 mL) and saturated brine (150 mL). The crude product was evaporated and was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)-3-fluoroaniline (10.10 g, 72.9 %) as a orange oil. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@H](CNC1=CC(=C(C=C1)OCC2=CC=CC=C2)F)O[Si](C)(C)C(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 72.88 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/12/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "434" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000551 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" - } - amount { - moles { - value: 0.00551 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" - } - amount { - moles { - value: 0.00551 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.000551 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000551 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "PdOAc2 (0.124 g, 0.55 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.263 g, 0.55 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (1.550 g, 5.51 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (1.044 g, 5.51 mmol) and cesium carbonate (2.69 g, 8.27 mmol) in toluene (20 mL) at 20C in a microwave vial. The microwave vial was sealed and the reaction was heated to 120 C for 10 hours in the microwave reactor and cooled to RT.b bThe reaction was incomplete so the reaction was heated to 120 C for 2 hours in the microwave reactor and cooled to RT. The reaction was incomplete and further PdOAc2 (0.124 g, 0.55 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.263 g, 0.55 mmol) was added and the suspension was stirred at 120 C for a further 6 hours in the microwave reactor and cooled to RT. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (50 mL) and (50 mL). The organic layer was filtered and dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was taken up in DCM (20 mL) and an isoluble white solid EN04063-48-1 (1.45 g, 3.72 mmol, 67.5 %)nbsp;was filtered off (not product). The filtrate was evaporated and was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)-3-fluoroaniline (1.450 g, 67.5 %) as a yellow oil.b bReaction is slow if done on 1.5g scale in a 20 ml reaction vial. Next time do 1g reaction per 20 ml vial. See EN04063-50" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@H](CNC1=CC(=C(C=C1)OCC2=CC=CC=C2)F)O[Si](C)(C)C(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 67.5 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/13/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "435" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0019 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.075 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" - } - amount { - moles { - value: 0.0228 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)COC2=CC=C(C=C2)Br" - } - amount { - moles { - value: 0.019 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.0019 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.0019 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;Palladium(II) acetate (0.427 g, 1.90 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.906 g, 1.90 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromobenzene (5 g, 19.00 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (4.32 g, 22.80 mmol) and Cesium carbonate (2.281 mL, 28.50 mmol) in toluene (75 mL) at 20C under nitrogen. The resulting suspension was stirred at 120C for 72 hours. The reaction mixture was diluted with EtOAc (150mL) and water (150mL) and the biphasic mixture was filtered through celite. The organic layer was seperated and washed sequentially with water (150mL) and saturated brine (150mL). The organic layer was evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)aniline (4.60 g, 65.1 %) as an orange " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@H](CNC1=CC=C(C=C1)OCC2=CC=CC=C2)O[Si](C)(C)C(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 65.15 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/03/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "437" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00342 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.2 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" - } - amount { - moles { - value: 0.041 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)COC2=CC=C(C=C2)Br" - } - amount { - moles { - value: 0.0342 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.00342 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00342 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Reaction carried out by Phill Walker in RSL EN04482-07-01 as follows:PdOAc2 (0.768 g, 3.42 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (1.631 g, 3.42 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromobenzene (9.00 g, 34.20 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (7.77 g, 41.04 mmol) and cesium carbonate (16.72 g, 51.31 mmol) in toluene (200 mL) at 20C in a 300 ml Milestone microwave reactor. The microwave reactor was sealed and the reaction was heated to 120 C for 10 hours in and cooled to RT. LCMS indicated some product but mainly sm so another aliquot of catalyst was added and put back on for 10 hours at 130C. LCMS-2 indicated complete reaction. Handed back to chemist for work-up.WorkupThe reaction mixture was diluted with EtOAc (100 mL) and was filtered. The solid (inorganics and catalyst) was washed with ethylacete (50 mL). The filtrates were combined and washed with water (1 x 150 mL) and brimL). The crude product was evaporated and was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)propyl)aniline (2.400 g, 18.88 %) as a orange oil. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@H](CNC1=CC=C(C=C1)OCC2=CC=CC=C2)O[Si](C)(C)C(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 18.88 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/28/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "438" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.002 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=C(N=C(O1)N)C(F)(F)F" - } - amount { - moles { - value: 0.001 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.001 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 140.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Repeat of EN04881-41 to get pure sample of product in potentially higher isolated yield.cesium carbonate (652 mg, 2.00 mmol), Pd2(dba)3 (22.89 mg, 0.025 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (43.4 mg, 0.075 mmol), 4-(trifluoromethyl)oxazol-2-amine (152 mg, 1.00 mmol) and 2,4-dichloropyridine (148 mg, 1.00 mmol) were added to an oven dried microwave vial, the vial was capped and placed under an inert atmosphere, dioxane (4 mL) was added and the resulting mixture was heated at 140 C for 1 h by microwave irradiation under a nitrogen atmosphere.Dichloromethane (10 mL) was added to the reaction mixture and the crude reaction mixture was adsorbed onto silica gel. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in heptane. Pure fractions were evaporated to dryness to afford N-(4-chloropyridin-2-yl)-4-(trifluoromethyl)oxazol-2-amine (46.0 mg, 17.45 %) as a pale yellow solid. Regioisomeric assignment confirmed by NOESY expent (see sample P1 analytical data for details)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)NC2=NC(=CO2)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 17.45 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/18/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "439" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNC(=O)CN1" - } - amount { - moles { - value: 0.000499 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1F)Br" - } - amount { - moles { - value: 0.000499 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 4.99e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.99e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (11.21 mg, 0.05 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (28.9 mg, 0.05 mmol) were dissolved in toluene (0.5 mL) under nitrogen. Stirred at 50C for 30min.sodium 2-methylpropan-2-olate (96 mg, 1.00 mmol) and piperazin-2-one (50 mg, 0.50 mmol) were added to a second microwave vial and inerted with nitrogen. 1-bromo-4-fluorobenzene (0.055 mL, 0.50 mmol) and toluene (0.500 mL) were added.The catalyst solution wad added to the reaction mixture and the resulting solution was stirred at 100C for 1h in the microwave. No reaction. Then 150C for 1h, still no reaction. The reaction was discarded." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CN(CC(=O)N1)C2=CC=C(C=C2)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/29/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "440" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNC(=O)CN1" - } - amount { - moles { - value: 0.000499 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1F)Br" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 4.99e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.99e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (11.21 mg, 0.05 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (28.9 mg, 0.05 mmol) were dissolved in toluene (0.5 mL) under nitrogen. Stirred at 50C for 30min.sodium 2-methylpropan-2-olate (96 mg, 1.00 mmol) and piperazin-2-one (50 mg, 0.50 mmol) were added to a second microwave vial and inerted with nitrogen. 1-bromo-4-fluorobenzene (0.110 mL, 1.00 mmol) and toluene (0.500 mL) were added.The catalyst solution wad added to the reaction mixture and the resulting solution was stirred at 100C for 1h in the microwave. No reaction. Heated to 150C for 1h, still no reaction, the reaction was discarded." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CN(CC(=O)N1)C2=CC=C(C=C2)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/30/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "441" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00113 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CN(CCN1)CC2=CC=CC=C2" - } - amount { - moles { - value: 0.000567 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1F)Br" - } - amount { - moles { - value: 0.000851 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 5.67e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 5.67e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 50.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (12.74 mg, 0.06 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (32.8 mg, 0.06 mmol) were suspended in toluene (0.5 mL) under N2. Heated to 50C for 30 min (microwave).sodium 2-methylpropan-2-olate (109 mg, 1.13 mmol) was suspended in toluene (0.500 mL) under N2. 1-benzylpiperazine (0.099 mL, 0.57 mmol) and 1-bromo-4-fluorobenzene (0.093 mL, 0.85 mmol) were added, followed by the catalyst solution.Heated to 100C for 2h in the microwave (high abs), then rt over night.The product was purified on silica (0-25% EtOAcheptane) Yield: 1-benzyl-4-(4-fluorophenyl)piperazine (115 mg, 75.0 %)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CN(CCN1CC2=CC=CC=C2)C3=CC=C(C=C3)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 74.98 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/06/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "442" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000734 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.00049 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.00049 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" - } - amount { - moles { - value: 4.9e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.45e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Charged a standard microwave vial with a mixture of 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (100 mg, 0.49 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (135 mg, 0.49 mmol), cesium carbonate (239 mg, 0.73 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.42 mg, 0.02 mmol), Tri-tert-butylphosphonium tetrafluoroborate (14.21 mg, 0.05 mmol), and 1,2-dimethoxyethane.nbsp;The atmosphere was inerted through vacuum-nitrogen cycles and the contents were heated at 120 C for a period of 30 min.LCMS indicates reaction progression is less than 10%.nbsp;Reaction aborted.nbsp;Not progressed." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=CC=CC=C5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/05/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "446" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[K+].[K+]" - } - amount { - moles { - value: 0.000912 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC=CC=C1" - } - amount { - volume { - value: 0.0018 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)N" - } - amount { - moles { - value: 0.00122 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.000608 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000134 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 6.69e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: Repeat of optimised conditions found in process research and devellopment screen for an isolated yield.An activated catalyst solution was prepared by adding TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (61.3 mg, 0.07 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (77 mg, 0.13 mmol) to an oven-dried microwave vial. The vial was then capped and purged with nitrogen and anisole (1 mL) was added. The solution was stirred at 50C for 40 mins, then 90C for 15 mins (activated catalyst solution, Soln. 1).To another oven-dried microwave vial was added potassium carbonate (126 mg, 0.91 mmol), ethyl 2-aminooxazole-5-carboxylate (190 mg, 1.22 mmol) and 2,4-dichloropyridine (90 mg, 0.61 mmol) and the vial was capped and purged with nitrogen. anisole (1.35 mL) and the activated catalyst solution (0.45 mL Soln. 1 from above) were added (this corresponds to a catalyst loading of 10% Pd) and the vessel was heated to 90 C for 16 h.LCMS of the crude reactioowed the presence of a significant amount of amine starting material (Rt=0.95 min) as well as some 2,4-dichloropyridine starting material (Rt=1.75 min) together with a small amount of the desired product (Rt= 2.08). The mass corresponding to the double addition product was not observed.Conclusion: Reaction produced a small amount of the desired product but mainly starting material remained." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/06/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "447" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[K+].[K+]" - } - amount { - moles { - value: 0.000912 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC=CC=C1" - } - amount { - volume { - value: 0.00205 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)N" - } - amount { - moles { - value: 0.00122 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.000608 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000134 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 6.69e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: Repeat of optimised conditions found in process research and devellopment screen for an isolated yield.An activated catalyst solution was prepared by adding TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (61.3 mg, 0.07 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (77 mg, 0.13 mmol) to an oven-dried microwave vial. The vial was then capped, purged with nitrogen and anisole (1 mL) (degassed) was added. The solution was stirred at 50C for 40 mins, then 90C for 15 mins (activated catalyst solution, Soln. 1).To another oven-dried microwave vial was added potassium carbonate (126 mg, 0.91 mmol), ethyl 2-aminooxazole-5-carboxylate (190 mg, 1.22 mmol) and 2,4-dichloropyridine (90 mg, 0.61 mmol) and the vial was capped and purged with nitrogen. anisole (1.6 mL) and the activated catalyst solution (0.45 mL of Soln. 1 from above) were added (this corresponds to a catalyst loading of 10% Pd). The vessel was then heated to 120C for 16 h. LCMS and TLC of the on mixture showed none of the desired product to be present. Some of the amine starting material appears to be present and none of the 2,4-dichloropyridine remains. The mass for the double addition product (addition at the 2- and 4-positions) is present, but co-elutes with the reaction solvent anisole and is not quantifiable asnbsp;a result.nbsp;Conclusion: This is a somewhat surprising result, based on the fact that the previous reaction (EN05378-17) results in the formation of significant coupled product. These reaction conditions are apparently not suitable for the coupling of the ester stituted 2-aminooxazole. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/07/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "448" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00699 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.018 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)N" - } - amount { - moles { - value: 0.0035 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.0035 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000262 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 8.74e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 160.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: Peparation of the above coupled product on a larger scale for hydrolysis-protodecarboxylation study.To an oven-dried microwave vial was added ethyl 2-aminooxazole-5-carboxylate (546 mg, 3.50 mmol), 2,4-dichloropyridine (0.378 mL, 3.50 mmol), cesium carbonate (2279 mg, 6.99 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (80 mg, 0.09 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (152 mg, 0.26 mmol) and the vial was capped and purged with nitrogen. dioxane (18 mL) (degassed) was added and the reaction mixture was heated to 160 C for 1 h under microwave irradiation. LCMS of the crude reaction mixture shows the required product to be the major product together with an isomer of the same mass (Rt= 1.91), the ratio of the desired product to this isomeric product being circa 5:1. LCMS also shows that a small amount of the 2-aminooxazole ester starting material remains (Rt= 0.99 min) and so the reaction with this particular strate may benefit from slightly er reaction times, maybe 90 mins. A small amount of the coupled and decarboxylated product was also present (Rt= 1.68 min). Saturated ammonium chloride (15 mL) was added to the crude reaction mixture and the mixture was transfrred to a separating funnel. Ethyl acetate (80 mL) was then added and the organic layer was separated (keeping the interfacial material with the organic layer). The aqueous layer was washed with ethyl acetate (2 x 80 mL portions). (Note: During this extraction, a solid, presumably the required product was seen to crash out in the organic layer. If this reaction is to be repeated a work-up free approach is recommended where the crude reaction mixture is dry-loaded directly onto silica for chromatographic purification). The solvent was removed from the combined organics under reduced pressure. The crude product was loaded onto a pre-wetted silica column using the minimum DCM and methanol. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% DCM (5% methanolic ammonia) in DCM. Pure fractions were evaporated to dryness to afford 744 mg of impure product. The crude residue was triturated with Et2O to give a solid which was collected by filtration and dried under vacuum to give ethyl 2-(4-chloropyridin-2-ylamino)oxazole-5-carboxylate (415 mg, 44.3 %) as a beige solid. nbsp;Conclusion: The desired product was isolated in moderate yield and high purity (95% based on strength NMR). The moderate yield may be improved under a longer reaction time, it is also probable that purification difficulties were also detrimental to the yield of this reaction." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 44.34 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/11/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "450" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00699 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.018 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)N" - } - amount { - moles { - value: 0.0035 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.0035 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000262 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 8.74e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 160.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: To make the coupled product on a larger scale for hydrolysisdecarboxylationPd2(dba)3 (80 mg, 0.09 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (152 mg, 0.26 mmol), 2,4-dichloropyridine (0.378 mL, 3.50 mmol), cesium carbonate (2279 mg, 6.99 mmol) and ethyl 2-aminooxazole-5-carboxylate (546 mg, 3.50 mmol) were added to an oven dried microwave vial and the vial was capped and placed under an inert atmosphere, dioxane (18 mL) was added and the resulting mixture was heated to 160 C for 1 h by microwave irradiation under a nitrogen atmosphere.The crude product was purified by flash silica chromatography, elution gradient 0 to 3% MeOH (7 N ammonia) in DCM. Pure fractions were evaporated to dryness to afford ethyl 2-(4-chloropyridin-2-ylamino)oxazole-5-carboxylate (892 mg, 95 %) as a brown solid. Analysis of the product after chromatography showed that it was ~ 75% pure by proton NMR and LCMS, therefore the actual yield of the desired product is closer to 70%.Note: the reaction was carried out twice on the above scale." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 95.3 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/16/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "451" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 5e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)N" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 140.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: Poisoning experiment to find out if 2-aminooxazole or the coupled product from reaction of 2-aminooxazole and 2,4-dichloropyridine are \'poisoning\' the catalyst.Reaction (a): Control reaction under identical conditions to EN04881-40 (should produce similar yield)Reaction (b): As for control but spiked with 2 eq. of 2-aminooxazole with respect to catalyst, before dioxane was added (will produce decreased yield if 2-aminooxazole is a poison)Reaction (c): As for control but spiked with 1 eq. of N-(4-chloropyridin-2-yl)oxazol-2-amine, before dioxane was added (will produce decreased yield if N-(4-chloropyridin-2-yl)oxazol-2-aminenbsp;is a poison)Pd2(dba)3 (22.89 mg, 0.025 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (43.4 mg, 0.075 mmol), 2,4-dichloropyridine (148 mg, 1.00 mmol), cesium carbonate (651 mg, 2.00 mmol),ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol) and 4,4\'-di-tert-butylbiphenyl (26.6 mg, 0.10 mmol) were added to an oven dried microwave vial, the vial was capped and placed under an inert atmosphere. Dioxane (4 mL) was added and the resulting mixture was heated to 140 C for 1 h by microwave irradiation under a nitrogen atmosphere.nbsp;An isolated yield was obtained for reaction (a). Dichloromethane (10 mL) was added to the crude reaction mixture and the mixture was adsorbed onto silica. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in heptane. Pure fractions were evaporated to dryness to afford ethyl 2-(4-chloropyridin-2-ylamino)oxazole-5-carboxylate (111 mg, 41.5 %) as a white solid. Taking into account that the crude LCMS for reaction (A) corresponds to a ~ 42% isolated yield, the amount of product can be calculated for reactions (B) and (C) using the ratio between the t-Butyl biphenyl and the required product in the LCMS. The amount of required product produced in reaction (B) was 41% and for reaction (C) 45% product was produced.Conclusion: Thove compounds do not poison the catalyst.Note: Significant amounts of what is assumed to be the regioisomeric 4-aminated product were also formed in these reactions. Major regioisomer formed in ~ 4:1 ratio." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 41.51 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/21/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "453" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.002 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)N" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 140.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: To find out if the regioisomeric ester is also a reaction strate in this C-N bond forming reactionPd2(dba)3 (22.89 mg, 0.025 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (43.4 mg, 0.075 mmol), 2,4-dichloropyridine (148 mg, 1.00 mmol), cesium carbonate (651 mg, 2.00 mmol),ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol) were added to an oven dried microwave vial, the vial was capped and placed under an inert atmosphere, dioxane (4 mL) was added and the resulting mixture was heated at 140 C for 1 h by microwave irradiation under a nitrogen atmosphere.The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in heptane. Pure fractions were evaporated to dryness to afford ethyl 2-(4-chloropyridin-2-ylamino)oxazole-5-carboxylate (135 mg, 50.5 %) as a white solid. nbsp;Conclusion: The desired product was isolated in gt; 50% isolated yield. The electron withdrawing ester group again has a positive effect on reaction. More work needs to be carried out to probe the origin of this effect. NOESY confirmed expected regioisomer was formed (see sample details)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 50.48 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/07/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "454" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 9.99e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)N" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C(C)(C)C)C(C)(C)C)C(C)C" - } - amount { - moles { - value: 9.99e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 160.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: Series of experiments to optimise yield of the above coupled product.Pd2(dba)3 (22.89 mg, 0.025 mmol), di-tert-butyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (42.4 mg, 0.10 mmol), 2,4-dichloropyridine (148 mg, 1.00 mmol), cesium carbonate (651 mg, 2.00 mmol),ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol) and 4,4\'-di-tert-butylbiphenyl (60 mg, 0.23 mmol) were added to an oven dried microwave vial, the vial was capped and placed under an inert atmosphere, dioxane (4 mL) was added and the resulting mixture was heated at 160 C for 1 h by microwave irradiation under a nitrogen atmosphere.Crude LCMS shows a complete switch in regioselectivity, with the other isomer becoming the major product in 26% yield based on internal standard (note: this is a rough estimate as the U.V absorbance may be significantly different for this regioisomer). The regioisomeric ratio is 2.8:1 and although the product was not formed in synthetically useful yields, it is an interesting result.Conclusion: Switch in regioselectivty with the change in ligand may be worth pursuing." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/11/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "455" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 9.99e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)N" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=C(C=CC(=C2P(C(C)(C)C)C(C)(C)C)OC)OC)C(C)C" - } - amount { - moles { - value: 9.99e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 160.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: Series of experiments to optimise yield of the above coupled product.Pd2(dba)3 (22.89 mg, 0.025 mmol), di-tert-butyl(2\',4\',6\'-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (48.4 mg, 0.10 mmol), 2,4-dichloropyridine (148 mg, 1.00 mmol), cesium carbonate (651 mg, 2.00 mmol),ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol) and 4,4\'-di-tert-butylbiphenyl (60 mg, 0.23 mmol) were added to an oven dried microwave vial, the vial was capped and placed under an inert atmosphere, dioxane (4 mL) was added and the resulting mixture was heated at 160 C for 1 h by microwave irradiation under a nitrogen atmosphere.Crude LCMS shows a switch in regioselectivity, with the other isomer becoming the major product in 25% yield based on internal standard (note: this is a rough estimate as the U.V absorbance may be significantly different to the other regioisomer). The regioisomeric ratio is 1.7:1 and although the product was not formed in synthetically useful yields, it is an interestinsult.Conclusion: Switch in regioselectivty with the change in ligand may be worth pursuing, although greater selectivity was seen for this prduct in the preceeding reaction." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/11/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "456" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 9.99e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)N" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=C(C=CC(=C2P(C3=CC(=CC(=C3)C(F)(F)F)C(F)(F)F)C4=CC(=CC(=C4)C(F)(F)F)C(F)(F)F)OC)OC)C(C)C" - } - amount { - moles { - value: 9.99e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 160.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: Series of experiments to optimise yield of the above coupled product.Pd2(dba)3 (22.89 mg, 0.025 mmol), bis(3,5-bis(trifluoromethyl)phenyl)(2\',4\',6\'-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (80 mg, 0.10 mmol), 2,4-dichloropyridine (148 mg, 1.00 mmol), cesium carbonate (651 mg, 2.00 mmol),ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol) and 4,4\'-di-tert-butylbiphenyl (60 mg, 0.23 mmol) were added to an oven dried microwave vial, the vial was capped and placed under an inert atmosphere, dioxane (4 mL) was added and the resulting mixture was heated at 160 C for 1 h by microwave irradiation under a nitrogen atmosphere.Crude LCMS shows a switch in regioselectivity again with respect to the bidentate ligand Xantphos, with the other isomer becoming the major product in 28% yield based on internal standard (note: this is a rough estimate as the U.V absorbance may be significantly different to the other regioisomer). None of the other regioisomer observed.Concln: Switch in regioselectivty with the change in ligand may be worth pursuing, this reaction is uapparentlyu completely selective for the 4-regioisomer. Note: Necessary to isolate product to confirm." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/11/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "457" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00799 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.016 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)N" - } - amount { - moles { - value: 0.004 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.004 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.0003 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 9.99e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 160.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: Isolate a larger quantity of product for hydrolysisdecarboxylation studyPd2(dba)3 (91 mg, 0.10 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (173 mg, 0.30 mmol), 2,4-dichloropyridine (591 mg, 4.00 mmol), cesium carbonate (2604 mg, 7.99 mmol) and ethyl 2-aminooxazole-5-carboxylate (624 mg, 4.00 mmol)nbsp;were added to an oven dried microwave vial. The vial was capped and placed under an inert atmosphere, dioxane (16 mL) was added and the resulting mixture was heated at 160 C for 1 h by microwave irradiation under a nitrogen atmosphere.This reaction was run in four portions, i.e. four identical microwave reactions were carried out on 14 of the above scale. The reactions were then combined and purified as a single sample.Purification by chromatography on silica using heptane:ethyl acetate as eluent, on alumina with heptane:ethyl acetate and via reverse phase on C18 silica failed. The crude product was purified by flash silica chromatography, elution gradiento 3% Methanolic ammonia (7 M) in DCM. Pure fractions were evaporated to dryness to afford ethyl 2-(4-chloropyridin-2-ylamino)oxazole-5-carboxylate (534 mg, 49.9 %) as a pale yellow solid. Althought the LCMS looks good for the fractions combined for this sample, the proton NMR shows significant impurities to be present. Conclusion: Sufficient material isolated for hydrolysisdecarboxylation study." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 49.92 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/12/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "459" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.002 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)N" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=C(C=CC(=C2P(C3=CC(=CC(=C3)C(F)(F)F)C(F)(F)F)C4=CC(=CC(=C4)C(F)(F)F)C(F)(F)F)OC)OC)C(C)C" - } - amount { - moles { - value: 9.99e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 160.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: Attempt to synthesise the 4-stituted product using jackiephos as ligand.To an oven-dried microwave vial was added ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol), 2,4-dichloropyridine (0.108 mL, 1.00 mmol), cesium carbonate (651 mg, 2.00 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.87 mg, 0.02 mmol) and bis(3,5-bis(trifluoromethyl)phenyl)(2\',4\',6\'-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (80 mg, 0.10 mmol) and the vial was capped and purged with nitrogen. dioxane (4 mL) (degassed) was added and the reaction mixture was heated to 160 C for 1 h under microwave irradiation. The reaction mixture was heated to 160Cnbsp;for a further 3 h due to incomplete conversion. DCM (10 mL) was added to the crude reaction mixture together with silica (2 g). The solvent was then removed from the reaction mixture under reduced pressure. The resulting residue was then added tom a dry-load tube prior to chromatography.The crude product was purifiesh silica chromatography, elution gradient 0 to 2.5% methanolic ammonia (7 M) in DCM. The desired product (4-stitution) was isolated as a mixture with the 2-stituted product. The ratio of the 2-isomer to the 4-isomer is 2.4:1 for the mxture with no other fractions containing either isomer. Conclusion: The apparent higher selectivity for the 4-isomer is due to the overlap of the 2,4-dichloropyridine starting material with this isomer. Therefore this reaction actually forms the 2-isomer selectively and is not a very active catalyst for this transformation. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/19/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "460" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.002 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)N" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.49e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: Comparison of the reactivity of 2-aminooxazole and ester stituted 2-aminooxazole under identical reaction conditions. To an oven-dried round bottomed flask was added ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol), cesium carbonate (651 mg, 2.00 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.87 mg, 0.02 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (43.4 mg, 0.07 mmol) and 2,4-dichloropyridine (0.108 mL, 1.00 mmol). A reflux condenser was fitted and the vessel was purged with nitrogen.nbsp;dioxane (2 mL)DMSO (2 mL) (degassed) was added and the reaction mixture was heated to 100 C for 16 h. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness to afford the crude product.The crude product was purified by flash silica chromatography, elution gradient 1 to 3% methanolic ammonia (7 M) in DCM. Puractions were evaporated to dryness to afford ethyl 2-(4-chloropyridin-2-ylamino)oxazole-5-carboxylate (128 mg, 47.9 %) as a pale yellow solid. Conclusion: The desired product was formed in moderate yield. Normal-phase column DCM:methanolic ammonia" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 47.86 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/08/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "463" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[K+].[K+]" - } - amount { - moles { - value: 0.000912 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC=CC=C1" - } - amount { - volume { - value: 0.0018 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=COC(=N1)N" - } - amount { - moles { - value: 0.00122 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.000608 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000134 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 6.69e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: Repeat of optimised conditions found in process research and devellopment screen for an isolated yield.An activated catalyst solution was prepared by adding TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (61.3 mg, 0.07 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (77 mg, 0.13 mmol) to an oven-dried microwave vial. The vial was then capped and purged with nitrogen and anisole (1 mL) (degassed) was added. The solution was stirred at 50C for 40 mins, then 90C for 15 mins (activated catalyst solution; Soln. 1).To another oven-dried microwave vial was added potassium carbonate (126 mg, 0.91 mmol), oxazol-2-amine (102 mg, 1.22 mmol) and 2,4-dichloropyridine (90 mg, 0.61 mmol) and the vial was capped and purged with nitrogen. anisole (1.35 mL) and the activated catalyst solution (0.45 mL of Soln. 1 from above) were then added (this corresponds to a catalyst loading of 10% Pd). The vessel was then heated to 120 C for 16 h. LCMS of the crude reaction mixed that the desired product was present (Rt= 1.70) along with a trace amount of the double addition product i.e. amine addition at the 2- and 4-position (Rt= 1.22 min). The reaction mixture was quenched with saturated ammonium chloride (8 mL) and transferred to a separating funnel. Ethyl acetate (15 mL) was then added and the organic layer was separated (keeping the interfacial material with the organic layer). The aqueous layer was washed with ethyl acetate (2 x 15 mL portions). The combined organics were then dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. DCM (1 mL) was then added to the resulting residue (which still contained anisole (4 mL)) and this solution was loaded directly onto a silica column (40 g).The crude product was purified by flash silica chromatography, elution gradient 0 to 30% DCM (5% methanolic ammonia) in DCM, then 100% DCM (5% methanolic ammonia). Pure fractions were evaporated to dryness to afford N-(4-chloropyridin-2-yl)oxazol-2-amine (59.0 mg, 49.6 %) as an off-white solid. Note: This product was only 52% pure based on NMR strength.Conclusion: The desired product was isolated but in relatively low yield and low purity." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)NC2=NC=CO2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 49.6 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/07/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "465" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000101 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=COC(=N1)N" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=C(C=CC(=C2P(C3=CC(=CC(=C3)C(F)(F)F)C(F)(F)F)C4=CC(=CC(=C4)C(F)(F)F)C(F)(F)F)OC)OC)C(C)C" - } - amount { - moles { - value: 0.000101 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.53e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 140.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: Reactions using ligands not previously tested under these conditions2,4-dichloropyridine (0.109 mL, 1.01 mmol), oxazol-2-amine (85 mg, 1.01 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (23.20 mg, 0.03 mmol), bis(3,5-bis(trifluoromethyl)phenyl)(2\',4\',6\'-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (81 mg, 0.10 mmol) and cesium carbonate (660 mg, 2.03 mmol) were added to an oven-dried microwave vail and the vial was purged with nitrogen. Degassed dioxane (4mL) was then added andnbsp;the reaction mixture was heated to 140 Cnbsp;for 1 h under microwave irradiation. Conclusion: None of the desired product was observed in the LCMS of the crude reaction mixture, not progressed." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)NC2=NC=CO2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/10/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "466" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00203 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=COC(=N1)N" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 140.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: To isolate some of the required product to provide an analytical sample for a large catalyst screen.2,4-dichloropyridine (0.109 mL, 1.01 mmol), oxazol-2-amine (85 mg, 1.01 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.89 mg, 0.02 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (44.0 mg, 0.08 mmol) (Xantphos) and cesium carbonate (660 mg, 2.03 mmol) were added to a microwave vail and the vial was purged with nitrogen. Degassed dioxane (4 mL) was then added andnbsp;the reaction mixture was heated to 140 Cnbsp;for 1 h under microwave irradiation. LCMS of crude reaction mixture showed some of the required product was formed, however the LCMS using acidic modifier was somewhat misleading as a side-product co-elutes with the required product thus giving the impression that a greater amount of product was formed than is the case. LCMS under acidic modifier is more informative.The crude product was purified by flash silica chromatography, elution grnt 0 to 20% heptane in EtOAc. Pure fractions were evaporated to dryness to afford N-(4-chloropyridin-2-yl)oxazol-2-amine (4.00 mg, 2.018 %) as a pale yellow residue. Conclusion: 4 mg of impure product was isolated." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)NC2=NC=CO2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 2.02 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/09/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "468" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "[H-].[Na+]" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=COC(=N1)N" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 140.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: If deprotonation is rate-determining in this coupling quantitative deprotonation prior to jection to coupling conditions should prove beneficial.To an oven dried microwave vial was added oxazol-2-amine (85 mg, 1.01 mmol) together with sodium hydride (40.5 mg, 1.01 mmol), the vial was capped and purged with nitrogen and dioxane (1 mL) was added. The mixture was then stirred at rt for 1 h (initially effervescence was observed but sided within 20 min of stirring).To the above vial was added 2,4-dichloropyridine (0.109 mL, 1.01 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.89 mg, 0.02 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (44.0 mg, 0.08 mmol) (Xantphos) as a solution innbsp;dioxane (2 mL) andnbsp;the reaction mixture was heated to 140 Cnbsp;for 1 h under microwave irradiation. Dichloromethane (10 mL) was added to the crude reaction mixture and the mixture was absorbed onto silica. The crude product was purified by flash silicromatography, elution gradient 0 to 20% EtOAc in heptane. Pure fractions were evaporated to dryness to afford N-(4-chloropyridin-2-yl)oxazol-2-amine (6.00 mg, 3.03 %) as a pale yellow dry film. Conclusion: The formal deprotonation appears to have had no benificial effect on this coupling." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)NC2=NC=CO2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 3.03 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/28/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "469" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "[O-]P(=O)([O-])[O-].[K+].[K+].[K+]" - } - amount { - moles { - value: 0.00203 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=COC(=N1)N" - } - amount { - moles { - value: 0.00122 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000608 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000203 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 160.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: Will increased catalyst loading lead to increased isolated yield of the desired product?2,4-dichloropyridine (0.109 mL, 1.01 mmol), oxazol-2-amine (102 mg, 1.22 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (186 mg, 0.20 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (352 mg, 0.61 mmol) (Xantphos) and potassium phosphate (430 mg, 2.03 mmol) were added to a microwave vail and the vial was purged with nitrogen. Degassed dioxane (4mL) was then added andnbsp;the reaction mixture was heated to 160 Cnbsp;for 6 h under microwave irradiation. Dichloromethane (10 mL) was added to the crude reaction mixture and the mixture was adsorbed onto silica gel. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in heptane. Unfortunately and somewhat surprisingly, none of the desired product was isolated, although only a trace of required product was observed in the LCMS of the crude reaction mixture. Conclusion: It appethat under this higher catalyst loading the reaction is less efficent, potentially a concentration effect?" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)NC2=NC=CO2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/28/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "474" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00142 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=COC(=N1)N" - } - amount { - moles { - value: 0.00122 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 1.52e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.01e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a vial containing oxazol-2-amine (102 mg, 1.22 mmol), , TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (9.28 mg, 10.14 mol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (9.47 mg, 0.02 mmol) and sodium 2-methylpropan-2-olate (136 mg, 1.42 mmol), was added degassed toluene (4 mL) and 2,4-dichloropyridine (0.109 ml, 1.01 mmol) and the reaction mixture was heated to 100 degrees C for 20 h. None of the desired product was observed by LCMS or in crude proton NMR.bIt is of note that although the 2,4-dichloropyridine is present in the crude proton NMR, the oxazole-2-amine is notb. It is possible that under the strongly basic reaction conditions that this starting material decomposed. Product not isolated." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)NC2=NC=CO2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/07/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "475" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)[O-].[Na+]" - } - amount { - moles { - value: 3.04e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=COC(=N1)N" - } - amount { - moles { - value: 0.00111 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.04e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.27e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 130.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a microwave vial containing 2,4-dichloropyridine (0.109 mL, 1.01 mmol), sodium phenolate (177 mg, 1.52 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (11.60 mg, 0.01 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (17.59 mg, 0.03 mmol) (Xantphos), was added degassed dioxane (4 mL) and the mixture allowed to stir under nitrogen atmosphere for 5 min. To this solution was added oxazol-2-amine (94 mg, 1.11 mmol) and the reaction mixture was heated to 130 Cnbsp;for 30 min under microwave irradiation. bApparently no 2-aminooxazole remains by proton NMR of crude reaction mixture upon removal of dioxane, however it\'s presence was observed by LCMS of the crude reaction mixture (see attached). It is possible that the presence of impuritiessolvent etc. have shifted the resonances slightly for this starting material in bb1bbH NMR. bThe crude product was purified by reverse-phase flash chromatography on C-18 modified silica, elution gradient 0 t0% MeCN in water. Pure fractions were evaporated to dryness to afford N-(4-chloropyridin-2-yl)oxazol-2-amine (6.00 mg, 3.03 %) as a pale yellow dry film. 3 % of the required product was isolated and this sample was impure. Microwave heating has no positive effect under these reaction conditions.Upon mission of a crude sample of the reaction mixture to PCQ both starting materials were observed.Conclusion: 3% of impure material isolated, look for alternative conditions." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)NC2=NC=CO2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 3.03 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/04/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "476" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00236 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0048 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=COC(=N1)N" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 5.07e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium(II) acetate (11.38 mg, 0.05 mmol) was added in a single portion to a degassed solution of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (44.0 mg, 0.08 mmol), oxazol-2-amine (85 mg, 1.01 mmol), cesium carbonate (768 mg, 2.36 mmol),2,4-dichloropyridine (0.109 mL, 1.01 mmol), dioxane (4 mL) and DMSO (0.8 mL) and the resulting mixture was heated at 100 C for 16 hours under a nitrogen atmosphere.Note: the reaction mixture was degassed by first combing the reagents (with the exception of Pd((OAc)2), sealing the vessel and carrying out three pump-purge cycles (vac-nitrogen). Dioxane was then added to this mixture via syringe, followed by the Pd(OAc)2 in a single portion and the vessel was heated for the required time as above. Solvent boiled dry from reaction overnight. Only DMSO remained. bCrude proton NMR shows mainly dichlorpyridine starting material and the 2-aminooxazole starting material was absentb. Crude LCMS indicates that a product of the required mas present. The crude product was purified by flash chromatography on C-18 modified silica, elution gradient 0 to 100% MeCN in water with basic modifier (1% ammonium hydroxide). Pure fractions were evaporated to dryness to afford N-(4-chloropyridin-2-yl)oxazol-2-amine (22.00 mg, 11.10 %) as a pale yellow residue. The product isolated, although impure, looks like the required product based on LCMS. The 1H NMR of the purified material is in D6-DMSO here and so not directly comparable with previous spectra in CDCl3. Conclusion: This may be worth pursuing (i.e. adding DMSO to aid solubility) based on the slightly increased yield.bRevision: Required product not isolated, spectral analysis of isolated sample does not match those of authentic samples of the coupled productb. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)NC2=NC=CO2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 11.1 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/09/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "478" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00203 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=COC(=N1)N" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000122 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000101 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;oxazol-2-amine (85 mg, 1.01 mmol), 2,4-dichloropyridine (0.151 mL, 1.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (70.4 mg, 0.12 mmol) and cesium carbonate (660 mg, 2.03 mmol) were stirred in DMA (5 mL).nbsp;The mixture was purged with nitrogen for 10 minutes.nbsp;Palladium(II) acetate (22.76 mg, 0.10 mmol) was added and the mixture heated at 100 C for 70h.nbsp;The mixture was cooled, filtered and concentrated.nbsp;The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-(4-chloropyridin-2-yl)oxazol-2-amine (3.90 mg, 1.967 " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)NC2=NC=CO2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 1.97 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/06/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "479" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)[O-].[Na+]" - } - amount { - moles { - value: 3.04e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=COC(=N1)N" - } - amount { - moles { - value: 0.00111 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.04e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.27e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a flask containing 2,4-dichloropyridine (0.109 mL, 1.01 mmol), sodium phenolate (177 mg, 1.52 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (11.60 mg, 0.01 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (17.59 mg, 0.03 mmol) (Xantphos), was added degassed dioxane (4 mL) and the mixture allowed to stir under nitrogen atmosphere for 5 min. To this solution was added oxazol-2-amine (94 mg, 1.11 mmol) and the reaction mixture was heated to 80 Cnbsp;for three hours.A 1H NMR was measured of the crude reaction after the solvent had been removed. bThis indicated the presence of significant amounts of 2,4-dichloropyridine as well as 2-amino oxazoleb. LCMS of the crude reaction mixture at t= 90 min and at t= 3 h showed the desired product was present. The crude reaction mixture was dry loaded without workup and purified by automated flash chromatography. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)NC2=NC=CO2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 2.52 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "12/10/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "481" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0105 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.039 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCC(CC1)CN" - } - amount { - moles { - value: 0.00526 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)OC(F)(F)F)C2=CN=C3N2N=C(C=C3)Cl" - } - amount { - moles { - value: 0.00351 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C1=CC=CC=C1C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 0.00105 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000351 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 300 ml round bottom lfask was charged with a magnetic stir bar, toluene (39 ml), 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (1.1 g, 3.51 mmol), Pd2(dba)3 (0.321 g, 0.35 mmol), 2-(DIMETHYLAMINO)-2\'-(DICYCLOHEXYLPHOSPHINO)BIPHENYL (0.414 g, 1.05 mmol), SODIUM TERT-BUTOXIDE (1.011 g, 10.52 mmol), and (1-methylpiperidin-4-yl)methanamine (0.674 g, 5.26 mmol). The mixture was degassed with N2, the vessel fitted with a reflux condenser, and then placed in an oil bath heated to 110 C for 16hrs. The mixture was cooled to r.t, filtered throught a bed of celite, washed with methanol, the filtrate was concentrated, the residue was pre-absorbed onto silca gel (~10g) and purified with ISCO (eluent methanolDCM (13) to afford the title compound N-((1-methylpiperidin-4-yl)methyl)-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-amine (0.510 g, 35.9 %).(Note: the ligand I used was old)(note: tried direct displacement under microwave radiation at 180C in 4MHCl or KOethoxyethanol; both condition didn\'t result in the desired product)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CCC(CC1)CNC2=NN3C(=NC=C3C4=CC(=CC=C4)OC(F)(F)F)C=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 35.87 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/24/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "482" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0835 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.2 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCC(CC1)CN" - } - amount { - moles { - value: 0.0355 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)OC(F)(F)F)C2=CN=C3N2N=C(C=C3)Cl" - } - amount { - moles { - value: 0.0209 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C1=CC=CC=C1C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 0.00626 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.00209 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 500 ml round bottom lfask was charged with a magnetic stir bar, toluene (200 ml), 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (6.55 g, 20.88 mmol), Pd2dba3 (1.912 g, 2.09 mmol),nbsp;fresh bottle of 2\'-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (2.465 g, 6.26 mmol),nbsp;SODIUM TERT-BUTOXIDE (8.03 g, 83.53 mmol) and (1-methylpiperidin-4-yl)methanamine (4.55 g, 35.50 mmol). The mixture was degassed with N2, the vessel fitted with a reflux condenser, and then placed in an oil bath heated to 120 C for 16hrs. The mixture was filtered throught a bed of celite, washed with methanolDCM (31), the filtrate was concentrated, the residue was taken into a mixture of water and DCMIsopropanol (51), separated, the water layer was extrated twice with DCMisopropanol (51), the combined organics were dried (MgSO4), concentrated, the residue was pre-absorbed onto silca gel (~80g) and purified with ISCO (eluent methanolDCM (13) to afford the title compound as which was taken into he, the solid was collected by filtration, washed with hexane, dried in vacum at 60C to yield a light yellow solid as N-((1-methylpiperidin-4-yl)methyl)-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-amine (5.51 g, 62.9 %).405mgs of the free base product was dissolved into 2ml of methanol, treated with 1M H2SO4 in methanol (1ml conc. H2SO4 + 17ml of methanol). The solution was stirred for 2min, solid crushed out, the suspension was continually stirred at r.t for overnight before being diluted with ethyl ether, the solid was collected by filtration, dried to yield a white solid as desired product-bi-sulfuric acid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CCC(CC1)CNC2=NN3C(=NC=C3C4=CC(=CC=C4)OC(F)(F)F)C=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 62.89 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/28/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "483" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 1.99e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC2=C(C=C1)C=C(C=C2)C(=O)N" - } - amount { - moles { - value: 0.000199 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)[N+](=O)[O-])Br" - } - amount { - moles { - value: 0.000199 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 1.99e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 9.94e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (9.10 mg, 9.94 mol) was added to 2-bromo-1-methyl-4-nitrobenzene (42.9 mg, 0.20 mmol), 2-methylquinoline-6-carboxamide (37.0 mg, 0.20 mmol), cesium carbonate (194 mg, 0.60 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (11.50 mg, 0.02 mmol) in dioxane (2 mL) at 20C under nitrogen. The resulting solution was stirred at 100 C for 6 hours. Reaction seen to be progressing but very sluggish (5% conversion). Reaction abandoned." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)[N+](=O)[O-])NC(=O)C2=CC3=C(C=C2)N=C(C=C3)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/13/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "484" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00257 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CN1CCCC1=O" - } - amount { - volume { - value: 0.006 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)NC1=C(C=CC(=C1)N)N2CC[C@H](C2)NC(=O)OC(C)(C)C" - } - amount { - moles { - value: 0.00128 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.00128 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C(C)(C)C)C(C)(C)C)C(C)C" - } - amount { - moles { - value: 0.000128 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 6.42e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 105.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (300 mg, 1.28 mmol), (R)-tert-butyl 1-(2-acetamido-4-aminophenyl)pyrrolidin-3-ylcarbamate (429 mg, 1.28 mmol), CESIUM CARBONATE (837 mg, 2.57 mmol) and di-tert-butyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (54.5 mg, 0.13 mmol) were added into NMP (6 mL) in a 50mL round bottle.nbsp;Pd2dba3 (58.8 mg, 0.06 mmol) was added to the solution.nbsp;The solution was purged by nitrogen, then heated at 105C overnight.nbsp;Crude product was separarted between water and ethyl acetate.nbsp;The organic layer was concentrated under reduced pressure.nbsp;The crude product was purified on the ISCO(17g silica column, EAhex 0-75%). Then the intermediate was put in 1N HClnbsp;in ether(5mL),.nbsp;The solution was stirred at rt for2hrs.nbsp;Crude product was purified on Gilson(0.1%TFA CH3CNwater 2-35%), 124.8mg final product was obtained as white solid" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)NC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)N5CC[C@H](C5)N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 17.82 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/19/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "485" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00483 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00372 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(O1)C=CC=C2Br" - } - amount { - moles { - value: 0.00372 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.000372 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000186 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 95.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "tert-butyl piperazine-1-carboxylate (0.692 g, 3.72 mmol), ethyl 4-bromobenzofuran-2-carboxylate (1 g, 3.72 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (0.177 g, 0.37 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.170 g, 0.19 mmol) and CESIUM CARBONATE (1.574 g, 4.83 mmol) were heated under argon to 95 C overnight.nbsp;The mixture was allowed to cool. The mixture was diluted with EtOAc and the mixture was filtered through a pad of Celite.nbsp;The filterate was collected and the solvent was removed by rotary evaporation.nbsp;The crude product was added to a silica gel column and was eluted withnbsp;0-50% EtOAc in heptane.nbsp;The collected fractions were combined and the solvent was removed to yield tert-butyl 4-(2-(ethoxycarbonyl)benzofuran-4-yl)piperazine-1-carboxylate (0.990 g, 71.1 %).1H NMR in CDCl3 is consistent with desired productMSnbsp;(m+1) = 375.6.HPLC Peak RT = 3.27 minutes is product.nbsp;Purity = 95%." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(C=CC=C2O1)N3CCN(CC3)C(=O)OC(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 71.15 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/13/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "487" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0372 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.04 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.0286 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(O1)C=CC=C2Br" - } - amount { - moles { - value: 0.0286 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.00286 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.00143 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 95.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "ethyl 4-bromobenzofuran-2-carboxylate (7.7 g, 28.61 mmol), tert-butyl piperazine-1-carboxylate (5.33 g, 28.61 mmol), Tris(dibenzylideneacetone)dipalladium(0) (1.310 g, 1.43 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (1.364 g, 2.86 mmol) and CESIUM CARBONATE (12.12 g, 37.20 mmol) in dioxane (40 mL) was heated under argon to 95 C overnight.nbsp;The mixture was allowed to cool. The mixture was diluted with EtOAc and the mixture was filtered through a pad of Celite.nbsp;The filterate was collected and the solvent was removed by rotary evaporation.nbsp;The crude product was added to a silica gel column and was eluted withnbsp;0-50% EtOAc in heptane.nbsp;The collected fractions were combined and the solvent was removed to yield tert-butyl 4-(2-(ethoxycarbonyl)benzofuran-4-yl)piperazine-1-carboxylate (4.92 g, 45.9 %).MSnbsp;(m+1) = 375.8.HPLC Peak RT = 3.27 minutes is product.nbsp;Purity = 96%." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(C=CC=C2O1)N3CCN(CC3)C(=O)OC(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 45.92 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/17/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "488" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00966 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00743 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(O1)C=CC=C2Br" - } - amount { - moles { - value: 0.00743 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.000743 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000372 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 95.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "ethyl 4-bromobenzofuran-2-carboxylate (2 g, 7.43 mmol), tert-butyl piperazine-1-carboxylate (1.384 g, 7.43 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.340 g, 0.37 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (0.354 g, 0.74 mmol) and CESIUM CARBONATE (3.15 g, 9.66 mmol) were heated under argon to 95 C overnight.nbsp;The mixture was allowed to cool. The mixture was diluted with EtOAc and the mixture was filtered through a pad of Celite.nbsp;The filterate was collected and the solvent was removed by rotary evaporation.nbsp;The crude product was added to a silica gel column and was eluted withnbsp;0-50% EtOAc in heptane.nbsp;The collected fractions were combined and the solvent was removed to yield tert-butyl 4-(2-(ethoxycarbonyl)benzofuran-4-yl)piperazine-1-carboxylate (1.250 g, 44.9 %).MSnbsp;(m+1) = 375.6.HPLC Peak RT = 3.29 minutes is product.nbsp;Purity = 99%." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC2=C(C=CC=C2O1)N3CCN(CC3)C(=O)OC(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 44.92 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/17/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "489" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CCC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00104 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=CC1=O)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000865 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CC(OC2=C(C1)C=CC(=N2)Cl)CC(F)(F)F" - } - amount { - moles { - value: 0.000865 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 8.65e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 8.65e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of 5-(6-amino-2-methoxypyridin-3-yl)-1-methylpyridin-2(1H)-one (0.2 g, 0.86 mmol), 8-chloro-4-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.243 g, 0.86 mmol), Palladium(II) acetate (0.019 g, 0.09 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (0.050 g, 0.09 mmol) and Sodium tert-pentoxide (0.114 g, 1.04 mmol) in dioxane (1.5 mL) was heated by microwave irradiation to 120 C for 30 min.nbsp;The mixture was allowed to cool.nbsp;DCM (5 mL) was added and the mixture was filtered through a short pad of Celite.nbsp;The filtrate was collected and the solvent was removed by rotary evaporation.nbsp;The crude product was added to a silica gel column and was eluted with 0-5% MeOH in DCM.nbsp;The collected fractions were combined and the solvent was removed by rotary evaporation.nbsp;The residue was mitted for separation by chiral SFC to yield 5-(2-methoxy-6-(4-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-ylamino)pyrid-yl)-1-methylpyridin-2(1H)-one (0.055 g, 26.8 %) and 5-(2-methoxy-6-(4-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-ylamino)pyridin-3-yl)-1-methylpyridin-2(1H)-one (0.051 g, 24.80 %).EN04155-91-001:1H NMR in DMSO-d6 is consistent with desired productMSnbsp;(m+1) = 476.1.HPLC Peak RT = 2.48 minutes is product.nbsp;Purity = 97%.EN04155-91-002:1H NMR in DMSO-d6 is consistent with desired productMSnbsp;(m+1) = 476.1.HPLC Peak RT = 2.48 minutes is product.nbsp;Purity = 98%." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CC(OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(C(=O)C=C4)C)OC)CC(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 26.75 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/05/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "490" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00251 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.012 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" - } - amount { - moles { - value: 0.00167 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=C(C=C1F)Br)F" - } - amount { - moles { - value: 0.00209 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00017 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)[PH+](C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5[PH+](C6=CC=CC=C6)C7=CC=CC=C7)C.C1=[C-]C=C(C=C1F)F.Br[Pd+]" - } - amount { - moles { - value: 0.00017 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Pd complexe (147 mg, 0.17 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (600 mg, 1.67 mmol), 1-bromo-3,5-difluorobenzene (0.241 ml, 2.09 mmol) and cesium carbonate (818 mg, 2.51 mmol) dissolved in 1,4-dioxane (12 ml). The resulting suspension was degased with argon and then stirred at 100 C (15:00) for 18 hours.The reaction mixture was allowed to cool to room temperature, filtered and concentrated.The crude product was adsorbed on silica gelnbsp;and purified by flash chromatography on silica gel eluting with 0 to 6% methanol in ethyl acetate. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (314 mg, 39.9 %) as a clear yellow solid.blow yield but LCMS of the crude showed a nice reaction!bLCMS is OK." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 39.87 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/29/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "491" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00113 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" - } - amount { - moles { - value: 0.000753 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=C(C=C1F)Br)F" - } - amount { - moles { - value: 0.000829 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 4e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)[PH+](C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5[PH+](C6=CC=CC=C6)C7=CC=CC=C7)C.C1=[C-]C=C(C=C1F)F.Br[Pd+]" - } - amount { - moles { - value: 4e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Pd complexe (33.2 mg, 0.04 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (270 mg, 0.75 mmol), 1-bromo-3,5-difluorobenzene (0.095 ml, 0.83 mmol) and cesium carbonate (368 mg, 1.13 mmol) dissolved in 1,4-dioxane (5 ml). The resulting suspension was degased with argon and then stirred at 80 C.After 18 hours, lcms showed incomplete reaction: 5% more reactants were added and heating was continued at 100 C for 5 additionnal hours.Lcms showed ~ complete reactionnbsp;after 23 hours.The reaction mixture was allowed to cool to room temperature, filtered and concentrated.The crude product was purified by flash chromatography on silica gel eluting with 0 to 6% methanol in ethyl acetate. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (206 mg, 58.1 %) as a clear yellow foam.LCMS and NMR ar" - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 58.12 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/14/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "492" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00241 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.012 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" - } - amount { - moles { - value: 0.00161 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=C(C=C1F)Br)F" - } - amount { - moles { - value: 0.00201 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00016 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)[PH+](C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5[PH+](C6=CC=CC=C6)C7=CC=CC=C7)C.C1=[C-]C=C(C=C1F)F.Br[Pd+]" - } - amount { - moles { - value: 0.00016 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Pd complexe (142 mg, 0.16 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (577 mg, 1.61 mmol), 1-bromo-3,5-difluorobenzene (0.232 ml, 2.01 mmol) and cesium carbonate (787 mg, 2.41 mmol) dissolved in 1,4-dioxane (12 ml). The resulting suspension was degased with argon and then stirred at 100 C (10:30).After 3 hours, lcms showed complete reaction.The reaction mixture was allowed to cool to room temperature, filtered and concentrated.The crude product was purified by flash chromatography on silica gel eluting with 0 to 6% methanol in ethyl acetate. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (315 mg, 41.6 %) as a clear yellow foam.blow yield but LCMS of the crude showed complete reaction!bLCMS and NMR are OK" - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 41.59 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/05/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "494" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.002 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=COC(=N1)N" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 140.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Pd2(dba)3 (22.89 mg, 0.025 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (43.4 mg, 0.075 mmol), 2,4-dichloropyridine (148 mg, 1.00 mmol), cesium carbonate (651 mg, 2.00 mmol),ethyl 2-aminooxazole-4-carboxylate (156 mg, 1.00 mmol) were added to an oven dried microwave vial, the vial was capped and placed under an inert atmosphere, dioxane (4 mL) was added and the resulting mixture was heated to 140 C for 1 h by microwave irradiation under a nitrogen atmosphere.The crude product was purified by reverse-phase flash chromatography, elution gradient 0 to 100% MeCN in water. Pure fractions were evaporated to dryness to afford ethyl 2-(4-chloropyridin-2-ylamino)oxazole-4-carboxylate (99 mg, 37.0 %) as a pale yellow solid. Conclusion: Yield produced under microwave conditions is essentially identical to overnight reaction with conventional heating. Therefore screening of other aminooxazoles can be carried out under microwave conditions in the interest of time.. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=COC(=N1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 37.02 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/28/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "495" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[K+].[K+]" - } - amount { - moles { - value: 0.00334 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.00245 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.00222 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000111 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 6.67e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Charged a standard microwave vial with a mixture of 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (0.500 g, 2.45 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.611 g, 2.22 mmol), palladium (II) acetate (0.015 g, 0.07 mmol), rac-BINAP (0.069 g, 0.11 mmol), potassium carbonate (0.461 g, 3.34 mmol), and toluene (20 mL).nbsp;The atmosphere was inerted through consecutive vacuum-nitrogen purge cycles, then heated at 120 C for 16 hours.HPLC-UV shows some starting materials remaining (lt;11% at 254 nm).nbsp;The mixture was cooled to room temperature and 20 mL of DCM was added to the vessel.nbsp;The pH was adjusted to pH 2 with 2.0N aqueous HCl and the phases were separated.nbsp;Basified the aqueous with 2.0 M aqueous NaOH and extracted with 2 X 30 mL DCM.nbsp;The organics were combined, dried with magnesium sulfate and concentrated by rotary evaporator to yield EN04092-36-001 (811 mg, 1.833 mmol, 82 %)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=CC=CC=C5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 82.41 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/06/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "496" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000181 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0105 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.00258 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.00258 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000181 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000181 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (528 mg, 2.58 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (710 mg, 2.58 mmol), Sodium tert-butoxide (373 mg, 3.88 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (113 mg, 0.18 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (166 mg, 0.18 mmol) were added to a microwave vial followed by toluene (10.5 mL). The reaction mixture was flushed with nitrogen and the mixture was heated to 100C and stirred overnight. The reaction was complete. The solids were filtered off and washed with ethyl acetate. The organic solution was extracted by sat NaHCO3 solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography using DCM : [DCM:MeOH:NH3=90:10:1] = 100:0 to 60:40 as gradient. The product was obtained as yellow foam 766 mg purity 95-99% depending on wavelength (95% on 220nm). The compound was dissolvn DCM and treated with activated carbon, then filtered and concentrated. The purity was bnot bincreased by the treatment!Preparative purification with Gilson prep was performed, 30-70% gradient was used. The material was collected manually. The fractions were pooled together, concentrated in vacuo then treated with DCM and sat NaHCO3 solution. The phases were separated, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The product was obtained as white foam and was dried overnight in a vacuum oven at 40C.nbsp;nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=CC=CC=C5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 54.92 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/27/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "497" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[K+].[K+]" - } - amount { - moles { - value: 0.0367 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.1 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.0245 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.0245 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00122 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000734 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Charged a round-bottom flask with a mixture of 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (5.0 g, 24.48 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (6.73 g, 24.48 mmol), palladium (II) acetate (0.165 g, 0.73 mmol), rac-BINAP (0.762 g, 1.22 mmol), potassium carbonate (5.08 g, 36.72 mmol), and toluene (100 mL).nbsp;The atmosphere was inerted through consecutive vacuum-nitrogen purge cycles, then heated at 120 C for 16 hours.HPLC-UV shows a small percentage (lt;5%) of starting materials remaining.nbsp;Heating was continued for another 2 hours, then the heating block was removed and the mixture was allowed to cool to room temperature.nbsp;Added 200 mL dichloromethane and adjusted the pH to 2 with 2.0N aqueous HCl.nbsp;Separated the phases and basified the aqueous with 1.0N aqueous sodium hydroxide.nbsp;Extracted with 200 mL DCM, followed by a second extraction with 100 mL DCM.nbsp;The organics were dried with magnesium sulfate and concentr by rotary evaporator to yield EN04092-37-001 (10.9 g, 24.63 mmol, 101 %) as an amber-coloured foam." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=CC=CC=C5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 100.61 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/13/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "498" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[K+].[K+]" - } - amount { - moles { - value: 0.0558 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.15 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.0372 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.0372 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00186 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00112 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Charged a round-bottom flask with a mixture of 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (7.6 g, 37.21 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (10.22 g, 37.21 mmol), palladium (II) acetate (0.251 g, 1.12 mmol), rac-BINAP (1.159 g, 1.86 mmol), potassium carbonate (7.71 g, 55.82 mmol), and toluene (150 mL).nbsp;The atmosphere was inerted through consecutive vacuum-nitrogen purge cycles, then heated at 120 C for 16 hours.HPLC-UV shows lt;9% of starting materials remaining.nbsp;Added an additional 25mg palladium acetate and 116 mg BINAP, then heating was continued for another 2 hours.nbsp;HPLC-UV does not show any additional progress.nbsp;The heating block was removed and the mixture was allowed to cool to room temperature.nbsp;Added 300 mL dichloromethane and adjusted the pH to 2 with 2.0N aqueous HCl.nbsp;Separated the phases and basified the aqueous with 1.0N aqueous sodium hydroxide.nbsp;Extracted with 200 mL DCM, followed by a sd extraction with 100 mL DCM.nbsp;The organics were dried with magnesium sulfate and concentrated by rotary evaporator to yield EN04092-38-001 (16.1 g, 36.4 mmol, 98 %) as an amber-coloured foam." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=CC=CC=C5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 97.77 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/15/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "499" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[K+].[K+]" - } - amount { - moles { - value: 0.0331 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.09 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.022 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.022 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.0011 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000661 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Charged a round-bottom flask with a mixture of 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (4.5 g, 22.03 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (6.05 g, 22.03 mmol), palladium (II) acetate (0.148 g, 0.66 mmol), rac-BINAP (0.686 g, 1.10 mmol), potassium carbonate (4.57 g, 33.05 mmol), and toluene (90 mL).nbsp;The atmosphere s inerted through itrogen purge cycles, then heated at 120 C or 16 hours.HPLC-UV shows lt;5% of starting materials remaining.nbsp;The heating block was removed and the mixture was allowed to cool to room temperature.nbsp;Added 300 mL dichloromethane and adjusted the pH to 2 with 2.0N aqueous HCl.nbsp;Separated the phases and basified the aqueous with 1.0N aqueous sodium hydroxide.nbsp;Extracted with 200 mL DCM, followed by a second extraction with 100 mL DCM.nbsp;The organics were dried with magnesium sulfate and concentrated by rotary evaporator to give EN04092-39-001 (9.90g, 22.37 mmol, 102%).autotext key=quot36C73quot; name=quot;[Samples]quot; index=quot;0quot; field=quot;Samplesquot; type=quot;fieldquot; length=quot;9quot;gt;ber-coloured foam." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=CC=CC=C5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 101.53 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/22/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "500" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000437 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.016 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.00437 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.00437 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000437 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000218 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (0.892 g, 4.37 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (1.20 g, 4.37 mmol), Sodium tert-butoxide (0.630 g, 6.55 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.272 g, 0.44 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (0.200 g, 0.22 mmol) were added to a microwave vial followed by toluene (16 mL). The reaction mixture was flushed with nitrogen and the mixture was heated to 100C and stirred overnight. The reaction was completed. The solids were filtered off and washed with DCM. The organic solution was extracted by sat NaHCO3 solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography using DCM : [DCM:MeOH:NH3=90:10:1] = 100:0 to 60:40 as gradient. The product was obtained as yellow foam 1.55 g with a purity 96-99% depending on wavelength (96% on 220nm). Preparative purificationh Gilson prep was performed, 30-70% gradient was used. The material was collected manually. The fractions were pooled together, concentrated in vacuo then treated with DCM and sat NaHCO3 solution. The phases were separated. The aqueous layer was extracted with DCM 2 more times than once with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The product was obtained as white foam and was dried overnight in a vacuum oven at 50C. According to 1H-NMR 1.5 % ethyl acetate was present in the sample. bEthyl acetate should be avoided for extraction!b The sample was dissolved in DCM and concentrated in vacuo then the process was repeated 2 more times. The product was dried in a vacuum oven overnight at 50C.n" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=CC=CC=C5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 58.78 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/01/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "501" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[K+].[K+]" - } - amount { - moles { - value: 0.0067 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.00372 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.00372 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000186 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000112 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Charged a round-bottom flask with a mixture of 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (0.76 g, 3.72 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (1.022 g, 3.72 mmol), palladium (II) acetate (0.025 g, 0.11 mmol), rac-BINAP (0.116 g, 0.19 mmol), potassium carbonate (0.926 g, 6.70 mmol), and toluene (15 mL).nbsp;The atmosphere was inerted through consecutive vacuum-nitrogen purge cycles, then heated at 110 C under N2(g) for 16 hours. HPLC-UV shows a small percentage (3-6% depending on wavelength) of oxazepine remaining, aminopyridine if fully converted. The mixture was allowed to cool to room temperature. DCM and 2M HCl was added and the orgaic phase were removed. The aqueous phase were basified using solid KOH and a 4M solution. Extracted with DCM, dried oved MgSO4 and concentrated." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=CC=CC=C5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 86.23 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/19/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "502" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[K+].[K+]" - } - amount { - moles { - value: 0.141 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.2 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.0783 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.0783 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00392 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00235 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2011-05-03; 16:30Charged a round-bottom flask with a mixture of 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (16 g, 78.34 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (21.52 g, 78.34 mmol), palladium (II) acetate (0.528 g, 2.35 mmol), rac-BINAP (2.439 g, 3.92 mmol), potassium carbonate (19.49 g, 141.02 mmol), and toluene (200 mL).nbsp;The atmosphere was inerted through consecutive vacuum-nitrogen purge cycles, then heated at 110 C under N2(g).2011-05-04;nbsp;10:52:55HPLC-UV shows a small percentage (3-6% depending on wavelength) of oxazepine remaining, aminopyridine if fully converted. The mixture was allowed to cool to room temperature. DCM and 2M HCl was added and the orgaic phase were removed. The aqueous phase were basified using solid KOH,nbsp;extracted with DCM and concentrated EN04644-87-001 (13 g, 29.4 mmol, 37.5 %) .The remaining organic phase was treated second time with HCl 2M, this aqueous phase ained also product ( 75% according with HPLC). The HCl solution was basified using KOH and extracted with DCM to give EN04644-87-002.EN04644-87-001 (13 g, 29.4 mmol, 37.5 %) (36g of crude) was dissolved in iPrOH (70mL) with heating and the slurry was left over a long weekend (4d). The precipitated obtained (after seeding with a sample from Jacob EN0) had 87% purity. The precipitated obtained (19g) were sent to Daniel for purification." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=CC=CC=C5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 37.5 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/03/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "503" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[K+].[K+]" - } - amount { - moles { - value: 0.0347 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.1 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.0231 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.0231 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00116 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000693 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a 250 mL roundbottomed flask was added 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (5.5 g, 23.11 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (6.50 g, 23.11 mmol), Palladium(II)acetate (0.157 g, 0.69 mmol), rac-BINAP (0.734 g, 1.16 mmol), Potassium carbonate (4.79 g, 34.66 mmol) and toluene (100 mL). The atmosphere was exchanged to nitrogen through consecutive vacuum-nitrogen purge cycles after which the mixture was heated at 120 C for 16 h. Still some starting material left according to HPLC and LCMS (IPC 1), so another 25 mg of Pd(OAc)2 and 116 mg of BINAP was added, and heating continued. After another 4 h, no further progress was detected (IPC 2), so the mixture was allowed to cool to r.t.Dichloromethane (200 mL) was added and pH was adjusted to 2 by addition of 2M HCl (aq) (80 mL was added, but made too acidic). The phases were separated and the aq phase was made basic by addition of 1M NaOH (aq) (ca 70 mL). The aq phase was acted with dichloromethane (200 mL) and re-extracted with another portion of dichloromethane (70 mL). Since the aq phase still contained some product, another portion of 1M NaOH (aq) (20 mL) was added and the aq phase was extracted with dichloromethane (100 mL). The combined organic layers were evaporated and toluene was added to co-evaporate water. The resulting brown solid was dried under vacuum o.n, yielding EN04391-37-001 (12 g, 27.1 mmol, 117 %).To the solid was added EtOAc (55 mL) and the slurry was stirred at r.t for 1 h. Stirring was turned off and the solid was allowed to sediment for 2 h. The solid was filtered off and washed with 2x 12 mL cold EtOAc, yielding EN04391-37-002 (5.7 g, 12.88 mmol, 55.7 %).The mother liquor still contained product so it was concentrated and to the residue was added isopropanol (18 mL, 2 mL g crude). The mixture was heated to dissolve everything (50 C for 5 min) and was then stirred at r.t over night. A white precipitate had formed. The mixture wasled on an ice bath (0-5 C) for 1 h after which the solid was filtered off, washed with 2x10 mL cold isopropanol and dried at 40 C under vacuum, yielding EN04391-37-003 (2.3 g, 5.20 mmol, 22.49 %).EN04391-37-002 and EN04391-37-003 were combined with EN04391-36-002 and EN04391-36-003 and further purified, see page EN04391" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=CC=CC=C5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 78.24 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/12/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "504" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[K+].[K+]" - } - amount { - moles { - value: 0.0378 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.1 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.0252 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.0252 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00126 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000756 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a 250 mL roundbottomed flask was added 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (6 g, 25.21 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (7.10 g, 25.21 mmol), Palladium(II)acetate (0.171 g, 0.76 mmol), rac-BINAP (0.801 g, 1.26 mmol), Potassium carbonate (5.23 g, 37.81 mmol) and toluene (100 mL). The atmosphere was exchanged to nitrogen through consecutive vacuum-nitrogen purge cycles after which the mixture was heated at 120 C for 18 h. Still some starting material left according to HPLC and LCMS (IPC 1), so another 25 mg of Pd(OAc)2 and 116 mg of BINAP was added, and heating continued. After another 3 h, approx. 2% starting material remained according to LCMS (IPC 2), so the mixture was allowed to cool to r.t. Dichloromethane (200 mL) was added and pH was adjusted to 2 by addition of 2M HCl (aq) (140 mL was added, but made too acidic). The phases were separated and the aq phase was made basic by addition of 1M NaOH (aq) (ca 200 mL). Tq phase was extracted with dichloromethane (200 mL) and re-extracted with another portion of dichloromethane (70 mL). Since an oily residue containing product had precipitated upon addition of acid base, the aq phase together with 100 mL dichloromethane was added to the residue in an attempt to dissolve it. More 1M NaOH (aq) was added to assure basic pH and the layers were separated. The combined organic layers were evaporated and the residue was dried under vacuum o.n. EN04391-36-001 (12.2 g, 27.6 mmol, 109 %) was obtained as a brown solid.To the solid was added isopropanol (48 mL, 4 mLg crude prod) and the thick suspension was heated at 95 C. After 30 min, the slurry was allowed to cool to r.t and left stirring over night. The still thick slurry was cooled on an ice bath at 0-5 C for 1 h before it was filtered. The solid was washed with 4x15 mL of cold isopropanol and dried at 40 C under vacuum o.n, yielding EN04391-36-002 (2.05 g, 4.63 mmol, 18.38 %) as a pale yellow solid liquor that still contained product was concentrated. An orange-brown foam was obtained. Toluene was added and evaporated and the residue (8 g) was dissolved in MeCN (13.5 mL) and purified by chromatography (200 g SiO2 in a filter funnel, elutent: EtOAc (750 mL) followed by MeCN (1 L) and MeCN:MeOH 9:1 (1 L)). Fractions 10-13 were combined, concentrated and dried, yielding EN04391-36-003 (5.5 g, 12.43 mmol, 49.3 %) as a solid. EN04391-36-002 and EN04391-36-003 were further purified on page EN04391-38. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=CC=CC=C5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 67.69 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/12/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "507" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000191 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.011 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.00273 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.00273 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000191 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000191 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (558 mg, 2.73 mmol), (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (750 mg, 2.73 mmol), Sodium tert-butoxide (394 mg, 4.09 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (119 mg, 0.19 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (175 mg, 0.19 mmol) were added to a microwave vial followed by toluene (11 mL). The reaction mixture was flushed with nitrogen and the mixture was heated to 100C and stirred overnight. The reaction was complete. The solids were filtered off and washed with ethyl acetate. The organic solution was extracted by sat NaHCO3 solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography using DCM : [DCM:MeOH:NH3=90:10:1] = 100:0 to 10:90 as gradient. fr1 :160 mg approx 60% purefr2: 804 mg purity 90-99% depending on wavelength, pH and solvent.Preparativrification with Gilson prep was performed on the combined mixture. 30-70% gradient was used. The first batch (38% of the crude) was lost due to the fact that the product gave bnegative UV-signal btherefore didn\'t trigger any collection! The rest of the material was collected manually. The fractions were pooled together, concentrated in vacuo then tretaed with DCM and sat NaHCO3 solution. The phases were separated, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The product was obtained as white foam was dried overnight in a vacuum owen at 50C.nbsp;nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=CC=CC=C5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 32.29 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/20/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "509" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000487 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000324 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC(=NC=C1)C2CN(CC3=C(O2)N=C(C=C3)Cl)C" - } - amount { - moles { - value: 0.000324 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 3.24e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.62e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (66.3 mg, 0.32 mmol), 8-chloro-4-methyl-2-(4-methylpyridin-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (94 mg, 0.32 mmol), Sodium tert-butoxide (46.8 mg, 0.49 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (20.20 mg, 0.03 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (14.85 mg, 0.02 mmol) were added to a microwave vial then toluene (2 mL) was added. The reaction mixture was flushed with nitrogen and the mixture was heated to 100C and stirred overnight. The reaction was complete. The solids were filtered off and washed with DCM. The organic solution was extracted by sat NaHCO3 solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography using DCM : [DCM:MeOH:NH3=90:10:1] = 100:0 to 20:80 as gradient. Beige foam." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CC(=NC=C1)C2CN(CC3=C(O2)N=C(C=C3)NC4=NC(=C(C=C4)C5=CN(N=C5)C)OC)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 43.12 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/25/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "510" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000823 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000549 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN=C(C=C1)C2CN(CC3=C(O2)N=C(C=C3)Cl)C" - } - amount { - moles { - value: 0.000549 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 5.49e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.74e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (0.112 g, 0.55 mmol), 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (0.112 g, 0.55 mmol), Sodium tert-butoxide (0.079 g, 0.82 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.034 g, 0.05 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (0.025 g, 0.03 mmol) were added to a microwave vial then toluene (3 mL) was added. The reaction mixture was flushed with nitrogen and the mixture was heated to 100C and stirred overnight. The reaction was complete. The solids were filtered off and washed with DCM. The organic solution was extracted by sat NaHCO3 solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography using DCM : [DCM:MeOH:NH3=90:10:1] = 100:0 to 20:80 as gradient. Yellow foam." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN=C(C=C1)C2CN(CC3=C(O2)N=C(C=C3)NC4=NC(=C(C=C4)C5=CN(N=C5)C)OC)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 67.71 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/26/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "511" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 2.75e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.00318 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" - } - amount { - moles { - value: 0.000323 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=C(C=C1F)Br)F" - } - amount { - moles { - value: 0.000404 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 2.75e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.29e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (2.90 mg, 0.01 mmol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (120 mg, 0.32 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (15.89 mg, 0.03 mmol), 1-bromo-3,5-difluorobenzene (46.5 l, 0.40 mmol) and cesium carbonate (158 mg, 0.48 mmol) suspended in 1,4-dioxane (3184 l). The resulting suspension was degased with argon and then stirred at 100 C for 20 hours. Purification made by NWAThe reaction mixture was allowed to cool to room temperature, The crude product was adsorbed on silica gel, the solvent was evaporated, and purified by flash chromatography on silica gel eluting with 0 to 10% methanol in ethyl acetate. The solvent was evaporated to dryness, the gum was triturated in Et2Opentane to give a solid; the solid was filtered and dried to affordnbsp;8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (80 mg, 51.2 %) ase solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 51.21 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/31/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "512" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 2.75e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.00318 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" - } - amount { - moles { - value: 0.000323 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=C(C=C1F)Br)F" - } - amount { - moles { - value: 0.000404 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 2.75e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.29e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (2.90 mg, 0.01 mmol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (120 mg, 0.32 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (15.89 mg, 0.03 mmol), 1-bromo-3,5-difluorobenzene (46.5 l, 0.40 mmol) and cesium carbonate (158 mg, 0.48 mmol) suspended in 1,4-dioxane (3184 l). The resulting suspension was degased with argon and then stirred at 100 C for 20 hours. The mixture was evaporated and diluted with DMF.Purification made by KOKOThe reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholinoromene-6-carboxamide (77 mg, 49.3 %)nbsp;as anbsp;beige solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 49.29 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/31/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "513" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0075 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0236 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CCNCC1" - } - amount { - moles { - value: 0.006 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC=C(C=C1)Br" - } - amount { - moles { - value: 0.005 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00025 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00025 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 250 mL round-bottomed flask was ethyl 4-bromobenzoate (816 l, 5 mmol), piperidine (593 l, 6.00 mmol), and CESIUM CARBONATE (2444 mg, 7.50 mmol) in dioxane (2.36E+04 l) to give a white suspension.nbsp;The solution was degassed with N2 (g) for 15 min and then added BINAP (156 mg, 0.25 mmol) and PALLADIUM(II) ACETATE (56.1 mg, 0.25 mmol).nbsp;The reaction was heated to 100 C and stirred under a reflux condenser overnight.nbsp;The reaction was checked by LC-MS (complete), filtered, rinsed with DCM, concentrated in vacuo and onto silica gel.nbsp;Purification by Iscos (25 g.) using 100% hexanes -gt; 40% EtOAc in Hexanes afforded a white solid.nbsp;950 mg of a white solid obtained.nbsp;1H NMR (300 MHz, DMSO-idi6) d ppm 1.28 (t, iJi=7.08 Hz, 3 H) 1.58 (s, 6 H) 3.31 - 3.38 (m, 4 H) 4.23 (q, iJi=7.11 Hz, 2 H) 6.94 (m, iJi=9.06 Hz, 2 H) 7.76 (m, iJi=9.25 Hz, 2 H)LC-MS:nbsp;Rt = 2.98 min.nbsp;Method:nbsp;Short Purity.sp;234.2 [M+H]+. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC=C(C=C1)N2CCCCC2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 81.44 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/29/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "514" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.003 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.00976 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CCNCC1" - } - amount { - moles { - value: 0.0024 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)C1=CN=C(C=C1)Br" - } - amount { - moles { - value: 0.002 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.0001 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.0001 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 100 mL round-bottomed flask was tert-butyl 6-bromonicotinate (516 mg, 2 mmol), piperidine (237 l, 2.40 mmol), and CESIUM CARBONATE (977 mg, 3.00 mmol) in dioxane (9763 l) to give a white suspension.nbsp;The solution was degassed with N2 (g) fo 20 mins.nbsp;PALLADIUM(II) ACETATE (22.45 mg, 0.10 mmol) and BINAP (62.3 mg, 0.10 mmol) were added under N2 (g) and the reaction was heated to 100 C.nbsp;Start Time:nbsp;01-Jul-10 1:10:32 PM -0400.nbsp;The reaction was checked by LC-MS (complete), filtered, rinsed with DCM, concentrated in vacuo.nbsp;u02 July 2010uPurification by Iscos (25 g) using 100% Hexanes -gt; 50% EtOAc in Hexanes afforded a white solid.nbsp;325 mg obtained.nbsp;1H NMR (300 MHz, DMSO-idi6) d ppm 1.51 - 1.57 (m, 12 H) 1.57 - 1.77 (m, 5 H) 3.58 - 3.74 (m, 4 H) 6.78 - 6.92 (m, 1 H) 7.88 (dd, iJi=9.16, 2.36 Hz, 1 H) 8.60 (dd, iJi=2.45, 0.57 Hz, 1 H).LC-MS:nbsp;Rt = 2.37 min.nbsp;Mehort Purity.nbsp;MS ES+:nbsp;263.2 [M+H]+." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)C1=CN=C(C=C1)N2CCCCC2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 61.94 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/30/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "515" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0552 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.1 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.0505 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC(=CC(=C1)Br)C(=O)OC" - } - amount { - moles { - value: 0.0366 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00401 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00401 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a solution of dimethyl 5-bromoisophthalate (10 g, 36.62 mmol) in toluene (100 mL) where BINAP (2.5 g, 4.01 mmol), morpholine (4.4 g, 50.50 mmol), CESIUM CARBONATE (18 g, 55.25 mmol) and PALLADIUM(II) ACETATE (0.9 g, 4.01 mmol) added. The solution was heated to reflux under inert atm for 14h. The silvent was filtered and the filtrate was concentrated. The residue was purified by column chropmatography (Hep:EA) 1:1 to give dimethyl 5-morpholinoisophthalate (8.00 g, 78 %)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC(=O)C1=CC(=CC(=C1)N2CCOCC2)C(=O)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 78.22 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/18/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "516" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0172 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.035 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.0115 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=NC=C1Br)Br" - } - amount { - moles { - value: 0.0127 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000689 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.00023 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of 3,5-dibromopyridine (3.01 mL, 12.66 mmol), morpholine (1.00 g, 11.48 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (0.210 g, 0.23 mmol), sodium 2-methylpropan-2-olate (1.655 g, 17.22 mmol) and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.429 g, 0.69 mmol) in degassed toluene (35 mL) was stirred for 16 hours at 110 C in a sealed vessel under inert atmosphere. Extraction with sat. aq. Na2CO3 solution and AE, then back extraction 2x NaCl sat using DCM. The organics were dried over MgSO4 and evaporated iin vacuoi. The residue (see structure below, LC MS FLA-04227-45-02: 3,5 dimorpholino pyridine) was washed off with diethylether, then AE. The liquors were vaporated iin vacuoi. The residue was purified by chromatography (11 cm SiO2, diameter: 5 cm) eluent: AEhex 2575to 4555 to provide 4-(5-bromopyridin-3-yl)morpholine (1.400 g, 50.2 %) as a yellow solid.1H NMR, LC MS: FLA-04227-45-03. OK-----------------------------------------------------" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1COCCN1C2=CC(=CN=C2)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 50.17 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/12/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "517" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00841 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNCCOC" - } - amount { - moles { - value: 0.00561 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=NC=C1Br)Br" - } - amount { - moles { - value: 0.00617 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00028 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000112 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of 3,5-dibromopyridine (1.468 mL, 6.17 mmol), 2-methoxy-N-methylethanamine (0.602 mL, 5.61 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (0.103 g, 0.11 mmol), sodium 2-methylpropan-2-olate (0.809 g, 8.41 mmol) and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.175 g, 0.28 mmol) in degassed toluene (15 mL) was stirred for 16 hours at 90 C in a sealed vessel under inert atmosphere. LC MS of the crude mixture: FLA 04227-53-01. Extraction with sat. aq. Na2CO3 solution and AE, then back extraction 2x NaCl sat using DCM. The organics were dried over MgSO4 and evaporated iin vacuoi. The residue was purified by chromatography (11 cm SiO2, diameter: 3.5 cm) eluent: AEhex 2575to 4060 to provide 5-bromo-N-(2-methoxyethyl)-N-methylpyridin-3-amine (0.930 g, 67.6 %)nbsp;as a yellow oil.1H NMR, LC MS: FLA-04227-53-02. OK" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(CCOC)C1=CC(=CN=C1)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 67.64 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/20/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "518" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 8.64e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CN1CCCC1=O" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1N)S(=O)(=O)N" - } - amount { - moles { - value: 0.0011 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC(=NC=C1)Cl" - } - amount { - moles { - value: 0.000938 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 8.64e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 5.79e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of 4-aminobenzenesulfonamide (190mg, 1.10 mmol), 2-chloro-4-methoxypyridine (135 mg, 0.94 mmol), diacetoxypalladium (13mg, 0.06 mmol), cesium carbonate (417mg, 1.28 mmol) andnbsp;(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (50 mg, 0.09 mmol) in NMP (2.0 mL) was heatedb in the microwaveb for 10 min at 150 C. LC MS crude mix. FLA-04227-80-01 showed no reaction. Another 30 min at 150C in the microwave provided FLA-04227-80-02 (crude mix.).No product. bDiscard." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=CC(=NC=C1)NC2=CC=C(C=C2)S(=O)(=O)N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/10/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "519" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000697 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.0018 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1N)S(=O)(=O)N" - } - amount { - moles { - value: 0.000581 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)Br" - } - amount { - moles { - value: 0.000581 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 4.65e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.32e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 130.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of 4-aminobenzenesulfonamide (100 mg, 0.58 mmol), bromobenzene (0.061 mL, 0.58 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (26.9 mg, 0.05 mmol), diacetoxypalladium (5.21 mg, 0.02 mmol) and cesium carbonate (227 mg, 0.70 mmol)nbsp;in degassed DMA (1.8 mL) was heatedb uin the microwaveub for 20 min at 130 C. LC MS FLA-04227-96-01 (pH extract 7-8) showed some product and a few bromobenzene left. Heating was continued for 15 min at 150C. LC MS FLA-04227-96-02 (pH extract 7-8) showed reaction stalled. Reaction was stopped. Extraction with AE + ethanol aq. sat NH4Cl (pH7), then back extraction with DCM.The organics were dried over MgSO4 and concentrated iin vacuo. iThe crude product was adsorbed on silica gel 40-60m and purified by flash chromatography on silica gel 15-40m eluting with 2 % of ethanol in dichloromethane (NH3 0.5 %) to provide 4-(phenylamino)benzenesulfonamide (60.0 mg, 41.6 %) as a gum. 1H 4227-96-03: OKbiNote: the product still contains 24% mol DMAibbiCorrected yield: 30%ib" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=CC=C(C=C2)S(=O)(=O)N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 41.61 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/23/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "520" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 3.5e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" - } - amount { - moles { - value: 0.00035 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC(=CC=C1)Br" - } - amount { - moles { - value: 0.000437 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.75e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (3.93 mg, 0.02 mmol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (130 mg, 0.35 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (20.25 mg, 0.03 mmol), 1-bromo-3-methoxybenzene (0.055 ml, 0.44 mmol) and cesium carbonate (171 mg, 0.52 mmol) dissolved in 1,4-dioxane (4 ml). The resulting suspension was degased with argon and then stirred at 100 C for 15 hours.The reaction mixture was allowed to cool to room temperature, filtered and concentrated in V-10 Evaporator (Biotage)The crude product was dissolved in 2ml of DMA.The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 60 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to rdnbsp;8-(1-(3-methoxyphenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (46.0 mg, 27.5 %) as anbsp;solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC=C4)OC)OC(=CC2=O)N5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 27.52 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/10/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "521" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0149 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.03 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)N" - } - amount { - moles { - value: 0.0132 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C(=C1)[N+](=O)[O-])Br" - } - amount { - moles { - value: 0.0104 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000318 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000131 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 200 mL roundbottom flask was charged with 1-bromo-2-nitrobenzene (Alfa Aesar; 2.10 g, 10.40 mmol), Pd2(dba)3 (Aldrich; 119.6 mg, 2.5 mol%), racemic BINAP (Strem; 197.8 mg, 3.1 mol%), and cesium carbonate (Aldrich; 4.87 g, 14.95 mmol).nbsp;The flask was evacuated and backfilled with N2 (3x), and then anhydrous toluene (20 mL) was added.nbsp;Aniline (Acros; 1.20 mL, 13.2 mmol) was added followed by additional toluene (30 mL), and the mixture was allowed to stir at room temperature for 5 minutes before being placed in a 100 C oil bath.After heating overnight, the reaction was allowed to cool and was partitioned between EtOAc and water.nbsp;The aqueous layer was extracted with EtOAc (2x), and the combined organics were concentrated under reduced pressure.nbsp;The crude material was purified by silica gel chromatography (gradient elution; Rf in 90:10 hexanes:EtOAc = 0.54) to give a red-orange solid.nbsp;1.89 g of solid was collected." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=CC=CC=C2[N+](=O)[O-]" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 84.87 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/28/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "522" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000609 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000406 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CSC(=N1)C2CN(CC3=C(O2)N=C(C=C3)Cl)C" - } - amount { - moles { - value: 0.000406 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 4.06e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.06e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To 8-chloro-4-methyl-2-(4-methylthiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (120 mg, 0.41 mmol) in DME (3 mL) were 6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-amine (83 mg, 0.41 mmol), cesium carbonate (198 mg, 0.61 mmol), 2-(Dicyclohexylphosphino)biphenyl (14.22 mg, 0.04 mmol) and Palladium acetate (9.11 mg, 0.04 mmol) added. The reaction was heated to 110C for 180 min under N2 atmosphere. The solids were filtered off and washed with DCM, the solvents were evaporated and the crude product was purified by silica flash chromatography, MeOH, 0-10%, in DCM yielding N-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methyl-2-(4-methylthiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (20.00 mg, 10.63 %)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(N=C(C=C2)NC3=NC4=C(CN(CC(O4)C5=NC(=CS5)C)C)C=C3)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 10.63 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/17/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "523" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000254 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000169 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CSC(=N1)C2CN(CC3=C(O2)N=C(C=C3)Cl)C" - } - amount { - moles { - value: 0.000169 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 1.69e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.69e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To 8-chloro-4-methyl-2-(4-methylthiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (50 mg, 0.17 mmol) in DME (3 mL) were 6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-amine (34.5 mg, 0.17 mmol), cesium carbonate (83 mg, 0.25 mmol), 2-(Dicyclohexylphosphino)biphenyl (5.92 mg, 0.02 mmol) and Palladium acetate (3.80 mg, 0.02 mmol) added. The reaction was heated to 110C for 90 min under N2 atmosphere. The solids were filtered off and washed with DCM, the solvents were evaporated and the crude product was purified by silica flash chromatography, MeOH, 0-10%, in DCM yielding N-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methyl-2-(4-methylthiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (16.00 mg, 20.42 %)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(N=C(C=C2)NC3=NC4=C(CN(CC(O4)C5=NC(=CS5)C)C)C=C3)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 20.42 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/17/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "524" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00862 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.00678 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=C(C=CC(=C1)Br)I" - } - amount { - moles { - value: 0.00616 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000616 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000616 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a solution of methyl 5-bromo-2-iodobenzoate (2.1 g, 6.16 mmol) in DME (15 mL) were morpholine (0.593 mL, 6.78 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.384 g, 0.62 mmol), Palladium acetate (0.138 g, 0.62 mmol) and CESIUM CARBONATE (2.81 g, 8.62 mmol) added. The mixture was heated in the microwave oven for 1h. The solvent was evaporated and the crude product was added to a silica gel column, 0-25% EtOAc in heptane yielding [Products]" - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC(=O)C1=C(C=CC(=C1)Br)N2CCOCC2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 17.85 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/15/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "525" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0116 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.00639 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC(=C(C=C1)I)Br" - } - amount { - moles { - value: 0.00581 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000581 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000581 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a solution of methyl 3-bromo-4-iodobenzoate (1.981 g, 5.81 mmol) in DME (10 mL) were morpholine (0.559 mL, 6.39 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.362 g, 0.58 mmol), Palladium acetate (0.130 g, 0.58 mmol) and CESIUM CARBONATE (3.79 g, 11.62 mmol) added. The mixture was heated in the microwave oven for 12h at 110C. The solids were filtered off through celite, the solvent was evaporated and the crude product was added to a silica gel column, 0-30% EtOAc in heptane yielding methyl 3-bromo-4-morpholinobenzoate (0.566 g, 32.5 %)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC(=O)C1=CC(=C(C=C1)N2CCOCC2)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 32.45 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/15/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "526" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 3.5e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" - } - amount { - moles { - value: 0.00035 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)Br)F" - } - amount { - moles { - value: 0.000437 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.75e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (3.93 mg, 0.02 mmol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (130 mg, 0.35 mmol), 1-bromo-3-fluorobenzene (0.049 ml, 0.44 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (20.25 mg, 0.03 mmol) and cesium carbonate (171 mg, 0.52 mmol) dissolved in 1,4-dioxane (4 ml). The resulting suspension was degased with argon and then stirred at 100 C for 16 hours.The reaction mixture was allowed to cool to room temperature, filtered and concentrated in V-10 Evaporator (Biotage)The crude product was dissolved in 2ml of DMA.The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 60 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to ad 8-(1-(3-fluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (67.0 mg, 41.1 %)nbsp;as anbsp;solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC=C4)F)OC(=CC2=O)N5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 41.12 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/10/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "527" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CCC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00131 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=CC1=O)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.00109 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.00109 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000109 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000109 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (300 mg, 1.09 mmol), 5-(6-amino-2-methoxypyridin-3-yl)-1-methylpyridin-2(1H)-one (253 mg, 1.09 mmol), Palladium(II) acetate (24.51 mg, 0.11 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (63.2 mg, 0.11 mmol) and Sodium tert-pentoxide (144 mg, 1.31 mmol) were mixed in dioxane (3 mL) and run in a microwave reactor for 40 min at 120C. the mixture was filtered thru celite and concetrated. purified using flash column chromatography using 0-6 % MeOH (1% NH3) in DCM." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(C(=O)C=C4)C)OC)C5=CC=CC=C5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 35.11 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/13/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "528" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000145 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN(C)CCOC1=CN=C(C=C1)N" - } - amount { - moles { - value: 0.000966 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(N=CN=C1Cl)N2C=NC3=CC=CC=C32" - } - amount { - moles { - value: 0.000966 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000145 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 4.83e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (44.2 mg, 0.05 mmol) was added to 5-(2-(dimethylamino)ethoxy)pyridin-2-amine (175 mg, 0.97 mmol), 1-(6-chloro-5-methylpyrimidin-4-yl)-1H-benzo[d]imidazole (236 mg, 0.97 mmol), sodium t-butoxide (139 mg, 1.45 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (84 mg, 0.14 mmol) in toluene (10 mL) at 20C under nitrogen. The resulting suspension was stirred at 100 C for 16 hours then cooled to room temperature. LCMS analysis indicates no SM, product peak present. The reaction mixture was diluted with DCMMeOH, filtered and filtrate concentrated iin vacuoi. The residue was dissolved in DCM (100 mL) and washed with water (100 mL). The organic layer was passed through phase separating cartridge and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN Fractions containing the desired compound were evaporated to dryness to afford 6-(1H-benzo[d]imidazol-1-yl)-N-(5-(2-(dimethylamino)ethoxy)pyridin-2-yl)-5-methylpyrimidin-4-amine (67.0 mg, 17.82 %) as a yellow solid. nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(N=CN=C1N2C=NC3=CC=CC=C32)NC4=NC=C(C=C4)OCCN(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 17.82 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/06/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "530" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000216 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.00216 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CC(OC2=C(C1)C=CC(=N2)Cl)CC(F)(F)F" - } - amount { - moles { - value: 0.00216 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" - } - amount { - moles { - value: 0.000216 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" - } - amount { - moles { - value: 0.000108 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A reaction mixture of 8-chloro-4-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.605 g, 2.16 mmol), 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (0.440 g, 2.16 mmol), Cs2CO3 (1.053 g, 3.23 mmol), Tri-t-butylphosphonium tetrafluoroborate (0.063 g, 0.22 mmol) and Bis(dibenzylideneacetone)palladium (0.062 g, 0.11 mmol) in DME (20 mL) was flushed with argon and run in the microwave at 120C for 60 minutes. Have unreacted startingmaterial left. Added Tri-t-butylphosphonium tetrafluoroborate (0.063 g, 0.22 mmol) and Bis(dibenzylideneacetone)palladium (0.062 g, 0.11 mmol) and ran the vial at 120C for another hour. The mixture was filtered through celite and washed with DCM. The solvent was evaporated and the crude prouduct was purified by silica flash chromatography using a gradient of metanol (0 to 5%) in dichloromethane giving N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-(0.483 g, 50.0 %). " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CC(OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)CC(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 49.97 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/20/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "532" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 9.41e-06 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 9.41e-05 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CC(OC2=C(C1)C=CC(=N2)Cl)CC(F)(F)F" - } - amount { - moles { - value: 9.41e-05 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" - } - amount { - moles { - value: 9.41e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" - } - amount { - moles { - value: 4.7e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A reaction mixture of 8-chloro-4-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.044 g, 0.09 mmol), 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (0.019 g, 0.09 mmol), Cs2CO3 (0.046 g, 0.14 mmol), Tri-t-butylphosphonium tetrafluoroborate (2.73 mg, 9.41 mol) and Bis(dibenzylideneacetone)palladium (2.70 mg, 4.70 mol) in DME (2 mL) was flushed with argon and stirred at rt overnight. No product according to LCMS. The reaction mixture was then run in the microwave at 120C for 30 minutes. Have unreacted startingmaterial left. Ran the sample again at 120C for 30 minutes. Doesnt seemnbsp;as if the microwave warmed the vial. Added Tri-t-butylphosphonium tetrafluoroborate (2.73 mg, 9.41 mol) and Bis(dibenzylideneacetone)palladium (2.70 mg, 4.70 mol) and ran the vial at 120C for 1 hr. Reaction complete. The mixture was filtered through celite and washed with DCM. The solvent was evaporated and the crude prouduct was purified by g a gradient of metanol (0 to 5%) in dichloromethane giving N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (0.036 g, 85 %). " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CC(OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)CC(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 85.35 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/16/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "534" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000671 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CC(OC2=C(C1)C=CC(=N2)Cl)CC(F)(F)F" - } - amount { - moles { - value: 0.000671 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 6.71e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 6.71e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "8-chloro-4-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (60 % purity, 314 mg, 0.67 mmol), 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (137 mg, 0.67 mmol), PALLADIUM(II) ACETATE (15.07 mg, 0.07 mmol), 2-(DICYCLOHEXYLPHOSPHINO)BIPHENYL (23.53 mg, 0.07 mmol) and Cs2CO3 (328 mg, 1.01 mmol) were placed in a microwave vial. The vial was capped and flushed with argon. DME (3 mL) was added via a syringe and the resulting mixture was heated to 100C in a microwave apparatus for 2 h. The reaction mixture was diluted with dichloromethane, filtered and concentrated. The residue was purified first by column chromatography using Silica stationary phase and gradient elution with increasing concentration of methanol, from 0 to 8 %, in dichloromethane, and then by reversed phase HPLC to give N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (102 mg, 33.9 %)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CC(OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)CC(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 33.89 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/22/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "536" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00182 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.00121 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CC(OC2=C(C1)C=CC(=N2)Cl)CC(F)(F)F" - } - amount { - moles { - value: 0.00121 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 0.000121 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000121 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A reaction mixture of 8-chloro-4-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.341 g, 1.21 mmol), 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (0.248 g, 1.21 mmol),nbsp;PALLADIUM(II) ACETATE (0.027 g, 0.12 mmol), 2-(DICYCLOHEXYLPHOSPHINO)BIPHENYL (0.043 g, 0.12 mmol) and Cs2CO3 (0.594 g, 1.82 mmol) in DME (2 mL) was degassed and flushed with argon in a microwave vial. The reaction mixture was stirred at 110C for 1 hr. The reaction mixture was filtrated through celite, washed with DCM and concentrated. The crude product was purified by silica flash chromatography using a gradient of methanol (0 to 5%) in DCM giving N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-4-methyl-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (0.200 g, 36.7 %)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CC(OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)CC(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 36.71 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/18/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "538" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000629 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.00042 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1C(OC2=C(CN1C)C=CC(=N2)Cl)C3=NC(=CS3)C" - } - amount { - moles { - value: 0.00042 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 4.2e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.2e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (0.086 g, 0.42 mmol) in DME (3 mL) were 8-chloro-3,4-dimethyl-2-(4-methylthiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.130 g, 0.42 mmol), cesium carbonate (0.205 g, 0.63 mmol), 2-(Dicyclohexylphosphino)biphenyl (0.015 g, 0.04 mmol) and Palladium acetate (9.42 mg, 0.04 mmol) added. The reaction was heated to 110C for 60 min under argon atmosphere. The reaction mixture was filtered through celite, washed with DCM and the solvents were evaporated. The crude product was purified by silica flash chromatography, MeOH, 0-5%, in DCM yielding N-(6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-3,4-dimethyl-2-(4-methylthiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (0.147 g, 73.4 %). The product was mitted to the prepgroup for chiral separation. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1C(OC2=C(CN1C)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5=NC(=CS5)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 73.35 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/01/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "539" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 2.87e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.00333 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" - } - amount { - moles { - value: 0.000338 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)Br)F" - } - amount { - moles { - value: 0.000422 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 2.87e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.48e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (3.33 mg, 0.01 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (121 mg, 0.34 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (16.61 mg, 0.03 mmol), 1-bromo-3-fluorobenzene (0.047 ml, 0.42 mmol) and cesium carbonate (165 mg, 0.51 mmol) suspended in 1,4-dioxane (3.329 ml). The resulting suspension was degased with argon and then stirred at 100 C for 20 hours i(iiUPLCMS ON showed that the SM was almost consumed). iThe reaction mixture was allowed to cool to room temperature, the crude product was adsorbed on silica gelnbsp;and purified by flash chromatography on silica gel eluting with 0 to 7% Propanol-CH2Cl2. The solvent was evaporated to dryness to afford methyl 8-(1-(3-fluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (120 mg, 79 %) as anbsp;yellow oil which solidified on standing." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC=C4)F)OC(=CC2=O)N5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 78.55 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/28/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "540" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000358 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.00894 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=C(C(=C1)Cl)C(=O)OC)Br" - } - amount { - moles { - value: 0.00894 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000358 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000179 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;Palladium(II) acetate (0.040 g, 0.18 mmol), methyl 2-chloro-4-methoxy-5-morpholinobenzoate (2.042 g, 80 %), cesium carbonate (4.08 g, 12.52 mmol) and racemic 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.223 g, 0.36 mmol) were mixed together in a round bottom flask and evacuated then purged with nitrogen. Morpholine (0.780 mL, 8.94 mmol) and degassed toluene (15 mL) were added and the resulting suspension (orangered) was degassed and purged with nitrogen 3 times. The mixture was heated to 100 C under nitrogen overnight. The mixture was allowed to cool to ambient temperature and filtered, washing with EtOAc. The filtrate was concentrated and the crude residue (a dark orange gum) wasnbsp;purified by flash silica chromatography, elution gradient 0 to 40% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-chloro-4-methoxy-5-morpholinobenzoate (2.042 g, 80 %) as a pale yellowcream crystalline solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=C(C=C(C(=C1)Cl)C(=O)OC)N2CCOCC2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 79.91 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/01/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "541" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000213 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.00532 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=C(C(=C1)Cl)C(=O)OC)Br" - } - amount { - moles { - value: 0.00532 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000213 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000106 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;Methyl 5-bromo-2-chloro-4-methoxybenzoate (1.486 g, 5.32 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.132 g, 0.21 mmol), palladium(II) acetate (0.024 g, 0.11 mmol) and cesium carbonate (2.425 g, 7.44 mmol) were mixed together and evacuated then purged with nitrogen. Toluene (10 mL) and morpholine (0.464 mL, 5.32 mmol) were added and the mixture evacuated and purged with nitrogen several times. The suspension (red) was heated to 100 C for 18 hours under nitrogen. The mixture was allowed to cool to ambient temperature and filtered, washing with EtOAc. The filtrate was concentrated to provide an orange residue. The crude product was purified by flash silica chromatography, elution gradient 0 to 35% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-chloro-4-methoxy-5-morpholinobenzoate (0.826 g, 54.4 %) as a cream crystalline solid. Lower than expected yield (previously recorded 80% EN04398-06).....not sure what has happened." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=C(C=C(C(=C1)Cl)C(=O)OC)N2CCOCC2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 54.38 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/21/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "542" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000332 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.03 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.00829 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=C(C(=C1)Cl)C(=O)OC)Br" - } - amount { - moles { - value: 0.00829 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000332 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000166 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;Cesium carbonate (3.78 g, 11.61 mmol), methyl 5-bromo-2-chloro-4-methoxybenzoate (2.317 g, 8.29 mmol), palladium(II) acetate (0.037 g, 0.17 mmol) and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.206 g, 0.33 mmol) were combined and evacuated and purged with nitrogen (3 times).Degassed toluene (30 mL) and morpholine (0.723 mL, 8.29 mmol) was added and the resulting suspension was evacuated and purged with nitrogen several times. The reaction mixture was heated to 100 C under nitrogen for 22 hours. The reaction was allowed to cool to ambient temperature and filtered through a celite pad, washing with EtOAc. The filtrate was concentrated and the crude product purified by flash silica chromatography, elution gradient 10 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-chloro-4-methoxy-5-morpholinobenzoate (1.865 g, 79 %) as a cream crystalline solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=C(C=C(C(=C1)Cl)C(=O)OC)N2CCOCC2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 78.74 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/20/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "543" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000175 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC2=C(C=NN2C=C1)C3=NC(=NC=C3Cl)N" - } - amount { - moles { - value: 0.000125 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)[N+](=O)[O-])Br" - } - amount { - moles { - value: 0.000125 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 1e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 7.5e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "iCrude SM used i2-bromo-1-methoxy-4-nitrobenzene (0.029 g, 0.13 mmol), 5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (0.031 g, 0.125 mmol) and cesium carbonate (0.057 g, 0.18 mmol) were suspended in dry dioxane (2 mL) the mixture degassed with nitrogen for 10 minutes. TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (6.87 mg, 7.50 mol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (5.79 mg, 10.00 mol) were added and the mixture was sealed into a microwave tube. The reaction was heated to 150 C for 2 hours in the microwave reactor and cooled to RT. Possibly product - not very much. The reaction was heated to 150 C for 10 hours in the microwave reactor and cooled to RT. Product now c4%, both starting materials still present.No" - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)[N+](=O)[O-])NC2=NC=C(C(=N2)C3=C4C=CC=CN4N=C3)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/07/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "544" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000175 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC2=C(C=NN2C=C1)C3=NC(=NC=C3Cl)N" - } - amount { - moles { - value: 0.000125 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)[N+](=O)[O-])Br" - } - amount { - moles { - value: 0.000125 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 3.75e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "iCrude SM used i2-bromo-1-methoxy-4-nitrobenzene (0.029 g, 0.13 mmol), 5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (0.031 g, 0.125 mmol) and cesium carbonate (0.057 g, 0.18 mmol) were suspended in dry dioxane (2 mL) the mixture degassed with nitrogen for 10 minutes. TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.034 g, 0.04 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.029 g, 0.05 mmol) were added and the mixture was sealed into a microwave tube. The reaction was heated to 150 C for 2 hours in the microwave reactor and cooled to RT. Possibly product - not very much. The reaction was heated to 150 C for 10 hours in the microwave reactor and cooled to RT. Product now c4%, both starting materials still present.Not contin" - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)[N+](=O)[O-])NC2=NC=C(C(=N2)C3=C4C=CC=CN4N=C3)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/22/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "546" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 4.05e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1C[C@@H](C2=NC(=NN2C1)N)C3=CC=C(C=C3)F" - } - amount { - moles { - value: 0.000405 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C(=O)CC1=CC=C(C=C1)Br" - } - amount { - moles { - value: 0.000405 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 4.05e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.05e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "8-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine (94 mg, 0.40 mmol), 2-(4-bromophenyl)-N,N-dimethylacetamide (103 mg, 0.40 mmol), Cesium carbonate (198 mg, 0.61 mmol), Palladium(II) acetate (9.09 mg, 0.04 mmol) and 2-(Dicyclohexylphosphino)biphenyl (14.18 mg, 0.04 mmol) were added to a 0.5-2 mL microwave vial. The vial was capped and flushed with nitrogen. dioxane (3 mL) was added and the vial was flushed with additional nitrogen before it was heated by microwave irradiation at 120C for 1.5h. The reaction mixture was cooled to r.t. and water and EtOAc were added and the layers were separated. The aqueous phase was extracted with EtOAc (3x). The combined organic phases were washed with brine, dried (phase separator) and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography using a gradient of 0-3% MeOH in EtOAc over 12 min. The desired fractions were combined to result in 2-(4-(8-(4-fluorophenyl)-5,6,7,8-teydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)phenyl)-N,N-dimethylacetamide (51.0 mg, 32.0 %)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(C)C(=O)CC1=CC=C(C=C1)NC2=NN3CCCC(C3=N2)C4=CC=C(C=C4)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 32.03 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/14/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "551" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00072 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000554 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CC(OC2=C(C1)C=CC(=N2)Cl)C3CC(C3)(F)F" - } - amount { - moles { - value: 0.000554 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000166 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 8.31e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 145.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium(II) acetate (0.019 g, 0.08 mmol) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.096 g, 0.17 mmol) were added to a degassed solution of 8-chloro-2-(3,3-difluorocyclobutyl)-4-methyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.160 g, 0.55 mmol), 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-amine (0.113 g, 0.55 mmol) and Cesium carbonate (0.058 mL, 0.72 mmol) in dry dioxane (15 mL). The reaction was heated in a microwave oven at 145C for 1h. About 50% of product. The reaction was heated at 145C for another 30 min. About 45% of product. The reaction was interrupted and the reaction mixture was pooled with the corresponding mixture in EN04426-52. The reaction mixture was filtered through a plug of celite. The celite was washed with DCM. The solvents were evaporated and the crude was purified by ISCO on a 25 g column with an increased gradient of DCMMeOH (9010) 0-50% in DCM) to give 0.176 g (35%) of the product. The enatiomers were also separated (see EN04426-" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CC(OC2=C(C1)C=CC(=N2)NC3=NC(=C(C=C3)C4=CN(N=C4)C)OC)C5CC(C5)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 69.57 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "12/01/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "552" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[K+].[K+]" - } - amount { - moles { - value: 0.0405 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.1 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=NC(=C1)Cl)Cl" - } - amount { - moles { - value: 0.0135 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C=C1Cl)N)C#N" - } - amount { - moles { - value: 0.0135 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.0027 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00135 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 112.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of 2,6-dichloropyridine (2 g, 13.51 mmol), 2-amino-4-chlorobenzonitrile (2.062 g, 13.51 mmol), PALLADIUM(II) ACETATE (0.303 g, 1.35 mmol), BINAP (1.683 g, 2.70 mmol) and potassium carbonate (5.60 g, 40.54 mmol) in toluene (100 mL) was stirred at reflux under N2 for 5hrs. LCMS detected major peak as desire product. The resulting suspension was cooled, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography of the residue on silica gel using 15% to 20% ethyl acetate in hexane, then 100% ethyl acetate as eluent gave the crude product which was recrystallized from methanolDCM to yield a light yellow solid as desired product 4-chloro-2-(6-chloropyridin-2-ylamino)benzonitrile (3.34 g, 93 %)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC(=NC(=C1)Cl)NC2=C(C=CC(=C2)Cl)C#N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 93.49 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/18/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "553" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0191 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=CC(=N1)S(=O)(=O)C)N" - } - amount { - moles { - value: 0.0127 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC(=O)N1CCC(CC1)OC2=C(C(=NC=N2)Cl)OC" - } - amount { - moles { - value: 0.0127 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3OC4=CC=CC=C4P(C5=CC=CC=C5)C6=CC=CC=C6" - } - amount { - moles { - value: 0.000508 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000254 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 60.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Bis[(2-diphenylphosphino)phenyl] ether (0.274 g, 0.51 mmol) was added in one portion to Palladium(II) acetate (0.057 g, 0.25 mmol) in toluene (5 mL) (degassed by bubbling N2 through it for 30 minutes) at 20C under nitrogen (this mixture was also degassed by vacuum N2 six times). After a few minutes a yellow suspension had formed. This was added by pipette to a mixture of isopropyl 4-(6-chloro-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate (4.19 g, 12.71 mmol),nbsp;2-methyl-6-(methylsulfonyl)pyridin-3-amine (2.366 g, 12.71 mmol) and Sodium tert-butoxide (2.333 mL, 19.06 mmol) in toluene (40 mL) at 60C under nitrogen. The resulting mixture was degassed using N2 vacuum six times. The resulting suspension was stirred at 60 C for 18 hours. Sodium tert-butoxide (2.333 mL, 19.06 mmol) was added to the reaction mixture followed by another amount of pre-formed catalyst using Bis[(2-diphenylphosphino)phenyl] ether (0.274 g, 0.51 mmol) was added in one portion to Palladium(II) acetate (0.0mol) in toluene (5 mL) as above. The mixture was heated at 60C for 7 hours then further catalyst added using Bis[(2-diphenylphosphino)phenyl] ether (0.274 g, 0.51 mmol) was added in one portion to Palladium(II) acetate (0.057 g, 0.25 mmol) in toluene (5 mL) as above. The mixture was stirred at 60C for 18 hours. Work up was by diluting with water (30 ml) and DCM (100 ml) then filtering through a pad of celite and washing through well with DCM (6 x 50 ml). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography (330g column), elution gradient 0 to 100% EtOAc in heptane (material applied in DCM). Pure fractions were evaporated to dryness to leave a yellow solid, EN05005-04-01. The solid was triturated with Et2O (20 ml) and the solid filtered off and washed with Et2O (2 x 10ml) then heptane ( 2 x 10ml) to afford isopropyl 4-(5-methoxy-6-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)pyrimidin-4-yloxy)piperidrboxylate (4.78 g, 78 %), EN05005-04-02, as a white solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=CC(=N1)S(=O)(=O)C)NC2=C(C(=NC=N2)OC3CCN(CC3)C(=O)OC(C)C)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 78.45 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/03/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "554" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00145 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.001 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=CC(=N1)S(=O)(=O)C)N" - } - amount { - moles { - value: 0.000964 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC(=O)N1CCC(CC1)OC2=C(C(=NC=N2)Cl)OC" - } - amount { - moles { - value: 0.000964 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3OC4=CC=CC=C4P(C5=CC=CC=C5)C6=CC=CC=C6" - } - amount { - moles { - value: 3.86e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.93e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 60.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Bis[(2-diphenylphosphino)phenyl] ether (0.021 g, 0.04 mmol) was added in one portion to Palladium(II) acetate (4.33 mg, 0.02 mmol) in toluene (1 mL) (degassed by bubbling N2 through it for 30 minutes) at 20C under nitrogen. After a few minutes a yellow suspension had formed. This added in one portion by pipette to a mixture of isopropyl 4-(6-chloro-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate (0.318 g, 0.96 mmol),nbsp;2-methyl-6-(methylsulfonyl)pyridin-3-amine (0.180 g, 0.96 mmol) and Sodium tert-butoxide (0.177 mL, 1.45 mmol) in toluene (3 mL) at 60C under nitrogen. The resulting mixture was degassed using N2 vacuum six times. The resulting suspension was stirred at 60 C for 18 hours. Work up was by diluting with water (10 ml) and DCM (10 ml) then filtering through a pad of celite and washing through well with DCM (6 x 10 ml). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography ( elution gradient 0 to 100% EtOAc in heptane (material applied in DCM). Pure fractions were evaporated to dryness to afford isopropyl 4-(5-methoxy-6-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)pyrimidin-4-yloxy)piperidine-1-carboxylate (0.231 g, 50.0 %) as a slightly off white foam. Trituration with Et2O (10 ml) and sctratching gave a free flowing white suspension. The solvent was removed under reduced pressure to give a white powder." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=CC(=N1)S(=O)(=O)C)NC2=C(C(=NC=N2)OC3CCN(CC3)C(=O)OC(C)C)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 49.95 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/17/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "556" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00202 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CN" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 0.00012 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 8.08e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "palladium(II) acetate (0.018 g, 0.08 mmol), (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (0.066 g, 0.12 mmol), sodium tert-butoxide (0.194 g, 2.02 mmol), phenylmethanamine (0.110 mL, 1.01 mmol) and 2,4-dichloropyridine (0.151 mL, 1.01 mmol) were suspended in DME (4 mL) and sealed into a microwave tube. The reaction was heated to 80 C for 30 minutes in the microwave reactor and cooled to RT. nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CNC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/18/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "557" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00203 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CN" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000122 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000101 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;phenylmethanamine (0.111 mL, 1.01 mmol), 2,4-dichloropyridine (0.151 mL, 1.01 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (70.4 mg, 0.12 mmol) and cesium carbonate (660 mg, 2.03 mmol) were stirred in 1,4-dioxane (5 mL).nbsp;The mixture was purged with nitrogen for 10 minutes.nbsp;Palladium(II) acetate (22.76 mg, 0.10 mmol) was added and sealed into a microwave tube. The reaction was heated to 100 C for 1 hour in the microwave reactor and cooled to RT. The reaction was heated to 100 C for 1 hour in the microwave reactor and cooled to " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CNC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/12/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "558" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00202 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)CN" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 0.00012 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 8.08e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;palladium(II) acetate (0.018 g, 0.08 mmol), (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (0.066 g, 0.12 mmol), sodium tert-butoxide (0.194 g, 2.02 mmol), 2-methylpropan-1-amine (0.100 mL, 1.01 mmol) and 2,4-dichloropyridine (0.151 mL, 1.01 mmol) were suspended in DME (4 mL) and sealed into a microwave tube. The reaction was heated to 80 C for 30 minutes in the microwave reactor and cooled to RT. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)CNC1=NC=CC(=C1)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/17/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "560" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 7.16e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.001 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC2=C(N1)C=C(C=C2)OC(F)(F)F" - } - amount { - moles { - value: 5.11e-05 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)COC2=CC(=CC=C2)Br" - } - amount { - moles { - value: 7.87e-05 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C1=CC=CC=C1C2=CC=CC=C2)C(C)(C)C" - } - amount { - moles { - value: 1.53e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.02e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "EN04773-53, iBuchwald coupling, toluene and bromideiThe indole from 4773-25, 1-(benzyloxy)-3-bromobenzene,Pd2(dba)3, JohnPhos and KOtBu were dissolved in toluene. The mixture was warmed at 100 C for 2h. Ca 60% conversion according to LCMS (product at 2.31 min). This conversion rate seemed faster than for the corresponding aryliodide. Big bacth was performed in 4773-54." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CC2=C(N1C3=CC(=CC=C3)OCC4=CC=CC=C4)C=C(C=C2)OC(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 59.07 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/01/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "561" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0338 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.2 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC2=C(N1)C=C(C=C2)OC(F)(F)F" - } - amount { - moles { - value: 0.0242 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)COC2=CC(=CC=C2)Br" - } - amount { - moles { - value: 0.029 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C1=CC=CC=C1C2=CC=CC=C2)C(C)(C)C" - } - amount { - moles { - value: 0.00242 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.00121 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "EN04773-54, iBuchwald coupling, toluene and bromideiThe indole from 4773-41, 1-(benzyloxy)-3-bromobenzene,Pd2(dba)3 (5mol%), JohnPhos (10mol%) and KOtBu (1.4eq) were dissolved in toluene. The mixture was warmed at 80 C for 40 hours.* The reaction was carefully monitored and analysis data from 2h, 4, 16 and 40 h are attached. According to LCMS there were ca 75% conversion to the product. The mixture was washed with water, concentrtaed and purified by silica column (HepEtOAc 6:1). The collected fractions contained product (6 g, 62.5% yield) but had some impurity (see TLC and NMR). Nevertheless Friedel crafts acylation was performed without further purifications. See e.g. 4773-56.###*JohnPhos, pd2(dba)3 and sodium tertbutoxide had been dissolved in toluene and was portionwise added to the reaction mixture during the first 16h. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CC2=C(N1C3=CC(=CC=C3)OCC4=CC=CC=C4)C=C(C=C2)OC(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 62.48 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/02/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "562" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000298 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNC1" - } - amount { - moles { - value: 0.0149 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1C#N)Br" - } - amount { - moles { - value: 0.00744 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000298 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000223 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "4-bromobenzonitrile (1.355 g, 7.44 mmol) and Sodium tert-butoxide (1.073 g, 11.17 mmol)nbsp;were mixed in toluene (10 mL) and degassed by passing nitrogen for 5 min. Thennbsp;Azetidine (1 mL, 14.89 mmol),nbsp;9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (0.172 g, 0.30 mmol) and Palladium(II) acetate (0.050 g, 0.22 mmol)were added and thenbsp;mixture was heated innbsp;oilbath at 100C for 15h. The reaction was complete by GCMS. Filtration through celite washing with CH2Cl2 and evaporation gave a crude product (1g).nbsp;Purification by chromatography on silica (0-50 % EtOAc in heptane) gave the desired product 4-(azetidin-1-yl)benzonitrile (0.730 g, 62.0 %)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CN(C1)C2=CC=C(C=C2)C#N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 61.99 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/02/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "564" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00872 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.027 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00581 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=CC=N1)Br" - } - amount { - moles { - value: 0.00581 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 0.000581 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000291 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium acetate (65 mg, 0.29 mmol) and RuPhos (271mg, 0.58mmol) were dissolved in toluene (10 mL), degassed and purged with nitrogen and warmed to 50C for 15 minutes. In a separate vessel, were mixed 3-bromo-2-methyl pyridine (1.00g, 5.81 mmol), BOC-piperazine (1.08g, 5.81mmol), sodium tertbutoxide and toluene (17 mL). The mixture was degassed, purged with nitrogen and warmed to 50C.The catalyst was transferred to the reaction vessel and the mixture degassed and purged with nitrogen. The reaction was heated at 100C overnight under nitrogen.The mixture was filtered through GFF paper, washing with MeOH. The filtrate was concentrated to provide a dark brown gum.The gum was purified by flash silica chromatography, elution gradient 30 to 80% EtOAc in heptane. Pure fractions were evaporated to provide the desired product as a gum (1.492g, 93%).Rf (1:1 EtOAchept" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=CC=N1)N2CCN(CC2)C(=O)OC(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 92.54 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/19/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "565" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0174 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.04 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.0116 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=CC=N1)Br" - } - amount { - moles { - value: 0.0116 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 0.00116 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000581 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "RuPhos (0.543 g, 1.16 mmol) and palladium (II) acetate (0.131 g, 0.58 mmol) were suspended in toluene (15 mL) at ambient temperature. The resulting mixture was degassed and purged several times and warmed to 50C under nitrogen for 20 mins.In a separate vessel were mixed 3-bromo-2-methylpyridine (2 g, 11.63 mmol), tert-butyl 4-(2-methylpyridin-3-yl)piperazine-1-carboxylate (2.67 g, 83 %), sodium tertbutoxide (1.676 g, 17.44 mmol) and toluene. The mixture was degassed and purged with nitrogen several times and warmed to 50C. The catalyst solution was added to the reaction vessel and the resulting mixture degassed and purged wtih nitrogen. The reaction was heated at 100C overnight.The reaction mixture was allowed to cool to ambient temperature and filtered through GFF paper, washing with MeOH. The filtrate was concentrated to provide the crude material. This was purified by flash silica chromatography, elution gradient 20 to 70% EtOAc in heptane. Pure fractions were o dryness to afford tert-butyl 4-(2-methylpyridin-3-yl)piperazine-1-carboxylate (2.67 g, 83 %) as a pale yellow oil.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=CC=N1)N2CCN(CC2)C(=O)OC(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 82.86 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/16/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "566" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00015 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.001 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC2=C(N1)C=C(C=C2)OC(F)(F)F" - } - amount { - moles { - value: 0.000107 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC(=CC=C1)Br" - } - amount { - moles { - value: 0.000128 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C1=CC=CC=C1C2=CC=CC=C2)C(C)(C)C" - } - amount { - moles { - value: 2.41e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 8.02e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "EN04773-51, iBuchwald coupling,ibi J. Med. Chem. 2009, page 3846-3854 (exactly same reaction).ibThe indole from 4773-41, 1-bromo-3-methoxybenzenee,Pd2(dba)3, JohnPhos and KOtBu were dissolved in toluene. The mixture was warmed at 120 C for 1h and ~65% conversion was observed on NMR*(see attached NMR). Reaction seems to work fine and assumed better yield than in 4773-50. This could be due to that bromides generally perform better than iodines in the Buchwald coupling. This test reaction was thrown away.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CC2=C(N1C3=CC(=CC=C3)OC)C=C(C=C2)OC(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 65.49 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/23/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "567" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0424 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.3 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@@H]1CNC[C@@H](N1)C" - } - amount { - moles { - value: 0.0424 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1Br)I" - } - amount { - moles { - value: 0.0283 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00566 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00283 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "sodium 2-methylpropan-2-olate (4.08 g, 42.42 mmol) was added to (2R,6S)-2,6-dimethylpiperazine (4.84 g, 42.42 mmol) in dioxane (300 mL) at 21Cnbsp;under nitrogen. Stirred for 5 mins. 1-bromo-4-iodobenzene (8 g, 28.28 mmol) added, followed by diacetoxypalladium (0.635 g, 2.83 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (3.27 g, 5.66 mmol). Reaction evacuated and refilled with nitrogen several times. Heated at 90C for 18hours.nbsp;Diluted with ethyl acetate and filtered through celite. The organic layer was washed with water ( 500ml) and then dried over Na2SO4, filterednbsp;and reduced in volume. Filtered - lcms messy. Dissolved in DCM and combined with the filtrate - adsorbed onto silica.The crude product was purified by flash silica chromatography, elution gradient 0 to 30% MeOH in EtOAc. Pure fractions were evaporated to dryness to afford (3S,5R)-1-(4-bromophenyl)-3,5-dimethylpiperazine (4.69 g, 61.6 %) as a yellow solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@@H]1CN(C[C@@H](N1)C)C2=CC=C(C=C2)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 61.61 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/25/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "568" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0053 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.04 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@@H]1CNC[C@@H](N1)C" - } - amount { - moles { - value: 0.0053 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1Br)I" - } - amount { - moles { - value: 0.00353 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000707 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000353 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "sodium 2-methylpropan-2-olate (0.510 g, 5.30 mmol) was added to (2R,6S)-2,6-dimethylpiperazine (0.605 g, 5.30 mmol) in dioxane (40 mL) at 21Cnbsp;under nitrogen. Stirred for 5 mins. 1-bromo-4-iodobenzene (1 g, 3.53 mmol) added, followed by diacetoxypalladium (0.079 g, 0.35 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.409 g, 0.71 mmol). Reaction evacuated and refilled with nitrogen several times. Heated at 90C for 18hours. left to cool ow.The reaction mixture was diluted with EtOAc (250 mL), and washed sequentially with water (150 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% MeOH in EtOAc. Pure fractions were evaporated to dryness to afford (3S,5R)-1-(4-bromophenyl)-3,5-dimethylpiperazine (0.420 g, 44.1 %) as a yellow solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@@H]1CN(C[C@@H](N1)C)C2=CC=C(C=C2)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 44.14 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/22/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "569" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00201 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@H](CN)O[Si](C)(C)C(C)(C)C" - } - amount { - moles { - value: 0.00187 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C(=C1)F)C2=CC=C(C=C2)Br)F" - } - amount { - moles { - value: 0.00134 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.000134 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000134 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "PdOAc2 (0.030 g, 0.13 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.064 g, 0.13 mmol) were added in one portion tonbsp;a degassed solution of 4\'-bromo-2,6-difluorobiphenyl (0.36 g, 1.34 mmol), (R)-2-(tert-butyldimethylsilyloxy)propan-1-amine (0.355 g, 1.87 mmol) and cesium carbonate (0.654 g, 2.01 mmol) in toluene (10 mL) at 20Cnbsp;under nitrogen. The resulting suspension was stirred at 120 C for 50 hours.The reaction mixture was diluted with EtOAc (150 mL)nbsp;and water (150 mL) and the biphasic mixture was filtered through celite. The organic layer was separated and washed sequentially with water (150 mL) and saturated brine (150 mL). The organic layer was evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-N-(2-(tert-butyldimethylsilyloxy)propyl)-2\',6\'-difluorobiphenyl-4-amine (0.300 g, 59.4 %) as a yellow so" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@H](CNC1=CC=C(C=C1)C2=C(C=CC=C2F)F)O[Si](C)(C)C(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 59.39 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/13/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "570" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00019 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.022 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" - } - amount { - moles { - value: 0.00223 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=C(C=C1F)Br)F" - } - amount { - moles { - value: 0.00279 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00019 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 8.93e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (0.020 g, 0.09 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (0.8g, 2.23 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.110 g, 0.19 mmol), 1-bromo-3,5-difluorobenzene (0.321 ml, 2.79 mmol) and cesium carbonate (1.091 g, 3.35 mmol) suspended in 1,4-dioxane (22.00 ml). The resulting suspension was degased with argon and then stirred at 100 C for 20 hours. imaybe not complete but have to go forwardiThe reaction mixture was allowed to cool to room temperature, the insoluble were removed by filtration and the filtrate concentrated.The crude product was adsorbed on silica gelnbsp;and purified by flash chromatography on silica gel eluting with 0 to 6% methanol in ethyl acetate. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (0.760 g, 66.2 %) as anbsp;beige foam." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 66.17 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/18/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "571" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 2.96e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" - } - amount { - moles { - value: 0.000349 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=C(C=C1F)Br)F" - } - amount { - moles { - value: 0.000384 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 2.96e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.4e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (3.13 mg, 0.01 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (125 mg, 0.35 mmol), 1-bromo-3,5-difluorobenzene (0.044 ml, 0.38 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (17.15 mg, 0.03 mmol) and cesium carbonate (170 mg, 0.52 mmol) dissolved in 1,4-dioxane (2 ml). The resulting suspension was degased with argon and then stirred at 100 C for 10 hours.The reaction mixture was allowed to cool to room temperature. The reaction mixture was quenched with water and extracted with dichloromethane (2 x 10 ml). The combined organic phases were dried over magnesium sulfate and concentrated to afford the crude product as a orangeyellow oil.The crude product was purified by flash chromatography on silica gel eluting with 0 to 10% methanol in dichloromethane. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carbote (118 mg, 71.9 %) as a yellow gum." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 71.91 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/28/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "572" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000315 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.036 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" - } - amount { - moles { - value: 0.0037 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=C(C=C1F)Br)F" - } - amount { - moles { - value: 0.00463 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000315 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000148 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (0.033 g, 0.15 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (1.326 g, 3.7 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.182 g, 0.31 mmol), 1-bromo-3,5-difluorobenzene (0.533 ml, 4.63 mmol) and cesium carbonate (1.808 g, 5.55 mmol) suspended in 1,4-dioxane (36 ml). The resulting suspension was degased with argon and then stirred at 100 C over the WE (66hours).Albeit Lcms showed ~ 7% SM remaining, the reaction was stopped. The reaction mixture was allowed to cool to room temperature, the insolubles were removed by filtration and the filtrate concentrated. The crude product was adsorbed on silica gelnbsp;and purified by flash chromatography on silica gel eluting with 2 to 5% methanol in ethyl acetate. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (1.172 g, 67.3 %) as anbsp;beige foam." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 67.33 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/01/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "573" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 5.58e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.008 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" - } - amount { - moles { - value: 0.000558 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=C(C=C1F)Br)F" - } - amount { - moles { - value: 0.000698 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 5.58e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.79e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (6.26 mg, 0.03 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (200 mg, 0.56 mmol), 1-bromo-3,5-difluorobenzene (0.080 ml, 0.70 mmol) and cesium carbonate (273 mg, 0.84 mmol) dissolved in 1,4-dioxane (8 ml). The resulting suspension was degased with argon and then stirred at 100 C (15:00) for 18 hours.The reaction mixture was allowed to cool to room temperature, filtered and concentrated.The crude product was adsorbed on silica gelnbsp;and purified by flash chromatography on silica gel eluting with 0 to 6% methanol in ethyl acetate. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (137 mg, 52.2 %) as a clear yellow foam.LCMS and NMR are OK." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 52.18 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/12/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "574" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 5.58e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.008 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" - } - amount { - moles { - value: 0.000558 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=C(C=C1F)Br)F" - } - amount { - moles { - value: 0.000698 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 5.58e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.79e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (6.26 mg, 0.03 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (200 mg, 0.56 mmol), 1-bromo-3,5-difluorobenzene (0.080 ml, 0.70 mmol) and cesium carbonate (273 mg, 0.84 mmol) dissolved in 1,4-dioxane (8 ml). The resulting suspension was degased with argon and then stirred at 100 C (18:00) for 15 hours.The reaction mixture was allowed to cool to room temperature, filtered and concentrated.The crude product was adsorbed on silica gelnbsp;and purified by flash chromatography on silica gel eluting with 0 to 6% methanol in ethyl acetate. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (173 mg, 65.9 %) as a clear yellow foam.LCMS and NMR are OK." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 65.89 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/12/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "575" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000251 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0161 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" - } - amount { - moles { - value: 0.00251 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=C(C=C1F)Br)F" - } - amount { - moles { - value: 0.00314 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000251 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000126 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (0.028 g, 0.13 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (0.9 g, 2.51 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.145 g, 0.25 mmol), 1-bromo-3,5-difluorobenzene (0.361 ml, 3.14 mmol) and cesium carbonate (1.227 g, 3.77 mmol) suspended in 1,4-dioxane (16.05 ml). The resulting suspension was degased with argon and then stirred at 100 C (18:00) for 15 hours.The reaction mixture was allowed to cool to room temperature, concentrated in presence of silica gel and purified by flash chromatography on silica gel eluting with 0 to 10% methanol in ethyl acetate. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (0.792 g, 67.0 %) as an yellow foam." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 67.04 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/04/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "576" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0586 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.25 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" - } - amount { - moles { - value: 0.0391 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=C(C=C1F)Br)F" - } - amount { - moles { - value: 0.0488 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00391 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00195 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (0.439 g, 1.95 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (14 g, 39.06 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2.260 g, 3.91 mmol), 1-bromo-3,5-difluorobenzene (5.62 ml, 48.83 mmol) and cesium carbonate (19.09 g, 58.60 mmol) suspended in 1,4-dioxane (250 ml). The resulting suspension was degased with argon and then stirred at 100 C for 16 hours.The reaction mixture was allowed to cool to room temperature, concentrated in presence of silica gel and purified by Chromatography on silica gelnbsp;(Novasep)nbsp;eluting with 0 to 10% methanol in ethyl acetate. The solvent was evaporated to dryness to afford methyl 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (10.30 g, 56.0 %) as an yellow foam." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 56.04 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/07/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "577" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000195 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0009 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC2=C(N1)C=C(C=C2)OC(F)(F)F" - } - amount { - moles { - value: 0.000139 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)COC2=CC(=CC=C2)I" - } - amount { - moles { - value: 0.000167 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C1=CC=CC=C1C2=CC=CC=C2)C(C)(C)C" - } - amount { - moles { - value: 3.14e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.05e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "EN04773-50, iBuchwald coupling,ibi J. Med. Chem. 2009, page 3846-3854 (changed: solvent to dioxane and bromide to iodide).ibThe indole from 4773-41, 1-(benzyloxy)-3-iodobenzene, Pd2(dba)3, JohnPhos and KOtBu were dissolved in toluene. The mixture was warmed at 120 C for 1hand ~40% conversion was observed on NMR. The reaction mixture was further heated at 80 C for 16h and 40 h, see attached 1H-NMR for reaction progress. A comparison with 4773-51 shows that using dioxane or iodide gives a lower yield (slower reaction). Switching the solvent to toluene was explored in 4773-52. The reaction in this experiment showed that the Buchwald conditions worked. Reaction mixture was thrown aw" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CC2=C(N1C3=CC(=CC=C3)OCC4=CC=CC=C4)C=C(C=C2)OC(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 40.17 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/23/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "578" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000651 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC2=C(N1)C=C(C=C2)OC(F)(F)F" - } - amount { - moles { - value: 0.000465 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)COC2=CC(=CC=C2)I" - } - amount { - moles { - value: 0.000558 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C1=CC=CC=C1C2=CC=CC=C2)C(C)(C)C" - } - amount { - moles { - value: 0.000167 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 5.58e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "EN04773-52, iBuchwald coupling, toluene and iodideiThe indole from 4773-25, 1-(benzyloxy)-3-iodobenzene,Pd2(dba)3, JohnPhos and KOtBu were dissolved in toluene. The mixture was warmed at 120 C for 1h and 50% conversion was observed on NMR*(see attached NMR). The mixture was warmed further 15h at 120C, still starting material left but the reaction mixture was directly applied to a silica column (heptane 3:1). Product was collected in fraction 22-23 (see attached NMR). Only 19.3 mg (10.45% yield) could be collected but NMR showed correct product. Test reaction with bromide was performed in 4773-53.#########################*Small amount from reaction mixture was dissolved in CDCl3 and 1HNMR analysis was perfor" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CC2=C(N1C3=CC(=CC=C3)OCC4=CC=CC=C4)C=C(C=C2)OC(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 10.45 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/25/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "579" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00602 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0075 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2" - } - amount { - moles { - value: 0.00301 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=NC=C1Br)C(F)(F)F" - } - amount { - moles { - value: 0.0015 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000361 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.00015 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 50 ml round bottom equipped with stir bar was charged with BINAP (225 mg, 0.36 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (138 mg, 0.15 mmol) dissolved in 1,4-dioxane (7.500 mL).nbsp;This was degassed and purged with nitrogen and stirred at RT for 10 mins.nbsp;3-bromo-5-(trifluoromethyl)pyridine (340 mg, 1.50 mmol) followed by tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (597 mg, 3.01 mmol) andnbsp;sodium tert-butoxide (578 mg, 6.02 mmol) were added, and the reaction was stirred at 80 C for 2 hrs. The crude material was loaded on a Snap KP-SIL 100g column and purified on a Biotage Isolera One instrument, eluting with 10% to 35% ethyl acetate in heptane to provide tert-butyl 5-(5-(trifluoromethyl)pyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (425 mg, 82 %) as an oil." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CC2CC1CN2C3=CN=CC(=C3)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 82.28 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/14/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "581" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00885 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0107 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00442 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=NC=C1Br)C(F)(F)F" - } - amount { - moles { - value: 0.00221 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000531 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000221 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 100 ml round bottom equipped with stir bar was charged with (S)-BINAP (331 mg, 0.53 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (203 mg, 0.22 mmol) dissolved in 1,4-dioxane (10.700 mL).nbsp;This was degassed and purged with nitrogen and stirred at RT for 10 mins.nbsp;3-bromo-5-(trifluoromethyl)pyridine (500 mg, 2.21 mmol) followed by tert-butyl piperazine-1-carboxylate (824 mg, 4.42 mmol) andnbsp;sodium tert-butoxide (850 mg, 8.85 mmol) were added, and the reaction was stirred at 80 C for 2 hrs. The crude material was loaded on a Snap KP-SIL 100g column and purified on a Biotage Isolera One instrument, eluting with 10% to 30% ethyl acetate in heptane to provide tert-butyl 4-(5-(trifluoromethyl)pyridin-3-yl)piperazine-1-carboxylate (630 mg, 86 %) as an oil." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CN=CC(=C2)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 85.94 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/15/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "584" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[K+].[K+]" - } - amount { - moles { - value: 0.033 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC#N" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCNCC" - } - amount { - moles { - value: 0.033 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1C#N)Br" - } - amount { - moles { - value: 0.011 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.0011 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000549 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 160.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "4-Bromobenzonitrile (2.000 g, 10.99 mmol), diethylamine (3.41 mL, 32.96 mmol) and POTASSIUM CARBONATE (4.56 g, 32.96 mmol) were mixed in dry acetonitrile (10 mL) under argon in a microwave vial. The vial was sealed and heated with microvawes for 60 minutes at 160C. Added diethylamine (3.41 mL, 32.96 mmol) and heated at 160C for 3 hours. Added Palladium(II) acetate (0.123 g, 0.55 mmol) and 2-(Dicyclohexylphosphino)-2\',4\',6\'-tri-i-propyl-1,1\'-biphenyl (0.524 g, 1.10 mmol), purged with argon for 5 minutes and heated in an oil bath at 100C for 24 hours. The reaction was cooled to rt and partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 (40 mL). The layers were separated and the aqueous phase extracted with EtOAc (100 mL). The organics were combined, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography on silica gel gave 4-(diethylamino)benzonitrile (0.750 g," - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCN(CC)C1=CC=C(C=C1)C#N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 39.17 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/03/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "585" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000906 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.0021 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)S(=O)(=O)N)N" - } - amount { - moles { - value: 0.000755 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=N1)Cl" - } - amount { - moles { - value: 0.000755 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 6.04e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.02e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 130.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of 3-aminobenzenesulfonamide (130mg, 0.75 mmol), 2-chloropyrazine (0.067 mL, 0.75 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (34.9 mg, 0.06 mmol), diacetoxypalladium (6.78 mg, 0.03 mmol) and cesium carbonate (295 mg, 0.91 mmol)nbsp;in degassed DMA (2.1 mL) was heatedb uin the microwaveub for 15 min at 130 C. LC MS FLA-04665-01-01 (pH extract 6-7) showed some product and few sulfanilamide left. Reaction was stopped. Extraction with AE + ethanol aq. sat NH4Cl (pH7), then back extraction with DCM.The organics were dried over MgSO4 and concentrated iin vacuo. iThe crude product was adsorbed on silica gel 40-60m and purified by flash chromatography on silica gel 15-40m eluting with 3.5 % of ethanol in dichloromethane (NH3 0.5 %) to provide 3-(pyrazin-2-ylamino)benzenesulfonamide (80 mg, 42.3 %) as a colourless solid. 1H NMR, LC MS FLA-04665-0" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)S(=O)(=O)N)NC2=NC=CN=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 42.34 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/28/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "586" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000767 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.0019 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)S(=O)(=O)N)N" - } - amount { - moles { - value: 0.000639 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=NC=N1)Br" - } - amount { - moles { - value: 0.000639 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 5.11e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.56e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 130.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of 3-aminobenzenesulfonamide (110mg, 0.64 mmol), 5-bromopyrimidine (102 mg, 0.64 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (29.6 mg, 0.05 mmol), diacetoxypalladium (5.74 mg, 0.03 mmol) and cesium carbonate (250 mg, 0.77 mmol)nbsp;in degassed DMA (1.9 mL) was heatedb uin the microwaveub for 35 min at 130C. LC MS FLA-04665-12-01 (pH extract 6-7) showed some product. Reaction was stopped. Extraction with AE + ethanol aq. sat NH4Cl (pH7), then back extraction with DCM.The organics were dried over MgSO4 and concentrated iin vacuo. iThe crude product was adsorbed on silica gel 40-60m and purified by flash chromatography on silica gel 15-40m eluting with 3.5 % of ethanol in dichloromethane (NH3 0.5 %) to provide 3-(pyrimidin-5-ylamino)benzenesulfonamide (30.0 mg, 18.77 %) as a yellow solid. 1H NMR,LC MS: FLA-04665-12" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)S(=O)(=O)N)NC2=CN=CN=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 18.77 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/05/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "587" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000633 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1C[C@@H](C2=NC(=NN2C1)N)C3=CC=C(C=C3)F" - } - amount { - moles { - value: 0.000422 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1CC#N)Br" - } - amount { - moles { - value: 0.000422 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 3.99e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "8-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine (98 mg, 0.42 mmol), 2-(4-bromophenyl)acetonitrile (83 mg, 0.42 mmol), Cesium carbonate (206 mg, 0.63 mmol), Palladium(II) acetate (9.47 mg, 0.04 mmol) and 2-(Dicyclohexylphosphino)biphenyl (14.79 mg, 0.04 mmol) were added to a 2-5 mL microwave vial. The vial was capped and flushed with nitrogen. dioxane (2 mL) was added and the vial was flushed with additional nitrogen before it was heated by microwave irradiation at 120C for 1.5h. PALLADIUM(II) ACETATE (10 mg, 0.04 mmol) and 2-(DICYCLOHEXYLPHOSPHINO)BIPHENYL (14 mg, 0.04 mmol) were added and the mixture was heated for 45+30 min at 120 in a microwave reactor.Water (2 ml) and dichloromethane (10 ml) was added and the mixture was added to a phase separator tube. The organic phase was collected and evaporated. The solvents were evaporated and the residue was purified by column chromatography on silica eluting with gradients of methanol and ammonia in dichloromethane. The swere evaporated to give EN04671-48-001 (55 mg, 0.158 mmol, 37.5 %). Ca 88% pure according to LC-UV. The residue was dissolved in MeCN (2 ml) and the solution was passed through a syringe filter. Water was added to give a cloudy mixture (sample-002). Not possible to isolate solid by filtration. The solvents were evaporated to give EN04671-48-002. Not pure. EtOAc (2ml) and DCM (0.5 ml) and two drops of methanol were added. Most solid into solution. The mixture was passed through a syringe filter. The filter was rinsed with EtOAc (1 ml). Heptane was added until a solid started to form. The mixture was left for 1 h (sample -003). The mixture was filtered, everything passed through the filter. The solvents were evaporated and the residue was dissolved in MeCN and purified by preparative HPLC. Fr 1-2 were pooled and evaporated to give EN04671-48-004 (6.7 mg, 0.019 mmol, 4.57 %). Fr 3-6 were pooled and evaporated." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CC(C2=NC(=NN2C1)NC3=CC=C(C=C3)CC#N)C4=CC=C(C=C4)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 42.09 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/14/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "588" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000103 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.006 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCC[C@@H]1COC2=CN=C(C=C2)N" - } - amount { - moles { - value: 0.000689 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C2C(=C1)N=CN2C3=CC(=NC=N3)Cl" - } - amount { - moles { - value: 0.000689 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000103 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 3.45e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (31.6 mg, 0.03 mmol) was added to (R)-5-((1-methylpyrrolidin-2-yl)methoxy)pyridin-2-amine (143 mg, 0.69 mmol), 1-(6-chloropyrimidin-4-yl)-1H-benzo[d]imidazole (159 mg, 0.69 mmol), sodium t-butoxide (99 mg, 1.03 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (59.8 mg, 0.10 mmol) in toluene (6 mL) at 20C under nitrogen. The resulting suspension was stirred at 100 C for 16 hours then cooled to room temperature. LCMS analysis indicates no SM, product peak present. The reaction mixture was concentrated iin vacuoi. The residue was dissolved in DCM (100 mL) and washed with water (100 mL). The organic layer was passed through phase separating cartridge and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford a yellow gum. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD 5 silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (R)-6-(1H-benzo[d]imidazol-1-yl)-N-(5-((1-methylpyrrolidin-2-yl)methoxy)pyridin-2-yl)pyrimidin-4-amine (39.0 mg, 14.09 %) as an pale yellow solid. Experiment was re-opened on 08062012 to record additional data for publication. 13C and HRMS data recorded as separate sections rather than within sample details due to ELN conflict when trying to sign and close with redundant project code.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CCC[C@@H]1COC2=CN=C(C=C2)NC3=CC(=NC=N3)N4C=NC5=CC=CC=C54" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 14.09 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/18/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "589" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00957 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.05 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCCC12OCCO2" - } - amount { - moles { - value: 0.00798 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC(=CN=C1)Br" - } - amount { - moles { - value: 0.00798 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.000479 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000479 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "1105 2011 07:58:54 +0200A mixture of 3-bromo-5-methoxypyridine (1.5 g, 7.98 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (1.023 ml, 7.98 mmol), palladium(II) acetate (0.107 g, 0.48 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.228 g, 0.48 mmol) in toluene (38.3 ml) and tBuOH (7.65 ml) was evacuated and flashed with N2 several times. Then sodium 2-methylpropan-2-olate (0.920 g, 9.57 mmol) was added and the reaction mixture was heated to 100C for 2hrs.LCMS showed complete conversion. Reaction mixture had turned black.The reaction mixture was filtered through celite. The celite was washed with DCM. The combined filtrates were concentrated to yield 2.2g of brown oil, which starts to crystalise patially.Crude NMR showed only little unreacted amine (ca. 14%).The crude was purified by flash:The residue was purified by automated flash chromatography on a 100gnbsp;column. A gradient from 40%nbsp;tonbsp;100% of EA in Hep over 12CV, EA over 6CV was used as mobile phase. The product was collected using the wavelength 254 nm.1.5g of desired product were obtained as a light yellow oil." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=CN=CC(=C1)N2CCC3(CC2)OCCO3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 75.12 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/11/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "590" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0349 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CN=C1)N" - } - amount { - moles { - value: 0.038 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CN=C1)Br" - } - amount { - moles { - value: 0.0316 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 2.43e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.43e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Stock solution: 2.43 M solution of CyPF-tBuPd(OAc)2 (1:1) in DME.pyridin-3-amine (3.57 g, 37.98 mmol) was dissolved in DME (10 mL). To the mixture was added 10 mL of stock solution, and sodium tert-butoxide (4.26 g, 44.30 mmol). 5 min later, to the mixtue was added a solution of 3-bromopyridine (3.05 mL, 31.65 mmol) in DME (10 mL). The mixture was heated at 100 C overnight. LCMS1 showed the result after 1 h heating. LCMS2 showed the result after 18 h heating, which showed the product formation, and the starting material 3-BrPy. LCMS3 showed the result after 40 h heating.nbsp;LCMS4 was after 60h. To the mixture was added 50 mL DCM and acetic acid (2 mL, 34.94 mmol). The mixture was stirred for 10 min, and then was filtered. The filtrate was concentrated, and the compound was purified by preparative HPLC on a XBridge C18 column (10 m 250x50 ID mm) using a gradient of 0-60% acetonitrile in H2OACNNH3 9550.2 buffer over 20 minutes with a flow of 100 mLmin. The compounds were dby UV at 254nm (LCMS5). After freezing-dried overnight, product dipyridin-3-ylamine (0.540 g, 9.97 %) was obtained.nbsp;nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC(=CN=C1)NC2=CN=CC=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 9.97 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/03/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "591" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.007 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CN=C1)N" - } - amount { - moles { - value: 0.006 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CN=C1)Br" - } - amount { - moles { - value: 0.005 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 4.86e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.86e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Stock solution: 2.43 M solution of CyPF-tBuPd(OAc)2 (1:1) in DME.3-bromopyridine (0.482 mL, 5.00 mmol) was dissolved in DME (10 mL). To the solution was added 2mL of stock solution, and sodium tert-butoxide (0.673 g, 7.00 mmol). To the mixture was added a solution of pyridin-3-amine (0.565 g, 6.00 mmol) in DME (10 mL). The mixture was heated at 90 C overnight. LCMS showed the product formation, but the starting material 3-BrPy was still . To the mixture was added 2 mL stock solution additionally, and the mixture was heated at 90 C for another 2h, but LCMS did not show improvement. The mixture was filtered. The filtrate was concentrated, and the compound was purified by preparative HPLC on a XBridge C18 column (10 m 250x50 ID mm) using a gradient of 0-50% acetonitrile in H2OACNNH3 9550.2 buffer over 15 minutes with a flow of 100 mLmin. The compounds were detected by UV at 254nm. To the fractions (ca. 60mL) were added 5 mL of HOAc. The product was freezing-dried to give the prdin-3-ylamine (0.031 g, 3.62 %). " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC(=CN=C1)NC2=CN=CC=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 3.62 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/30/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "592" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0623 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CN=C1)N" - } - amount { - moles { - value: 0.0747 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CN=C1)Br" - } - amount { - moles { - value: 0.0623 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 2.43e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.43e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Stock solution: 2.43 M solution of CyPF-tBuPd(OAc)2 (1:1) in DME.3-bromopyridine (6 mL, 62.28 mmol) was dissolved in DME (10 mL). To the solution was added 10 mL of stock solution, and sodium tert-butoxide (8.38 g, 87.19 mmol). To the mixture was added a solution of pyridin-3-amine (7.03 g, 74.74 mmol) in DME (10 mL). The mixture was heated at 100 C overnight. LCMS showed the product formation, and the starting material 3-BrPy . To the mixture was added 4 mL stock solution additionally, and the mixture was heated at 100 C for another 5h. LCMS showed more impurities peaks. The mixture was filtered. The filtrate was concentrated, and the compound was purified by preparative HPLC on a XBridge C18 column (10 m 250x50 ID mm) using a gradient of 0-50% acetonitrile in H2OACNNH3 9550.2 buffer over 15 minutes with a flow of 100 mLmin. The compounds were detected by UV at 254nm. To the fractions (ca. 1000mL) were added 20 mL of HOAc. The product was freezing-dried to give the 1.56 g out NMR1 showed that there was 5 eq. acetic acid in the crude. The residue was dissolved in 10 mL methanol. To the solution was added 10 mL of aq. ammonia solution, and the crude was freezing-dried overnight to give the product dipyridin-3-ylamine (1.300 g, 12.19 %) .nbsp;nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC(=CN=C1)NC2=CN=CC=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 12.19 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "12/01/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "594" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000648 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0025 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1C[C@@H](C2=NC(=NN2C1)N)C3=CC=C(C=C3)F" - } - amount { - moles { - value: 0.000435 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC=C(C=C1)Br" - } - amount { - moles { - value: 0.000438 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 4.51e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.37e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "8-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine (101 mg, 0.43 mmol), 4-bromo-N,N-dimethylbenzamide (100 mg, 0.44 mmol), Cesium carbonate (211 mg, 0.65 mmol), Palladium(II) acetate (9.8 mg, 0.04 mmol) and 2-(Dicyclohexylphosphino)biphenyl (15.8 mg, 0.05 mmol) were added to a microwave vial. The vial was capped and flushed with nitrogen. Dioxane (2.5 mL) was added and the vial was flushed with additional nitrogen before it was irradiated in a microwave reactor at 120 C for 1.5 h. The reaction mixture was diluted with dichloromethane and filtered through a pad of diatomaceous earth. The pad was rinced repeatedly with dichloromethane, then the solvents were removed iin vacuoi. Handed over to the preparative chromatography group for purification (see attached report). The desired fractions were pooled and concentrated iin vacuoi. The residue was partitioned between water and dichloromethane (x1), the organic layer was passed through a phase separator and concentrated n vacuoi. The residue was redissolved in acetonitrile and water was added. Freeze-dried over weekend to give 4-(8-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-N,N-dimethylbenzamide (67.5 mg, 40.9 %)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC=C(C=C1)NC2=NN3CCCC(C3=N2)C4=CC=C(C=C4)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 40.91 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/15/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "595" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 3.5e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" - } - amount { - moles { - value: 0.00035 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=C(C=C1F)Br)C#N" - } - amount { - moles { - value: 0.000437 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.75e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (3.93 mg, 0.02 mmol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (130 mg, 0.35 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (20.25 mg, 0.03 mmol), 3-bromo-5-fluorobenzonitrile (88 mg, 0.44 mmol)nbsp;and cesium carbonate (171 mg, 0.52 mmol) dissolved in 1,4-dioxane (4 ml). The resulting suspension was degased with argon and then stirred at 100 C (18:00) for 15 hours.The reaction mixture was allowed to cool to room temperature, filtered and concentrated in V-10 Evaporator (Biotage)The crude product was dissolved in 2ml of DMA.The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 60 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated tyness to afford 8-(1-(3-cyano-5-fluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (90 mg, 52.4 %)nbsp;as anbsp;solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)C#N)F)OC(=CC2=O)N5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 52.42 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/10/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "596" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 3.5e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" - } - amount { - moles { - value: 0.00035 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)Br" - } - amount { - moles { - value: 0.000437 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.75e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (3.93 mg, 0.02 mmol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (130 mg, 0.35 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (20.25 mg, 0.03 mmol), bromobenzene (0.046 ml, 0.44 mmol) and cesium carbonate (171 mg, 0.52 mmol) dissolved in 1,4-dioxane (4 ml). The resulting suspension was degased with argon and then stirred at 100 C (18:00) for 15 hours.The reaction mixture was allowed to cool to room temperature, filtered and concentrated in V-10 Evaporator (Biotage)The crude product was dissolved in 2ml of DMA.The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 60 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afforsp;N,N-dimethyl-2-morpholino-4-oxo-8-(1-phenylpyrrolidin-2-yl)-4H-chromene-6-carboxamide (59.0 mg, 37.7 %) as anbsp;solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC=CC=C4)OC(=CC2=O)N5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 37.67 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/10/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "597" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000841 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" - } - amount { - moles { - value: 0.000673 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1F)Br" - } - amount { - moles { - value: 0.000841 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 6.73e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.37e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (7.56 mg, 0.03 mmol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (250 mg, 0.67 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (38.9 mg, 0.07 mmol), 1-bromo-4-fluorobenzene (0.092 ml, 0.84 mmol) and cesium carbonate (329 mg, 1.01 mmol) dissolved in 1,4-dioxane (5 ml). The resulting suspension was degased with argon and then stirred at 100 C for 15 hours.The reaction mixture was allowed to cool to room temperature and concentrated.The crude product was dissolved in 2ml of DMA.The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 60 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-(4-fluorophenyl)pyrrolidin-2-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (47.0 mg, 15.00 %) as anbsp;solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC=C(C=C4)F)OC(=CC2=O)N5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 15.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/06/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "599" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 6.73e-06 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" - } - amount { - moles { - value: 6.73e-05 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1F)Br" - } - amount { - moles { - value: 8.41e-05 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 6.73e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.37e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (0.756 mg, 3.37 mol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (25 mg, 0.07 mmol), [Reactants], 1-bromo-4-fluorobenzene (9.24 l, 0.08 mmol) and cesium carbonate (32.9 mg, 0.10 mmol) dissolved in 1,4-dioxane (1.5 ml). The resulting suspension was degased with argon and then stirred at 100 C for 15 hours.The reaction mixture was allowed to cool to room temperature and concentrated.The crude product was dissolved in 2ml of DMA.The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 60 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-(4-fluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carbo mg, 19.15 %) as anbsp;solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC=C(C=C4)F)OC(=CC2=O)N5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 19.15 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/20/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "600" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 6.73e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" - } - amount { - moles { - value: 0.000673 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1F)Br" - } - amount { - moles { - value: 0.000841 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 6.73e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.37e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (7.56 mg, 0.03 mmol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (250 mg, 0.67 mmol), biphenyl-2-yldicyclohexylphosphine (23.59 mg, 0.07 mmol), 1-bromo-4-fluorobenzene (0.092 ml, 0.84 mmol) and cesium carbonate (329 mg, 1.01 mmol) dissolved in 1,4-dioxane (5 ml). The resulting suspension was degased with argon and then stirred at 100 C for 15 hours.The reaction mixture was allowed to cool to room temperature and concentrated.The crude product was dissolved in DMA.The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 60 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-(4-fluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholinoxo-4H-chromene-6-carboxamide (155 mg, 49.5 %) as anbsp;gum200mg (155mg from EN05368-13 and 45mg from EN04870-97) was sent to the collection and purified by chiral separation by Fiona Bell." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC=C(C=C4)F)OC(=CC2=O)N5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 49.47 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/21/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "601" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 1.35e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" - } - amount { - moles { - value: 0.000135 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1F)Br" - } - amount { - moles { - value: 0.000168 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 1.35e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 6.73e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (1.511 mg, 6.73 mol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (50 mg, 0.13 mmol), biphenyl-2-yldicyclohexylphosphine (4.72 mg, 0.01 mmol), 1-bromo-4-fluorobenzene (0.018 ml, 0.17 mmol) and cesium carbonate (65.8 mg, 0.20 mmol) dissolved in 1,4-dioxane (1.5 ml). The resulting suspension was degased with argon and then stirred at 100 C for 15 hours.The reaction mixture was allowed to cool to room temperature and concentrated.The crude product was dissolved in 2ml of DMA.The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 60 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-(4-fluorophenyl)pyrrolidin-2-yl)-N,N-dimethyholino-4-oxo-4H-chromene-6-carboxamide (10.00 mg, 15.96 %) as anbsp;gum." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC=C(C=C4)F)OC(=CC2=O)N5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 15.96 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/20/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "602" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000437 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" - } - amount { - moles { - value: 0.00035 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1F)Br" - } - amount { - moles { - value: 0.000437 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.75e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (3.93 mg, 0.02 mmol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (130 mg, 0.35 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (20.25 mg, 0.03 mmol), 1-bromo-4-fluorobenzene (0.048 ml, 0.44 mmol) and cesium carbonate (171 mg, 0.52 mmol) dissolved in 1,4-dioxane (4 ml). The resulting suspension was degased with argon and then stirred at 100 C for 15 hours.The reaction mixture was allowed to cool to room temperature, filtered and concentrated in V-10 Evaporator (Biotage)The crude product was dissolved in 2ml of DMA.The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 60 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to af 8-(1-(4-fluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (31.0 mg, 19.03 %) as anbsp;solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC=C(C=C4)F)OC(=CC2=O)N5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 19.03 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/10/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "603" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00785 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)CN.Cl" - } - amount { - moles { - value: 0.00524 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=NC(=C1N)Br)F" - } - amount { - moles { - value: 0.00262 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000262 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000262 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 50 mL round-bottomed flask 2-bromo-5-fluoropyridin-3-amine (500 mg, 2.62 mmol) ethyl 2-aminoacetate hydrochloride (731 mg, 5.24 mmol)nbsp;BINAP (163 mg, 0.26 mmol) palladium(II) acetate (58.8 mg, 0.26 mmol)nbsp;CESIUM CARBONATE (2559 mg, 7.85 mmol) were taken.The solids were mixed well and degassed.The toluene was taken in another RB and degassed using Nitrogen.The degassed toluene was then added to the solids.The resulting RM was heated to reflux for 16 hrs.The reaction was monitored by LCMS, which indicated starting material only and no required product.Therefore, the batch was discarded. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)CNC1=C(C=C(C=N1)F)N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/19/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "604" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00244 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C1=CC=CC=C1)N" - } - amount { - moles { - value: 0.00175 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=N1)Cl" - } - amount { - moles { - value: 0.00175 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000227 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000227 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 70.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a solution of 1-phenylethanamine (212 mg, 1.75 mmol) and 2-chloropyrazine (200 mg, 1.75 mmol) in toluene (10 mL) while bubbling N2 was added binap (141 mg, 0.23 mmol), sodium tert-butoxide (235 mg, 2.44 mmol) and palladium(II) acetate (51.0 mg, 0.23 mmol). The reaction mixure was heated at 70 oC for 3 hours. The reaction was concentrated, partitioned between ethyl acetate and water. The aqueous phase was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated.nbsp;The crude material was loaded on a 40g silica gel column and purified on a Teledyne Isco instrument, eluting with 20% to 70% ethyl acetate in heptane to provide N-(1-phenylethyl)pyrazin-2-amine (148 mg, 42.5 %) as a solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C1=CC=CC=C1)NC2=NC=CN=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 42.54 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/21/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "605" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 5.11e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CS(=O)(=O)C1=CC=C(C=C1)N" - } - amount { - moles { - value: 0.000426 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)Cl)C" - } - amount { - moles { - value: 0.000426 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 5.11e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.98e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 10 mL microwave reactor 3-(2-chloropyridin-4-yloxy)-2,6-dimethylpyridine (100 mg, 0.43 mmol) andnbsp;4-(methylsulfonyl)aniline (73.0 mg, 0.43 mmol) were dissolved in DMA (3 mL) to give a tan solution.To the resultant solution Cesium carbonate (0.068 mL, 0.85 mmol) was added and sparged with nitrogen for 1 minute. Then Palladium(II) acetate (6.70 mg, 0.03 mmol) and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (29.6 mg, 0.05 mmol) were added and the reaction mixture was sealed. The reaction was heated to150 C for 25 minutes in the biotage microwave.The reaction was cooled to room temperature and LCMS shows reaction was completed. Reaction mixture was filtered through Celite Bed and washed with Dichloromethane. Filtrate was jected to concentration to get DMA solution which was given to analytical department to purify using Mass based HPLC. After purification compound was isolated to get pale yellow solid ofnbsp; 4-(2,6-dimethylpyridin-3-yloxy)-N-(4-(methylsulfonyl)phenyl)pyridin-2-amine (80 50.8 %)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)NC3=CC=C(C=C3)S(=O)(=O)C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 50.82 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/07/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "606" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 5.11e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1CCNS(=O)(=O)C2=CC=C(C=C2)N" - } - amount { - moles { - value: 0.000426 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)Cl)C" - } - amount { - moles { - value: 0.000426 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 5.11e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.98e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 10 mL microwave reactor 3-(2-chloropyridin-4-yloxy)-2,6-dimethylpyridine (100 mg, 0.43 mmol) andnbsp;4-amino-N-(2-morpholinoethyl)benzenesulfonamide (122 mg, 0.43 mmol) were dissolved in DMA (5 mL) to give a tan solution.To the resultant solution Cesium carbonate (0.068 mL, 0.85 mmol) was added and sparged with nitrogen for 1 minute. Then Palladium(II) acetate (6.70 mg, 0.03 mmol) and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (29.6 mg, 0.05 mmol) were added and the reaction mixture was sealed. The reaction was heated to150 C for 25 minutes in the biotage microwave.The reaction was cooled to room temperature and LCMS shows reaction was completed. Reaction mixture was filtered through Celite Bed and washed with Dichloromethane. Filtrate was jected to concentration to get DMA solution which was given to analytical department to purify using Mass based HPLC. After purification compound was isolated to get pale yellow solid ofnbsp; 4-(4-(2,6-dimethylpyridin-3-yloxy)pyridin-2-ylamino)-N-(2-holinoethyl)benzenesulfonamide (125 mg, 60.7 %)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)NC3=CC=C(C=C3)S(=O)(=O)NCCN4CCOCC4)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 60.66 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/11/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "607" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 5.11e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(COC)NS(=O)(=O)C1=CC=C(C=C1)N" - } - amount { - moles { - value: 0.000426 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)Cl)C" - } - amount { - moles { - value: 0.000426 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 5.11e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.98e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 10 mL microwave reactor 3-(2-chloropyridin-4-yloxy)-2,6-dimethylpyridine (100 mg, 0.43 mmol) andnbsp;4-amino-N-(1-methoxypropan-2-yl)benzenesulfonamide (104 mg, 0.43 mmol) were dissolved in DMA (3 mL) to give a brown solution.To the resultant solution Cesium carbonate (0.068 mL, 0.85 mmol) was added and sparged with nitrogen for 1 minute. Then Palladium(II) acetate (6.70 mg, 0.03 mmol) and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (29.6 mg, 0.05 mmol) were added and the reaction mixture was sealed. The reaction was heated to150 C for 25 minutes in the biotage microwave.The reaction was cooled to room temperature and LCMS shows reaction was completed. Reaction mixture was filtered through Celite Bed and washed with Dichloromethane. Filtrate was jected to concentration to get DMA solution which was given to analytical department to purify using Mass based HPLC. After purification compound was isolated to get pale yellow solid ofnbsp;4-(4-(2,6-dimethylpyridin-3-yloxy)pyridin-2-ylamino)-Nmethoxypropan-2-yl)benzenesulfonamide (98 mg, 52.0 %)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC(=C(C=C1)OC2=CC(=NC=C2)NC3=CC=C(C=C3)S(=O)(=O)NC(C)COC)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 51.97 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/11/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "608" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00288 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0065 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCC1CN" - } - amount { - moles { - value: 0.00192 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)I)Br" - } - amount { - moles { - value: 0.00192 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000288 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000144 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium (II) acetate (0.032 g, 0.14 mmol) and racemic-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.179 g, 0.29 mmol) were suspended in toluene (3 mL). The mixture was evacuated and purged with nitrogen, and warmed to 50C.In a separate vessel, 2-bromo-4-iodo-1-methoxybenzene (0.6 g, 1.92 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (0.221 g, 1.92 mmol) and sodium-t-butoxide (0.276 g, 2.88 mmol) were suspended in toluene (3.5 mL). The resulting mixture was evacuated, purged with nitrogen and warmed to 50C. After ~30 mins, the catalyst mixture was transferred to the reaction vessel. The reaction was evacuated and purged with nitrogen and heated at 80C overnight. The mixture was filtered and purified by flash silica chromatography, elution 30% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 3-bromo-4-methoxy-N-((tetrahydro-2H-pyran-4-yl)methyl)aniline (0.060 g, 10.42 %) as a brown solid. 60mg of product formed by LC-MS and major product is unknown buttain pyran signals in NMR and not SM iodide." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)NCC2CCOCC2)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 10.42 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/27/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "609" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00671 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCC1CN" - } - amount { - moles { - value: 0.00447 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)I)Br" - } - amount { - moles { - value: 0.00447 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000358 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000336 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium (II) acetate (0.075 g, 0.34 mmol) and racemic-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.223 g, 0.36 mmol) were suspended in dioxane (5mL). The mixture was evacuated and purged with nitrogen, and warmed to 50C.In a separate vessel, 2-bromo-4-iodo-1-methoxybenzene (1.4 g, 4.47 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (0.547 mL, 4.47 mmol) and sodium-t-butoxide (0.645 g, 6.71 mmol) were suspended in dioxane (5ML). The resulting mixture was evacuated, purged with nitrogen and warmed to 50C. After ~30 mins, the catalyst mixture was transferred to the reaction vessel. The reaction was evacuated and purged with nitrogen and heated at 80C overnight. Very little product and mainly SM so reaction ab" - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)NCC2CCOCC2)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/03/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "610" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000427 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.035 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" - } - amount { - moles { - value: 0.00502 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)Br)F" - } - amount { - moles { - value: 0.00502 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000427 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000201 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (0.045 g, 0.20 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (1.8 g, 5.02 mmol), methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (1.8 g, 5.02 mmol) and cesium carbonate (2.455 g, 7.53 mmol) dissolved in 1,4-dioxane (35 ml). The resulting suspension was degased with argon and then stirred at 100 C for 11 hours.The reaction mixture was allowed to cool to room temperature, filtered and concentrated.The crude product was purified by flash chromatography on silica gel eluting with 0 to 20% methanol in ethyl acetate (on 50 min). The solvent was evaporated to dryness to afford methyl 8-(1-(3-fluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (1.610 g, 70.8 %) as a clear yellow foam." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC=C4)F)OC(=CC2=O)N5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 70.85 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/18/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "611" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 2.96e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" - } - amount { - moles { - value: 0.000349 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC(=CC=C1)Br" - } - amount { - moles { - value: 0.000384 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 2.96e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.4e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (3.13 mg, 0.01 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxylate (125 mg, 0.35 mmol), 1-bromo-3-methoxybenzene (0.049 ml, 0.38 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (17.15 mg, 0.03 mmol) and cesium carbonate (170 mg, 0.52 mmol) dissolved in 1,4-dioxane (2 ml). The resulting suspension was degased with argon and then stirred at 100 C for 11 hours.The reaction mixture was allowed to cool to room temperature. The reaction mixture was quenched with water and extracted with dichloromethane (2 x 10 ml). The combined organic phases were dried over magnesium sulfate and concentrated to afford the crude product as a orangeyellow oil.The crude product was purified by flash chromatography on silica gel eluting with 0 to 10% methanol in dichloromethane. The solvent was evaporated to dryness to afford methyl 8-(1-(3-methoxyphenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate mg, 55.6 %) as a yellow gum." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=CC=CC(=C1)N2CCCC2C3=CC(=CC4=C3OC(=CC4=O)N5CCOCC5)C(=O)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 55.55 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/28/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "612" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000948 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)CN1CCNCC1" - } - amount { - moles { - value: 0.000632 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1Br)Br" - } - amount { - moles { - value: 0.00158 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 3.79e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.26e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 85.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a reaction vial, 1,4-dibromobenzene (0.373 g, 1.58 mmol), methyl 2-(piperazin-1-yl)acetate (0.100 g, 0.63 mmol), CS2CO3 (0.309 g, 0.95 mmol), and BINAP (0.024 g, 0.04 mmol) were taken up in 1,4-dioxane (1.5 ml).nbsp;Argon was bubbled through the solution for 1 minute.nbsp;Pd2(dba)3 (0.012 g, 0.01 mmol) was added, followed by additional purging with argon.nbsp;The vial was capped and placed on the heater-shaker.nbsp;The reaction was stirred (450 rpm) at 100 C overnight. LCMS at this point did not indicate any formation of the dp.nbsp;Experiment not progressed." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC(=O)CN1CCN(CC1)C2=CC=C(C=C2)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/04/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "613" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0461 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1CCNCC1" - } - amount { - moles { - value: 0.0154 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=CC(=C1)Br)F" - } - amount { - moles { - value: 0.0154 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000922 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000569 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 100 mL round-bottomed flask methyl piperidine-4-carboxylate (2.2 g, 15.36 mmol),4-bromo-1-fluoro-2-methylbenzene (1.954 mL, 15.36 mmol),Pd2(dba)3 (0.521 g, 0.57 mmol),BINAP (0.574 g, 0.92 mmol) and sodium tert-butoxide (4.43 g, 46.09 mmol) was taken in toluene (10 mL) under N2.The resulting reaction was stirred at 110 C for 3 hrs.LCMS did not show product MS.Material was discrded." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=CC(=C1)N2CCC(CC2)C(=O)OC)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/13/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "614" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.014 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.01 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CC2=C(C1=O)C=C(C=C2)Br" - } - amount { - moles { - value: 0.01 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.0001 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 60.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In an oven-dried RB flask was added Tris(dibenzylideneacetone)dipalladium(0) (0.046 g, 0.05 mmol) and rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.062 g, 0.10 mmol). The flask was evacuated and back-filled with nitrogen. Anhydrous toluene (3 mL) was added and the mixture was stirred at rt for 10 min to give a purple solution. 6-bromo-2-methylisoindolin-1-one (2.261 g, 10 mmol), 1-Boc-piperazine (1.863 g, 10.00 mmol) and Sodium tert-butoxide (1.714 mL, 14.00 mmol) were added in one portion followed by anhydrous toluene (15 mL). The flask was evacuated and back-filled with nitrogen and the resulting mixture was stirred at 60 C under a nitrogen atmosphere for 2 days. LCMS shows 10% conversion. Tris(dibenzylideneacetone)dipalladium(0) (0.183 g, 0.20 mmol) and 2-Dicyclohexylphosphino-2\',6\'-diisopropoxybiphenyl (0.187 g, 0.40 mmol) (RuPhos) were added and the mixture was heated to 80 C and stirred for 5 h. LCMS shows complete conversion. When cooled to rt the mixture was diluted with EtOAc (25 stirred for 1 h. The solid was filtered off and washed with EtOAc (50 mL). The filtrate was washed with saturated aqueous Na2CO3 (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated. The crude producr was purified on a silica gel column eluted with 20-100% EtOAc in Heptane to give a yellow solid; tert-butyl 4-(2-methyl-3-oxoisoindolin-5-yl)piperazine-1-carboxylate (1.890 g, 57.0 %)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC3=C(CN(C3=O)C)C=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 57.03 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/30/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "615" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00015 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)O" - } - amount { - volume { - value: 0.000241 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.000105 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=NC(=C1Br)Cl)Cl" - } - amount { - moles { - value: 0.0001 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 4e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 25.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2011-05-18r1 was checked by NMR and LCMS:Vial a:3-bromo-2,6-dichloropyridine (0.023 g, .1 mmol), morpholine (9.15 l, 0.11 mmol), Pd2dba3 (1.831 mg, 2.00 mol),4-(2,6-dichloropyridin-3-yl)morpholine (0.00 g) were mixed innbsp;tBuOH (0.241 ml) in microwave vial. The vial was flushed with N2 and sealed and the mix was strd at rt.Vial b: As above, but in PhCF3.1100:start2011-05-190800: LCMS: around 50% r1 in both vials.vial a: new peak at 1.53 min (20%), at 2.90 min (17%) and some small peaks as well.vial b: new peak at 1.54 min (32%), 2.61 min (25%) and at 2.90 min (5%) and some small peaks as well.MW100 degr20 min. LCMS, pH3: vial a: 1.17 min: new peak (8-9%, not integrated); 2.11 min: new peak (31%), no right mass track.vial b: 1.17 min: new, small peak; 2.11 min: new peak (17%), no right mass track.The peak from the 2.11 peak is relatively higher in vial a than in b. ation: r1 has logD 3.60, product has logD 1.92.Any Br-gt;H? Check of ret time of 2,6-diCl-pyridine (commercial ref. material): 1.86 min. NO such thing.at rt over night2011-05-200800: LCMS: around 50% r1 in both vials.MW100 degr20 min. LCMS: vial a: 1.17 min (8%); 1.51 min (ca. 5%); 2.12 min (32%); 2.47 min (r1 peak; 38%) + other small peaks.vial b: 1.54 min (19%); 2.12 min (21%); 2.48 (24%); 2.90 min (11%).The crudes were mixed, concentrated and kept at rt over night.2011-05-21Passed thru Si-plug with MeOH. NMR on crude: very messy. Scrutiny of the arom. region did not show anything that seemed like the right product.Not taken further." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1COCCN1C2=C(N=C(C=C2)Cl)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/16/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "616" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 1e-06 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1CCOC1" - } - amount { - volume { - value: 0.000474 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.0003 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=NC(=C1Br)Cl)Cl" - } - amount { - moles { - value: 5e-05 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 2e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "sodium tert-butoxide (0.012 g, 0.13 mmol), were transfered to a microwave vial. Pd2dba3 (0.916 mg, 1.00 mol),dicyclohexyl(2\',6\'-diisopropoxybiphenyl-2-yl)phosphine (0.933 mg, 2.00 mol),nbsp;(2-DICYCLOHEXYLPHOSPHINO-2\',6\'-DIISOPROPYL-1,1\'-BIPHENYL)[2-(2-AMINOETHYL)PHENYL]PALLADIUM(II) (0.729 mg, 1.00 mol) were added. 3-bromo-2,6-dichloropyridine (0.011 g, .05 mmol) in tetrahydrofuran (0.474 ml) was added. The vial was flushed with N2, sealed, and the reaction mix was heated on an oil bath at 100 C.2011-10-050900: interrupted, cooled-LCMS, 5 min method, pH11:1H NMR on crude:not good spectra.2011-10-06The mix was filtered thru Si-plug and conc. 1H NMR and COSY.Very complex. Lower rection temp and time needed. Discarded.----Info from -25:2011-09-18Lit. ref: Maiti,D....Buchwald, S. iChem. Sci.i b2011b, i2i, 57sodium tert-butoxidemmol), were transfered to a microwave vial. Pd2dba3 (1.831 mg, 2.00 mol),dicyclohexyl(2\',6\'-diisopropoxybiphenyl-2-yl)phosphine (1.867 mg, 4.00 mol), (2-DICYCLOHEXYLPHOSPHINO-2\',6\'-DIISOPROPYL-1,1\'-BIPHENYL)[2-(2-AMINOETHYL)PHENYL]PALLADIUM(II) (1.457 mg, 2.00 mol) were added. [Reactants] in tetrahydrofuran (0.948 ml) was added. The vial was flushed with N2, sealed, and the reaction mix was heated on an oil bath at 100 C.2115: start2011-09-190915: LCMS, 5 min method, pH11: some r1 remained3.62 major peak1200: heating at 120 degr2011-09-201400 lcms:5 min method, pH11: right mass peak appeared at 0.12 and 0.18 min.! seeemed very unlikely4.20 still peak, probabaly r1 ,but difficult to say since no iionizationThis was a test experiment, starting from a mix of r1 and one monost. starting material. Repeated with pure r1, see -66.Report Cannot be finalized, since this program" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1COCCN1C2=C(N=C(C=C2)Cl)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/01/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "620" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0266 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCCC12OCCO2" - } - amount { - moles { - value: 0.0266 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=NC(=CC=C1)Br" - } - amount { - moles { - value: 0.0266 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.0266 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.0266 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: nan - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "The same procedure as EN03653-93-01." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=CC=CC(=N1)N2CCC3(CC2)OCCO3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 69.11 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/30/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "621" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0051 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)N" - } - amount { - moles { - value: 0.00408 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC(=CC(=C1)Br)Br" - } - amount { - moles { - value: 0.0034 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00051 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00034 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "aniline (0.380 g, 4.08 mmol), methyl 3,5-dibromobenzoate (1.000 g, 3.40 mmol), Pd(OAc)2 (0.076 g, 0.34 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.295 g, 0.51 mmol) and CESIUM CARBONATE (1.663 g, 5.10 mmol) were stirred in toluene (10 mL) and degassed with nitrogen for 15 minutes. The mixture was then heated at 110 C under nitrogen fornbsp;24 hours. No evidence of any significant amount of product (ester or acid) therfore abandaned." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC(=O)C1=CC(=CC(=C1)Br)NC2=CC=CC=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/06/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "622" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000326 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=C(C=C1F)F)CN" - } - amount { - moles { - value: 0.0093 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC=C(C=C1)Br" - } - amount { - moles { - value: 0.00465 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000326 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000233 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "methyl 4-bromobenzoate (1 g, 4.65 mmol), (3,5-difluorophenyl)methanamine (1.100 mL, 9.30 mmol) and Cesium carbonate (1.515 g, 4.65 mmol) were mixed in toluene (4 mL) and degassed by bubbling nitrogen through solution. Palladium acetate (0.052 g, 0.23 mmol) and rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.203 g, 0.33 mmol) were added and the vial was capped and heated at 100C over 5 days. Workup by dilution with EtOAc, washing with water, then extraction with 2M HCl. The HCl extract was neutralized with 2M NaOH and extracted with EtOAc and the EtOAc phase was dried (K2CO3) and evaporated to give the crude product. The identity of product was doubtful but it was already used in exp 60-68." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC(=O)C1=CC=C(C=C1)NCC2=CC(=CC(=C2)F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/09/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "623" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000586 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=C(C=C1F)F)CN" - } - amount { - moles { - value: 0.0167 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC=C(C=C1)Br" - } - amount { - moles { - value: 0.00837 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000586 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000419 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "methyl 4-bromobenzoate (1.8 g, 8.37 mmol), (3,5-difluorophenyl)methanamine (1.980 mL, 16.74 mmol) and Cesium carbonate (2.73 g, 8.37 mmol) were mixed in toluene (4 mL) and degassed by bubbling nitrogen through solution. Palladium acetate (0.094 g, 0.42 mmol) and rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.365 g, 0.59 mmol) were added and the vial was capped and heated at 100C over 5 days. Workup by dilution with EtOAc, washing with water, then extraction with 2M HCl. The HCl extract was neutralized with 2M NaOH and extracted with EtOAc and the EtOAc phase was dried (K2CO3) and evaporated to give the crude product. The desired amine was not the compound isolated. Discarded." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC(=O)C1=CC=C(C=C1)NCC2=CC(=CC(=C2)F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/19/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "624" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000465 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCC2=CC=CC=C21" - } - amount { - moles { - value: 0.00093 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC=C(C=C1)Br" - } - amount { - moles { - value: 0.000465 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 3.26e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.33e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "methyl 4-bromobenzoate (100 mg, 0.47 mmol), [Reactants] and Cesium carbonate (152 mg, 0.47 mmol) were mixed in toluene (4 mL) and degassed by bubbling nitrogen through solution. Palladium acetate (5.22 mg, 0.02 mmol) and rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (20.27 mg, 0.03 mmol) were added and the vial was capped and heated at 100C over 5 days. Product had formed in mixture. Workup by dilution with EtOAc, washing with water, then extraction with 2M HCl. The HCl extract was neutralized with 2M NaOH and extracted with EtOAc and the EtOAc phase was dried (K2CO3) and evaporated to give the crude product. No product. Discarded." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC(=O)C1=CC=C(C=C1)N2CCC3=CC=CC=C3C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/09/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "625" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00119 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1N)N2C=CN=C2" - } - amount { - moles { - value: 0.000597 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CC(OC2=C(C1=O)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.000398 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 3.98e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.98e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "8-chloro-4-methyl-2-phenyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (115 mg, 0.40 mmol), 4-(1H-imidazol-1-yl)aniline (95 mg, 0.60 mmol), PdOAc2 (8.94 mg, 0.04 mmol), biphenyl-2-yldicyclohexylphosphine (13.96 mg, 0.04 mmol) and CS2CO3 (389 mg, 1.19 mmol)nbsp;were placed in a microwave vial equipped with a stirring bar. The vial was capped and flushed with argon. DME (1.5 mL) was added via a syringe and the mixture was heated to 100C in a microwave apparatus for 1 h. The residue was diluted with ethyl acetate and filtered through a short plug og Celite. The filtrate was evaporated and the residue was purified by HPLC to give 62 mg of the product as a solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CC(OC2=C(C1=O)C=CC(=N2)NC3=CC=C(C=C3)N4C=CN=C4)C5=CC=CC=C5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 37.83 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/15/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "628" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[K+]" - } - amount { - moles { - value: 0.004 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.005 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=CC=C1C(F)(F)F)CN2C(=NC3=C(C=C(C=C32)Br)C(=O)OC)C" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CCCCP(CCCC)CCCC" - } - amount { - moles { - value: 0.0002 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 9.99e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: nan - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "methyl 6-bromo-2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-4-carboxylate (441 mg, 1.00 mmol) was taken up with morpholine (435 l, 5.00 mmol), potassium tert-butoxide (449 mg, 4.00 mmol), tri-n-butylphosphine (49.3 l, 0.2 mmol) and palladium(II) acetate (22.44 mg, 0.10 mmol) in dioxane (10ml) and heated for 18 hrs at 100C. The reaction profile showed no required product and only dimer adduct to be present.the reaction was therefore ab" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=CC=C1C(F)(F)F)CN2C(=NC3=C(C=C(C=C32)N4CCOCC4)C(=O)OC)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/29/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "629" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.002 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)N" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=NC(=C1)Cl)C(F)(F)F" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 160.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: To test strate scope in 5-ester stituted 2-aminooxazole coupling.TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.87 mg, 0.02 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (43.4 mg, 0.075 mmol), cesium carbonate (651 mg, 2.00 mmol), ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol) and 2-chloro-6-(trifluoromethyl)pyridine (181 mg, 1.00 mmol) were placed in an oven dried microwave vial. The vial was then capped and placed under an inert atmosphere. Dioxane (4 mL) was added and the mixture was heated to 160 C for 1 h under microwave irradiation. LCMS of the crude reaction mixture indicated the presence of the desired product.DCM (10 mL) was added to the crude reaction mixture together with C-18 silica (2 g), and the solvent was removed under reduced pressure. The solid residue was then placed in a dry-load tube prior to chromatography. The crude product was purified by reverse-phase flash chromatography on C-18 silica, elution gradient 30 to 80% MeCNwater (1% ammonium hydroxide). Pure fractions were evaporated to dryness to afford ethyl 2-(6-(trifluoromethyl)pyridin-2-ylamino)oxazole-5-carboxylate (204 mg, 67.8 %) as a beige solid. Conclusion: The desired product was isolated in moderate yield and high purity." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)NC2=CC=CC(=N2)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 67.78 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/27/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "630" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.002 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)N" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1C#N)Cl" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 160.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: To test strate scope in 5-ester stituted 2-aminooxazole coupling.TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.87 mg, 0.02 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (43.4 mg, 0.075 mmol), cesium carbonate (651 mg, 2.00 mmol), ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol) and 2-chloroisonicotinonitrile (138 mg, 1.00 mmol) were placed in an oven dried microwave vial. The vial was then capped and placed under an inert atmosphere. Dioxane (4 mL) was added and the mixture was heated to 160 C for 1 h under microwave irradiation. LCMS of the crude reaction mixture indicated the presence of the desired product as well as a significant amount of amine starting material.DCM (10 mL) was added to the crude reaction mixture together with C-18 silica (2 g), and the solvent was removed under reduced pressure. The solid residue was then placed in a dry-load tube prior to chromatography. The crude product was purified by reverse-phase flash chromatograph C-18 silica, elution gradient 20 to 60% MeCN in water (1% ammonium hydroxide). Pure fractions were evaporated to dryness to afford ethyl 2-(4-cyanopyridin-2-ylamino)oxazole-5-carboxylate (155 mg, 60.1 %) as a beige solid. Conclusion: The desired product was isolated in moderate yield." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)NC2=NC=CC(=C2)C#N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 60.08 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/27/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "631" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.002 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)N" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=NC(=C1)Cl" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 160.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: To test the strate scope in 5-ester stituted 2-aminooxazole coupling.TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.87 mg, 0.02 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (43.4 mg, 0.075 mmol), cesium carbonate (651 mg, 2.00 mmol), ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol) and 2-chloropyridine (113 mg, 1.00 mmol) were placed in an oven dried microwave vial. The vial was then capped and placed under an inert atmosphere. Dioxane (4 mL) was added and the mixture was heated to 160 C for 1 h under microwave irradiation. LCMS of the crude reaction mixture indicated the presence of the desired product.DCM (10 mL) was added to the crude reaction mixture together with C-18 silica (2 g), and the solvent was removed under reduced pressure. The solid residue was then placed in a dry-load tube prior to chromatography. The crude product was purified by reverse-phase flash chromatography on C-18 silica, elution gradient 10 to 60% MeCN in water (1% amum hydroxide). Pure fractions were evaporated to dryness to afford ethyl 2-(pyridin-2-ylamino)oxazole-5-carboxylate (88 mg, 37.8 %) as a beige solid. Conclusion: The desired product was isolated in moderate yield, but in only 84% purity based on LCMS." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)NC2=CC=CC=N2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 37.77 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/27/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "632" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.002 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)N" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=NC=C1[N+](=O)[O-])Cl" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.49e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 160.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: Test of strate scope in couple of ester stituted aminooxazole To an oven-dried microwave vial was added ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol), cesium carbonate (651 mg, 2.00 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.87 mg, 0.02 mmol) 2-chloro-5-nitropyridine (158 mg, 1.00 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (43.4 mg, 0.07 mmol) and the vial was capped and purged with nitrogen. dioxane (4 mL) (degassed) was added and the reaction mixture was heated to 160 C for 1 h under microwave irradiation. LCMS of the crude reaction mixture indicated that the desired product had been formed while only a trace of the amine starting material remained.DCM (20 mL) was added to the crude reaction mixture together with silica (2 g) and the solvent was removed under reduced pressure. The resulting residue was then placed in a dry-load tube prior to chromatography.The crude product was purified by flash silica chromraphy, elution gradient 0 to 2.5% methanolic ammonia in DCM. Pure fractions were evaporated to dryness to afford ethyl 2-(5-nitropyridin-2-ylamino)oxazole-5-carboxylate (238 mg, 86 %) as a orange solid. nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)NC2=NC=C(C=C2)[N+](=O)[O-]" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 85.62 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/22/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "633" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000907 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CC(NC1)C2=CC(=CC3=C2OC(=CC3=O)N4CCOCC4)C(=O)N5CCOCC5" - } - amount { - moles { - value: 0.000605 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1F)Br" - } - amount { - moles { - value: 0.000756 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 6.05e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.02e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (6.79 mg, 0.03 mmol) was added to a stirred mixture of 6-(morpholine-4-carbonyl)-2-morpholino-8-(pyrrolidin-2-yl)-4H-chromen-4-one (250 mg, 0.60 mmol), biphenyl-2-yldicyclohexylphosphine (21.19 mg, 0.06 mmol), 1-bromo-4-fluorobenzene (0.083 ml, 0.76 mmol) and cesium carbonate (296 mg, 0.91 mmol) dissolved in 1,4-dioxane (5 ml). The resulting suspension was degased with argon and then stirred at 100 C for 15 hours.The reaction mixture was allowed to cool to room temperature and concentrated.The crude product was dissolved in DMA.The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 30 mm diameter, 150 mm length, flow rate of 60 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-(4-fluorophenyl)pyrrolidin-2-yl)-6-(morpholine-4-carbonyl)-2pholino-4H-chromen-4-one (140 mg, 45.6 %) as anbsp;gum.The product was sent to the collection and purified by chiral separation by Fiona Bell." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CC(N(C1)C2=CC=C(C=C2)F)C3=CC(=CC4=C3OC(=CC4=O)N5CCOCC5)C(=O)N6CCOCC6" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 45.62 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/27/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "634" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.002 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)N" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(C=C1)Cl" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 160.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: Test of scope in the coupling of ester stituted aminooxazoleTo an oven-dried microwave vial was added ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol), cesium carbonate (651 mg, 2.00 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.87 mg, 0.02 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (43.4 mg, 0.075 mmol) and the vial was capped and purged with nitrogen. ethyl 6-chloronicotinate (185 mg, 1.00 mmol) and dioxane (4 mL) (degassed) were added and the reaction mixture was heated to 160 C for 1 h under microwave irradiation.LCMS of the crude reaction mixture indicated that the desired product had formed with minimal formation of side-products.DCM (20 mL) was added to the crude reaction mixture together with silica (2 g). The solvent was removed under reduced pressure and the resulting residue was placed in a dry-load tube prior to chromatography.The crude product was purified by flash silica chromatography, elution gradient 05% Methanolic ammonia in DCM. Pure fractions were evaporated to dryness to afford the desired product (270 mg, 88% isolated yield in 86% purity). This solid was triturated with hot MeCN and allowed to cool to room temperature to give a solid which was collected by filtration and dried under vacuum to give ethyl 2-(5-(ethoxycarbonyl)pyridin-2-ylamino)oxazole-5-carboxylate (205 mg, 67.2 %) as a cream solid. Conclusion: The desired product was isolated in moderate yield and high purity." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(C=C1)NC2=NC=C(O2)C(=O)OCC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 67.21 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/04/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "635" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.002 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)N" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(N=C(C=N1)Cl)C#N" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 160.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: Test of scope in the coupling of ester stituted aminooxazoleTo an oven-dried microwave vial was added ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol), 6-chloropyrazine-2-carbonitrile (139 mg, 1.00 mmol), cesium carbonate (651 mg, 2.00 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.87 mg, 0.02 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (43.4 mg, 0.075 mmol) and the vial was capped and purged with nitrogen. dioxane (4 mL) (degassed) was added and the reaction mixture was heated to 160 C for 1 h under microwave irradiation.DCM (20 mL) was added to the crude reaction mixture together with silica (2 g) and the solvent was removed under reduced pressure. The resulting residue was added to a dry-load tube prior to chromatography.The crude product was purified by flash silica chromatography, elution gradient 0 to 1% methanolic ammonia in DCM.. Pure fractions were evaporated to dryness to afford ethyl 2-(6-cyanopyrazin-2-ylamino)oxazole-5-carbate (121 mg, 46.7 %) as a cream solid. nbsp;Conclusion: The desired product was formed in moderate yield purity." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)NC2=NC(=CN=C2)C#N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 46.72 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/13/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "636" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0015 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC=CN1C2=CC=C(C=C2)N" - } - amount { - moles { - value: 0.00072 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CC(OC2=C(C1=O)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.0006 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "8-chloro-4-methyl-2-phenyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (173 mg, 0.60 mmol), 4-(2-methyl-1H-imidazol-1-yl)aniline (125 mg, 0.72 mmol), PdOAc2 (13.47 mg, 0.06 mmol), biphenyl-2-yldicyclohexylphosphine (21.03 mg, 0.06 mmol) and cesium carbonate (489 mg, 1.50 mmol)nbsp;were placed in a microwave vial equipped with a stirring bar. The vial was capped, DME (4 mL) was added, the vial was flushed with nitrogen via a syringe and the mixture was heated to 100C in a microwave reactor for 1 h. The residue was diluted with CH2Cl2 and filtered through a short plug of Celite. The filtrate was evaporated and the residue was purified by ISCO column chromatography on silica (gradient elution 0-6% methanol in dichloromethane) to give 4-methyl-8-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-2-phenyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (105 mg, 41.1 %).68 mg given to Per Svensson crystallography." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC=CN1C2=CC=C(C=C2)NC3=NC4=C(C=C3)C(=O)N(CC(O4)C5=CC=CC=C5)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 41.13 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/23/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "637" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000883 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC=CN1C2=CC=C(C=C2)N" - } - amount { - moles { - value: 0.000412 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CC(OC2=C(C1=O)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.000294 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 2.94e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.94e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: " were placed in a microwave vial equipped with a stirring bar. The vial was capped and flushed with argon. DME (2 mL) was added via a syringe and the mixture was heated to 100C in a microwave apparatus for 1h. The reaction mixture was filtered, the solvent was evaporated and the residue was purified by HPLC to give 53 mg (42 % yield) of the product as a solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC=CN1C2=CC=C(C=C2)NC3=NC4=C(C=C3)C(=O)N(CC(O4)C5=CC=CC=C5)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 42.31 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/22/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "638" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00269 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC=CN1C2=CC=C(C=C2)N" - } - amount { - moles { - value: 0.00108 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CC(OC2=C(C1=O)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.000897 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 8.97e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 8.97e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Not continued." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC=CN1C2=CC=C(C=C2)NC3=NC4=C(C=C3)C(=O)N(CC(O4)C5=CC=CC=C5)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 74.93 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/11/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "640" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000244 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CS(=O)(=O)CC1=CC(=CC=C1)N" - } - amount { - moles { - value: 0.000974 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=CC(=C1)F)C2=NC(=NC=C2F)Cl" - } - amount { - moles { - value: 0.000974 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000244 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000195 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine (0.25 g, 0.97 mmol), 3-((methylsulfonyl)methyl)aniline (0.180 g, 0.97 mmol), cesium carbonate (1.270 g, 3.90 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.141 g, 0.24 mmol)and Pd2(dba)3 (0.178 g, 0.19 mmol) were suspended in degassed 1,4-dioxane (3 mL) at ambient temperature. The resulting mixture was degassed, purged with nitrogen and heated at 100 C for 3 hours after which time reaction was shown to be complete by LC-MS. The mixture was allowed to cool overnight. The reaction mixture was diluted with water (250 mL), and extracted with DCM (250 mL).nbsp;The organic was dried over MgSO4, filtered and evaporated to afford crude product.nbsp;The crude product was purified by flash silica chromatography, elution 50% ethyl acetate in Heptane. Fractions were evaporated to dryness to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 50 mm diameter, 150th), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-(3-((methylsulfonyl)methyl)phenyl)pyrimidin-2-amine (0.200 g, 50.6 %) as a white solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=C(C=CC(=C1)F)C2=NC(=NC=C2F)NC3=CC=CC(=C3)CS(=O)(=O)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 50.64 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/01/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "641" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00665 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.00266 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=NC=C1Br)CO" - } - amount { - moles { - value: 0.00266 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000199 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 6.65e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 10 mL Microwave vial was (5-bromopyridin-2-yl)methanol (500 mg, 2.66 mmol), morpholine (0.233 mL, 2.66 mmol),cesium carbonate (2166 mg, 6.65 mmol), Pd2(dba)3 (60.9 mg, 0.07 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (115 mg, 0.20 mmol) in dioxane (10 mL) () to give a brown suspension. The reaction mixture was heated to 110 C for 3h.The reaction mixture was passed over Celite and washed with ethylacetate. The Filtrate was concentrate to dryness to get as a syrupy brown liquid. Water 30ml was added and extracted with ethylacetate (20x 2)ml. THe organic layers are collected, dried over Sodium Sulphate and concentrated to get as a liquid.The crude product was added to a silica gel column and was eluted with ethylacetate 0-70%nbsp;Pure Collected fractions are evaporated to get as a (5-morpholinopyridin-2-yl)methanol (100 mg, 19.36 %)colorless liquid .The compound was carried to next step." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1COCCN1C2=CN=C(C=C2)CO" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 19.36 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/12/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "642" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000823 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.06 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@@H]1CNCCN1" - } - amount { - moles { - value: 0.0216 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C=C1F)C(F)(F)F)Br" - } - amount { - moles { - value: 0.0206 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000823 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000412 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "1-bromo-4-fluoro-2-(trifluoromethyl)benzene (5 g, 20.58 mmol), (R)-2-methylpiperazine (2.164 g, 21.61 mmol), sodium tert-butoxide (3.95 g, 41.15 mmol) and BINAP (0.512 g, 0.82 mmol) in anhydrous toluene (60 mL) was degassed under vacuum with inlet of nitrogen. TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.377 g, 0.41 mmol) was added, the mixture again degassed. The resulting suspension was stirred at 100 C for 6 hours under nitrogen.LCMS: Product formed.Cooled and evaporated. Residue diluted with diethyl ether (75 mL), filtered through Celite and the filtrates extracted with 2M HCl (2x30 mL). The combined aqueous layers were basified with solid NaOH to pH ~10, extracted with diethyl ether (2x50 mL), the organic extracts washed with water (2x10 mL) and brine, dried over mgSO4, filtered and evaporated to give crude product (3.2g, 59%) as an orange oil which was used without further purification." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@@H]1CN(CCN1)C2=C(C=C(C=C2)F)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/06/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "643" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00165 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.1 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@@H]1CNCCN1" - } - amount { - moles { - value: 0.0432 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C=C1F)C(F)(F)F)Br" - } - amount { - moles { - value: 0.0412 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00165 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000823 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "1-bromo-4-fluoro-2-(trifluoromethyl)benzene (10 g, 41.15 mmol), (R)-2-methylpiperazine (4.33 g, 43.21 mmol), sodium tert-butoxide (7.91 g, 82.31 mmol) and BINAP (1.025 g, 1.65 mmol) in anhydrous toluene (100 mL) was degassed under vacuum with inlet of nitrogen. TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.754 g, 0.82 mmol) was added, the mixture again degassed. The resulting suspension was stirred at 100 C for 4 hours under nitrogen.LCMS: Product formed.Heated for a further 2 hours.LCMS: Reaction complete.Cooled and evaporated. Residue diluted with diethyl ether (75 mL), filtered through Celite and the filtrates extracted with 2M HCl (2x30 mL). The combined aqueous layers were basified with solid NaOH to pH ~10, extracted with diethyl ether (2x50 mL), the organic extracts washed with water (2x10 mL) and brine, dried over MgSO4, filtered and evaporated to give crude product (3.2g, 59%) as an orange oil which was used without further purification." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@@H]1CN(CCN1)C2=C(C=C(C=C2)F)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/09/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "644" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "[O-]P(=O)([O-])[O-].[K+].[K+].[K+]" - } - amount { - moles { - value: 0.00208 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.006 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)N" - } - amount { - moles { - value: 0.00178 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "B1(OC(C(O1)(C)C)(C)C)C2=CC(=CC(=C2)Cl)C(=O)OC" - } - amount { - moles { - value: 0.00148 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" - } - amount { - moles { - value: 4.45e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.48e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "aniline (0.162 mL, 1.78 mmol) was added to methyl 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (440mg, 1.48 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (13.59 mg, 0.01 mmol), tri-tert-butylphosphine (10.80 L, 0.04 mmol) and potassium phosphate (441 mg, 2.08 mmol) in degassed DME (6 mL) at 20C under nitrogen. The reaction was stirred at 100 C for 2 days. The reaction mixture was diluted with Et2O (50 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution 10 to 60% EtOAc in " - } - outcomes { - products { - identifiers { - type: SMILES - value: "B1(OC(C(O1)(C)C)(C)C)C2=CC(=CC(=C2)NC3=CC=CC=C3)C(=O)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 2.29 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/19/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "645" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "[O-]P(=O)([O-])[O-].[K+].[K+].[K+]" - } - amount { - moles { - value: 0.000455 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)N" - } - amount { - moles { - value: 0.00395 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "B1(OC(C(O1)(C)C)(C)C)C2=CC(=CC(=C2)Cl)C(=O)OC" - } - amount { - moles { - value: 0.00303 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" - } - amount { - moles { - value: 0.000455 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000152 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "aniline (0.360 mL, 3.95 mmol) was added to methyl 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (900 mg, 3.03 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (139 mg, 0.15 mmol), [Reactants] and potassium phosphate (1546 mg, 7.28 mmol) in degassed DME (10 mL) at 20C under nitrogen. The reaction was stirred at 100 C for 24 hours. The reaction mixture was allowed to cool then filtered through celite, washing with ethyl acetate. The filtrate was evaporated under reduced pressure to give a brown residue.Not progressed any furt" - } - outcomes { - products { - identifiers { - type: SMILES - value: "B1(OC(C(O1)(C)C)(C)C)C2=CC(=CC(=C2)NC3=CC=CC=C3)C(=O)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/06/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "647" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[K+].[K+]" - } - amount { - moles { - value: 0.000751 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C2=C(N1C)C=CC(=C2)N)Cl" - } - amount { - moles { - value: 0.000275 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1CN2CC(C2)O)C3=NC(=NC=C3)Cl" - } - amount { - moles { - value: 0.00025 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 2.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.25e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 40 mL scintillation vial charged with 3-chloro-1,2-dimethyl-1H-indol-5-amine (53.6 mg, 0.28 mmol), 1-((1-(2-chloropyrimidin-4-yl)-3-methyl-1H-pyrazol-4-yl)methyl)azetidin-3-ol (70mg, 0.25 mmol), palladium(II) acetate (2.81 mg, 0.01 mmol), dicyclohexyl(2\',4\',6\'-triisopropyl-[1,1\'-biphenyl]-2-yl)phosphine (x--phos) (11.93 mg, 0.03 mmol) and Dioxane (3 mL) After being degassed by nitrogen bubbling , the reaction mixture was heated to 100 C for 5 hours. LCMS analysis indicated no desired product and chloropyrimidine starting material was decomposed. The reaction mixture was discarded.nbsp;Need to reverse the sequence." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C2=C(N1C)C=CC(=C2)NC3=NC=CC(=N3)N4C=C(C(=N4)C)CN5CC(C5)O)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/31/2014" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "648" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00783 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCCN1" - } - amount { - moles { - value: 0.0157 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C(=C1)Cl)Br" - } - amount { - moles { - value: 0.00522 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000261 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000261 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a stirred sol of 1-bromo-2-chlorobenzene (0.606 mL, 5.22 mmol) in toluene (10 mL) was added Pd2(dba)3 (0.239 g, 0.26 mmol), BINAP (0.163 g, 0.26 mmol), sodium tert-butoxide (0.753 g, 7.83 mmol) and piperazine (1.350 g, 15.67 mmol) and the resulting sol was heated at 110 C for 16h.Cooled to rt, filtered through a celeite pad, volatiles were evaporated off and residue was column chromatographed (DCM:MeOH 90:10) to afford 1-(2-chlorophenyl)piperazine (0.450 g, 43.8 %) as a gum." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CN(CCN1)C2=CC=CC=C2Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 43.8 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/22/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "649" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00783 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCCN1" - } - amount { - moles { - value: 0.0157 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C(=C1)Cl)Br" - } - amount { - moles { - value: 0.00522 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000261 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000261 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a stirred sol of 1-bromo-2-chlorobenzene (0.606 mL, 5.22 mmol) in toluene (10 mL) was added Pd2(dba)3 (0.239 g, 0.26 mmol), BINAP (0.163 g, 0.26 mmol), sodium tert-butoxide (0.753 g, 7.83 mmol) and piperazine (1.350 g, 15.67 mmol) and the resulting sol was heated at 110 C for 16 h.Filtered through a celeite pad amp; crude mixture was purified by column chromatography to afford (DCM:MeOH 90:10) to afford 1-(2-chlorophenyl)piperazine (0.600 g, 58.4 %) as a brown gum." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CN(CCN1)C2=CC=CC=C2Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 58.41 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/23/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "651" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0113 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1CNC1" - } - amount { - moles { - value: 0.00469 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1Br)Br" - } - amount { - moles { - value: 0.00469 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 9.38e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.69e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "3-methylazetidine (0.5 g, 4.69 mmol), diacetoxypalladium (10.53 mg, 0.05 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.058 g, 0.09 mmol) and cesium carbonate (3.67 g, 11.26 mmol), degassed toluene (15 mL) were heated at 100 C over the weekend. The RM was filtered and washed with EtOAc the filtrate was then concentrated and the crude product purified by flash silica chromatography, elution gradient 20 to 30% EtOAc in heptane. Purest fractions were collected and combined with EN05604-93. The combined product was then recrystalised from EtOAc to give 1-(4-bromophenyl)-3-methylazetidine (0.899 g, 85 %)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1CN(C1)C2=CC=C(C=C2)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 84.74 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/29/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "652" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00241 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.016 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CC1CNC2=CC=C(C3=CC=CC=C32)Cl.Cl" - } - amount { - moles { - value: 0.0012 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1CC1C(=O)C2=C(C=C(C=N2)Br)OC" - } - amount { - moles { - value: 0.001 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 7.02e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 5.01e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 70.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Repeat from Orexa Patent write up and cfnbsp;uEN06741-39\\ReactionubuAim:-u bto Prepare target for further useb. NB. the SM is either the (R,R) or (S,S) isomerbethyl 2-(5-bromo-3-methoxypicolinoyl)cyclopropanecarboxylate (0.329 g, 1.00 mmol), 4-chloro-N-(cyclopropylmethyl)naphthalen-1-amine, HCl (0.323 g, 1.20 mmol), PALLADIUM(II) ACETATE (0.011 g, 0.05 mmol), rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthalene (0.044 g, 0.07 mmol) and cesium carbonate (0.784 g, 2.41 mmol) were mixed in toluene (16 mL), purged with nitrogen and stirred in a sealed tube at 70 C for 19 hours.The reaction mixture was diluted with EtOAc (20 ml), filtered through a celite pad and concentrated to give 902 mgnbsp;brown oil.TLC (1 : 1 - EtOAc : n-heptane) see diagram UV onlyThe residue was absorbed onto a samplet and purified on a 25 g Biotage SNAP column, eluting with a step-wise gradient from 0 : 10 to 4 : 6 EtOAc : n-heptane using a Thomson pump collecting 25 ml tions.nbsp;Pure fractions were evaporated to give 318 mg of orange solid - the product eluted with the 4 : 6 mixture. The front spot was probably binap bis oxideLCMS (pH = 3) Rt = 1.66 min (85% by UV),nbsp;mz: 479 (MH+). 1H NMR (DMSO-d6) - looks ok - Aromatics are ok - aliphatics more or less ok but 1 proton missing but there are a number of small peaks as well!buConclusion:u- bOK to use for further reactions - See EN06995-01" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1CC1C(=O)C2=C(C=C(C=N2)N(CC3CC3)C4=CC=C(C5=CC=CC=C54)Cl)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 66.22 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/20/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "653" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000951 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N" - } - amount { - moles { - value: 0.00679 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CN=C1)CN2C=CC3=C2C=C(C=C3)Br" - } - amount { - moles { - value: 0.00453 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.000951 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000317 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "6-bromo-1-(pyridin-3-ylmethyl)-1H-indole (1.3 g, 4.53 mmol), cesium carbonate (2.213 g, 6.79 mmol),nbsp;tert-butyl carbamate (0.796 g, 6.79 mmol), dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.453 g, 0.95 mmol) and PALLADIUM(II) ACETATE (0.071 g, 0.32 mmol) were placed under a nitrogen atmosphere. dry degassed dioxane (20 mL) was added and the reaction was warmed to 110 C (using microwave). After reaction completion (3h) the the reaction was diluted with EtOAc(20mL) and water (10mL) and the organic layer was separated. The aqueous layer was washed with a further portion of EtOAc(10mL) and the combined organic layers were dried (MgSO4), filtered and evaporated to afford crude product.The crude product was purified by flash silica chromatography, elution gradient 30 to 70% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 1-(pyridin-3-ylmethyl)-1H-indol-6-ylcarbamate (1.200 g, 82 %) as a colourless gum. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC1=CC2=C(C=C1)C=CN2CC3=CN=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 81.96 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/25/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "654" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000522 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N" - } - amount { - moles { - value: 0.000522 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CN=C1)CN2C=CC3=C2C=C(C=C3)Br" - } - amount { - moles { - value: 0.000348 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 7.31e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.44e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "6-bromo-1-(pyridin-3-ylmethyl)-1H-indole (0.1 g, 0.35 mmol), cesium carbonate (0.170 g, 0.52 mmol),nbsp;tert-butyl carbamate (0.061 g, 0.52 mmol), dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.035 g, 0.07 mmol) and PALLADIUM(II) ACETATE (5.47 mg, 0.02 mmol) were placed under a nitrogen atmosphere. dry degassed dioxane (2 mL) was added and the reaction was warmed to 100 C (using microwave). After reaction completion (2.5h) the the reaction was diluted with EtOAc(20mL) and water (10mL) and the organic layer was separated. The aqueous layer was washed with a further portion of EtOAc(10mL) and the combined organic layers were dried (MgSO4), filtered and evaporated to afford crude product.The crude product was purified by flash silica chromatography, elution gradient 30 to 70% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford tert-butyl 1-(pyridin-3-ylmethyl)-1H-indol-6-ylcarbamate (0.094 g, 83 %) as a colourless gum. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC1=CC2=C(C=C1)C=CN2CC3=CN=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 83.47 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/24/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "655" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0218 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.08 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C(=C1)N)Br" - } - amount { - moles { - value: 0.0164 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC=C(C=C1)I" - } - amount { - moles { - value: 0.0156 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00125 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000779 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-Bromoaniline (1.851 mL, 16.35 mmol) and ethyl 4-iodobenzoate (2.60 mL, 15.58 mmol) were dissolved in toluene (argon bubbled through for 10 min) (80 mL). To the stirred mixture were palladium acetate (0.175 g, 0.78 mmol), rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.776 g, 1.25 mmol) and cesium carbonate (7.10 g, 21.81 mmol) added, argon bubbled through the reaction for 2 min and heated then at 100 C for 3 h. The reaction was not complete (the reaction was checked on a worked-up portion on GCMS and the product was 20% on GCMS). The following were added to the cooled reaction mixture: rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (400 mg) and palladium acetate (100 mg) and then argon bubbled through the reaction for 1 min and heated then at 100 C overnight. The reaction was checked on a worked-up portion on GCMS =gt; 85% product.nbsp;The following were added to the cooled reaction mixture: rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (200 mg) and palladium acetate (50 mg) and then bbled through the reaction for 1 min and heated then at 100 C for 3 h =gt; done.The reaction was poured on a filter-funnel (silica, packed in toluene, eluted with toluene, Rf 0.32). The product came out in fractions 5-8 (Note 1) and they were pooled and the solvent was removed on the rotovap to give ethyl 4-(2-bromophenylamino)benzoate (3.00 g, 60.2 %) as a light brown oil." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC=C(C=C1)NC2=CC=CC=C2Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 60.16 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "12/05/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "657" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000624 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@@H]1CN(CCN1)C(=O)OC(C)(C)C" - } - amount { - moles { - value: 0.000499 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CN=C1)Br" - } - amount { - moles { - value: 0.000418 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 8.32e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.16e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (9.34 mg, 0.04 mmol) and RuPhos (0.039 g, 0.08 mmol) were suspended in 1,4 dioxane (5 mL), degassed and stirred at 50 C for 10 minutes.nbsp;Thennbsp;(R)-tert-butyl 3-methylpiperazine-1-carboxylate (0.100 g, 0.50 mmol), 3-bromopyridine (0.040 mL, 0.42 mmol) and cesium carbonate (0.203 g, 0.62 mmol) were added and the reaction mixture was stirred at 100 C for 16 h.nbsp;LCMS showed only 5% conversion to desired product.nbsp;This was part of a screen and Ruphos, sodium tert-butoxide in toluene gave far better conversion so this was abando" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@@H]1CN(CCN1C2=CN=CC=C2)C(=O)OC(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/09/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "658" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00949 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@@H]1CN(CCN1)C(=O)OC(C)(C)C" - } - amount { - moles { - value: 0.00949 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CN=C1)Br" - } - amount { - moles { - value: 0.00633 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000316 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000158 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 85.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.145 g, 0.16 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.183 g, 0.32 mmol) were added to a mixture of Sodium tert-butoxide (0.912 g, 9.49 mmol), 3-bromopyridine (0.610 mL, 6.33 mmol),(R)-tert-butyl 3-methylpiperazine-1-carboxylate (1.901 g, 9.49 mmol) andnbsp;toluene (20 mL) under nitrogen. The mixture was heated at 85 C for 16 hours before being cooled to RT and filtered through celite. The filtrate was concentrated and the reaction mixture was seperated by flash silica chromatography, elution gradient 20 to 40% EtOAc in heptane. No product was isolated.. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@@H]1CN(CCN1C2=CN=CC=C2)C(=O)OC(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/29/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "659" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00749 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.025 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@@H]1CN(CCN1)C(=O)OC(C)(C)C" - } - amount { - moles { - value: 0.00499 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CN=C1)Br" - } - amount { - moles { - value: 0.00499 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000499 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;uRepeat of reaction EN05798-78uDiacetoxypalladium (0.112 g, 0.50 mmol) and dicyclohexyl(2\',6\'-diisopropoxybiphenyl-2-yl)phosphine (0.466 g, 1.00 mmol) were dissolved in toluene (15 mL) at ambient temperature under nitrogen. The mixture was degassed and purged with nitrogen several times and heated to 50C for 20 mins.In a separate vessel, were mixed 3-bromopyridine (0.789 g, 4.99 mmol), sodium 2-methylpropan-2-olate (0.720 g, 7.49 mmol), (R)-tert-butyl 3-methylpiperazine-1-carboxylate (1g, 4.99 mmol) and toluene (10 mL). The mixture was degassed and purged with nitrogen several times.The catalyst mixture was added to the reaction vessel and the resulting mixture was degassed and purged with nitrogen, and heated at 100 C under nitrogen overnight.The reaction mixture was filtered through celite, washing with EtOAcMeOH. The filtrate was concentrated and the residue purified by flash silica chromatography, elution gradient 20 to 100% EtOAc in heptane. Purens were evaporated to dryness to afford (R)-tert-butyl 3-methyl-4-(pyridin-3-yl)piperazine-1-carboxylate (1.426 g, 103 %) as a pale orange gum. [Rf ~ 0.1 in 1:1 EtOAchept]Note: Trace Ruphos contaminating productnbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@@H]1CN(CCN1C2=CN=CC=C2)C(=O)OC(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 102.97 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/10/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "661" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000911 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000304 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.000304 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 3.04e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.04e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A solution of (R)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (83 mg, 0.30 mmol) and 6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-amine (62.0 mg, 0.30 mmol) in DME (3 mL) was added to a microwave vial containing palladium(II) acetate (6.82 mg, 0.03 mmol), 2-(Dicyclohexylphosphino)biphenyl (10.64 mg, 0.03 mmol) and CS2CO3 (297 mg, 0.91 mmol) under an athmosphere of argon. The resulting mixture was heated to 100C in a microwave apparatus for 2 h. The reaction mixture was diluted with dichloromethane and methanol and filtered through a plug of Celite. The solvents were evaporated and the residue was purified by HPLC to give 21 mg of the title product (16 % Yield)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(N=C(C=C2)NC3=NC4=C(CN(C[C@H](O4)C5=CC=CC=C5)C)C=C3)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 15.63 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/23/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "663" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00103 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N" - } - amount { - moles { - value: 0.00103 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC(=C(N=C1)Cl)F" - } - amount { - moles { - value: 0.000687 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 6.87e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 6.87e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (15.42 mg, 0.07 mmol) and(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (39.8 mg, 0.07 mmol)nbsp;were added to a degassed mixture of 2-chloro-3-fluoro-5-methylpyridine (100 mg, 0.69 mmol), tert-butyl carbamate (121 mg, 1.03 mmol) and cesium carbonate (336 mg, 1.03 mmol) in dioxane (10 mL) at 21C.nbsp;The resulting mixture was stirred at 100 C for 16 hours.Filtered through celite and adsorbed onto silica.The crude product was purified by flash silica chromatography, elution gradient 0 to 50% DCM in heptane. Pure fractions were evaporated to dryness to afford sm by HNMRAbandoned.nbsp;nbsp;p" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CC(=C(N=C1)NC(=O)OC(C)(C)C)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 25.74 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/02/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "664" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "[OH-].[Na+]" - } - amount { - moles { - value: 0.00103 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N" - } - amount { - moles { - value: 0.000893 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC(=C(N=C1)Cl)F" - } - amount { - moles { - value: 0.000687 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 6.87e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 6.87e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (15.42 mg, 0.07 mmol) and(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (39.8 mg, 0.07 mmol)nbsp;were added to a degassed mixture of 2-chloro-3-fluoro-5-methylpyridine (100 mg, 0.69 mmol), tert-butyl carbamate (105 mg, 0.89 mmol) and 2-chloro-3-fluoro-5-methylpyridine (100 mg, 0.69 mmol) in dioxane (10 mL) at 21C.nbsp;The resulting mixture was stirred at 100 C for 2 hours.Cooled. Adsorbed onto silica.The crude product was purified by flash silica chromatography, elution gradient 10 to 30% DCM in heptane. Pure fractions were evaporated to dryness to afford tert-butyl 3-fluoro-5-methylpyridin-2-ylcarbamate (40.0 mg, 25.7 %) as a cream solid. not pure enough to registernbsp;nbsp;p" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CC(=C(N=C1)NC(=O)OC(C)(C)C)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 25.74 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/06/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "665" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.7 [N-arylation with Ar-X] Chloro N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0079 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H](C1)C(=O)N" - } - amount { - moles { - value: 0.00263 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CCC2=C(C=NN2CC1)C3=CC(=NC=C3F)Cl" - } - amount { - moles { - value: 0.00263 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000527 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.[Pd]" - } - amount { - moles { - value: 0.000263 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Tetrakis(triphenylphosphine)palladium(0) (0.304 g, 0.26 mmol) was added to 3-(2-chloro-5-fluoropyridin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepine (0.700 g, 2.63 mmol), tert-butyl ((1R,3S)-3-carbamoylcyclohexyl)carbamate (0.638 g, 2.63 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.305 g, 0.53 mmol) and Cesium carbonate (2.58 g, 7.90 mmol) innbsp;1,4-dioxane (10 mL)Degassed for 5 mins under nitrogen and the resulting suspension was stirred at 120 C for 17 hours in the microwave reactor. The reaction mixture was partitioned between water (20ml) and ethyl acetate (100ml) filtered and separated. The organics were absorbed onto silica and purified by flash silica chromatography, elution gradient 1:1 EtOAc in heptane. Pure fractions were evaporated to dryness to afford tert-butyl ((1R,3S)-3-((5-fluoro-4-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)pyridin-2-yl)carbamoyl)cyclohexyl)carbamate (0.900 g, 72.4 %) as a white solid. Product is crude so used directly in the next step." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H](C1)C(=O)NC2=NC=C(C(=C2)C3=C4CCCCCN4N=C3)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 72.45 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/09/2015" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "666" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0254 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.06 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1CCNCC1" - } - amount { - moles { - value: 0.0212 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1Br)Br" - } - amount { - moles { - value: 0.0212 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00159 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.00053 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 85.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A suspension of ethyl piperidine-4-carboxylate (3.27 mL, 21.20 mmol), 1,4-dibromobenzene (5 g, 21.20 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.485 g, 0.53 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.990 g, 1.59 mmol) and Sodium Tert-Butoxide (2.444 g, 25.43 mmol) in anhydrous toluene (60 mL) was stirred at 85 C under nitrogen for 16 hours.nbsp;The reaction was cooled to ambient temperature, diluted with Ether (100 mL) and filtered through celite.nbsp;The filtrate was evaporated in vacuo to yield crude product.nbsp;The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in heptane.nbsp;Pure fractions were evaporated to dryness to afford ethyl 1-(4-bromophenyl)piperidine-4-carboxylate (3.91 g, 59.1 %) as a yellow oil. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1CCN(CC1)C2=CC=C(C=C2)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 59.1 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/17/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "667" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00743 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.03 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1CCNC1" - } - amount { - moles { - value: 0.00619 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1Br)Br" - } - amount { - moles { - value: 0.00619 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000465 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000155 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 85.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A suspension of methyl pyrrolidine-3-carboxylate (800 mg, 6.19 mmol), 1,4-dibromobenzene (1461 mg, 6.19 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (142 mg, 0.15 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (289 mg, 0.46 mmol) and Sodium Tert-Butoxide (714 mg, 7.43 mmol) in anhydrous toluene (30 mL) was stirred at 85 C under nitrogen for 4 hours.nbsp;The reaction was cooled to ambient temperature, diluted with Ether (100 mL) and filtered through celite.nbsp;The filtrate was evaporated in vacuo to yield crude product.nbsp;The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in heptane.nbsp;Pure fractions were evaporated to dryness to afford methyl 1-(4-bromophenyl)pyrrolidine-3-carboxylate (513 mg, 29.1 %) as a yellow solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC(=O)C1CCN(C1)C2=CC=C(C=C2)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 29.15 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/24/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "668" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0195 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.06 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1CCNC1" - } - amount { - moles { - value: 0.0163 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1Br)Br" - } - amount { - moles { - value: 0.0163 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00122 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000406 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 85.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A suspension of methyl pyrrolidine-3-carboxylate (2.1 g, 16.26 mmol), 1,4-dibromobenzene (3.84 g, 16.26 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.372 g, 0.41 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.759 g, 1.22 mmol) and Sodium Tert-Butoxide (1.875 g, 19.51 mmol) in anhydrous toluene (60 mL) was stirred at 85 C under nitrogen for 16 hours.nbsp;The reaction was cooled to ambient temperature, diluted with Ether (100 mL) and filtered through celite.nbsp;The filtrate was evaporated in vacuo to yield crude product.nbsp;The crude product was purified by flash silica chromatography, elution gradient 5 to 20% EtOAc in heptane.nbsp;Pure fractions were evaporated to dryness to afford methyl 1-(4-bromophenyl)pyrrolidine-3-carboxylate (1.460 g, 31.6 %) as a yellow solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC(=O)C1CCN(C1)C2=CC=C(C=C2)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 31.6 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/28/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "671" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00451 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00205 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)NC1=CC(=C(C=C1)OC)Br" - } - amount { - moles { - value: 0.00205 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 0.00041 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000205 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A solution of N-(3-bromo-4-methoxyphenyl)acetamide (0.5 g, 2.05 mmol) dissolved in toluene (5 mL) was treated with tert-butyl piperazine-1-carboxylate (0.382 g, 2.05 mmol), diacetoxypalladium (0.046 g, 0.20 mmol), dicyclohexyl(2\',6\'-diisopropoxybiphenyl-2-yl)phosphine (0.191 g, 0.41 mmol) and sodium 2-methylpropan-2-olate (0.433 g, 4.51 mmol)nbsp;in a sealed tube. The resulting mixture was degassed and stirred at 100 C for 8 hours in a microwave. The mixture was pre-absorbed onto silica. The crude product was purified by flash silica chromatography, elution 50% ethyl acetate in Heptane. Pure fractions were evaporated to dryness to afford intermediate. The intermediate was dissolved in 4M HCl in dioxane (10mL) and stirred at RT overnight. The mixture was evaporated to give N-(4-methoxy-3-(piperazin-1-yl)phenyl)acetamide (0.260 g, 50.9 %) as a tan solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)NC1=CC(=C(C=C1)OC)N2CCNCC2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 50.91 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/31/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "672" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000177 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0025 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCN(CC1)CC2=CC(=CC=C2)N" - } - amount { - moles { - value: 0.000177 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)NC(=O)C2=CC3=C(C=C2)OCCO3)NC(=O)C4=CN=C(C=C4)Cl" - } - amount { - moles { - value: 0.000118 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.08e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 3.54e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of 6-chloro-N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamido)-2-methylphenyl)nicotinamide (50 mg, 0.12 mmol),3-((4-methylpiperazin-1-yl)methyl)aniline (36.3 mg, 0.18 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4.10 mg, 7.08 mol),TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (3.24 mg, 3.54 mol),sodium 2-methylpropan-2-olate (17.01 mg, 0.18 mmol) in toluene (2 mL)IPA (0.500 mL)was degassed with nitrogen and heated at reflux for 18 hours.The reaction mixture was filtered and filtered solid washed with ethyl acetate. The organic filtrate was washed with water (50ml), and organic layer dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N-(5-(2,3-dihydrobenzo[b][1,4]dioxine-6-carboxamlphenyl)-6-(3-((4-methylpiperazin-1-yl)methyl)phenylamino)nicotinamide (18.10 mg, 25.9 %) as a beige solid. nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)NC(=O)C2=CC3=C(C=C2)OCCO3)NC(=O)C4=CN=C(C=C4)NC5=CC=CC(=C5)CN6CCN(CC6)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 25.89 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/21/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "675" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00127 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0065 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCC1CN" - } - amount { - moles { - value: 0.000848 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)I)Br" - } - amount { - moles { - value: 0.000848 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000127 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 6.36e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium (II) acetate (14.28 mg, 0.06 mmol) and racemic-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (79 mg, 0.13 mmol) were suspended in toluene (3 mL). The mixture was evacuated and purged with nitrogen, and warmed to 50C.In a separate vessel, 1-bromo-3-iodobenzene (240 mg, 0.85 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (98 mg, 0.85 mmol) and sodium-t-butoxide (122 mg, 1.27 mmol) were suspended in toluene (3.5 mL). The resulting mixture was evacuated, purged with nitrogen and warmed to 50C. After ~30 mins, the catalyst mixture was transferred to the reaction vessel. The reaction was evacuated and purged with nitrogen and heated at 80C overnight.This reaction was combined with EN06953-06 for purification.The mixture was filtered and purified by flash silica chromatography, elution gradient 0 to 40% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 3-bromo-N-((tetrahydro-2H-pyran-4-yl)methyl)aniline (71.0 mg, 31.0 %) as a colourless ostallised on standing. The main impurity was isolated (EN06953-09-02) but this was not identified; assume it is BINAP or the catalyst- ligand complex. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1COCCC1CNC2=CC(=CC=C2)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 30.98 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/22/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "677" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.9 [N-arylation with Ar-X] Iodo N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0119 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.137 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)N" - } - amount { - moles { - value: 0.014 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC(=CC(=C1)I)Br" - } - amount { - moles { - value: 0.014 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.0014 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.0014 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (0.314 g, 1.40 mmol) and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.871 g, 1.40 mmol) were added to a degassed mixture of methyl 3-bromo-5-iodobenzoate (4.77 g, 13.99 mmol), aniline (2.55 ml, 13.99 mmol) and cesium carbonate (3.87 g, 11.89 mmol) in toluene (137 ml) under nitrogen. The resulting mixture was stirred at 110 C for 18 hours. The resulting mixture was evaporated to dryness and the residue was diluted with EtOAc (150 mL), and washed with water (100 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 15% EtOAc in heptane. Pure fractions were evaporated to dryness to afford methyl 3-bromo-5-(phenylamino)benzoate (1.735 g, 40.5 %) as a pale yellow solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC(=O)C1=CC(=CC(=C1)Br)NC2=CC=CC=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 40.51 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/19/2016" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "678" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000977 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CN=C1)CN" - } - amount { - moles { - value: 0.000537 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Pyridin-3-ylmethanamine (58.1 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford N2-phenyl-N4-(pyridin-3-ylmethyl)pyridine-2,4-diamine (80 mg, 59.2 %) as an off white solid.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)NCC3=CN=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 59.25 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/05/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "680" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.7 [N-arylation with Ar-X] Chloro N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00113 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H](C1)C(=O)N" - } - amount { - moles { - value: 0.000452 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1(CC2=NC=C(N2C1)C3=CC(=NC=C3F)Cl)C" - } - amount { - moles { - value: 0.000376 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.53e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.[Pd]" - } - amount { - moles { - value: 3.76e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Tetrakis(triphenylphosphine)palladium(0) (43.5 mg, 0.04 mmol) was added to 3-(2-chloro-5-fluoropyridin-4-yl)-6,6-dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (100 mg, 0.38 mmol), tert-butyl ((1R,3S)-3-carbamoylcyclohexyl)carbamate (109 mg, 0.45 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (43.6 mg, 0.08 mmol) and Cesium carbonate (368 mg, 1.13 mmol) in 1,4-dioxane (5.98 ml).nbsp;Degassed for 5 mins under nitrogen and the resulting suspension was stirred at 120 C for 3 hours in the microwave reactor. The reaction mixture was partitioned between water (20ml) and DCM (40ml) and separated using a phase separation cartridge.nbsp;The organics were absorbed onto silica and purified by flash silica chromatography, elution gradient 0 to 60% EtOAc in heptane. Pure fractions were evaporated to dryness to afford starting material (100mg)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1(CC2=NC=C(N2C1)C3=CC(=NC=C3F)NC(=O)[C@H]4CCC[C@H](C4)NC(=O)OC(C)(C)C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 80.01 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/07/2015" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "681" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 4.84e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1CCNCC1" - } - amount { - moles { - value: 0.000678 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC(=NC=C1Br)Cl" - } - amount { - moles { - value: 0.000484 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 4.84e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.42e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.18 mg, 0.02 mmol) was added to a degassed mixture of ethyl piperidine-4-carboxylate (0.105 mL, 0.68 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)(xantphos) (28.0 mg, 0.05 mmol) and ethyl 1-(6-chloro-4-methylpyridin-3-yl)piperidine-4-carboxylate and sodium 2-methylpropan-2-olate (65.2 mg, 0.68 mmol) in toluene (3 mL). The resulting suspension was stirred at 100 C for 20 hours under nitrogen. LCMS indicated little reaction so reaction abandoned. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1CCN(CC1)C2=CN=C(C=C2C)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/21/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "682" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 9.69e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1CCNCC1" - } - amount { - moles { - value: 0.000678 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC(=NC=C1Br)Cl" - } - amount { - moles { - value: 0.000484 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 9.69e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.84e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A solution of diacetoxypalladium (10.87 mg, 0.05 mmol) and dicyclohexyl(2\',6\'-diisopropoxy-[1,1\'-biphenyl]-2-yl)phosphine (45.2 mg, 0.10 mmol) dissolved in toluene (3 mL) was degassed and heated to 50C for 30 minutes before adding ethyl piperidine-4-carboxylate (0.105 mL, 0.68 mmol), 5-bromo-2-chloro-4-methylpyridine (100 mg, 0.48 mmol) and sodium 2-methylpropan-2-olate (74.5 mg, 0.77 mmol) under nitrogen. The mixture was heated to 100C for 2 hours. nbsp;LCMS indicated little product so reaction abandon" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1CCN(CC1)C2=CN=C(C=C2C)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/23/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "683" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000977 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC=CC=C1CN" - } - amount { - moles { - value: 0.000537 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.91e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(2-methoxyphenyl)methanamine (73.7 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford N4-(2-methoxybenzyl)-N2-phenylpyridine-2,4-diamine (90 mg, 60.3 %) as an off-white solid.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=CC=CC=C1CNC2=CC(=NC=C2)NC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 60.32 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/05/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "684" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000977 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC=CC=C1CN" - } - amount { - moles { - value: 0.000537 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.91e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(2-methoxyphenyl)methanamine (73.7 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness and purified by C18 silica chromatography, elution gradient 40 to 70% MeCN in Water + 1% NH4OH. Fractions containproduct were evaporated to dryness to afford N4-(2-methoxybenzyl)-N2-phenylpyridine-2,4-diamine (16.00 mg, 10.72 %) as a yellow gum.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=CC=CC=C1CNC2=CC(=NC=C2)NC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 10.72 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/01/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "685" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000852 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CN" - } - amount { - moles { - value: 0.000469 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000426 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Phenylmethanamine (50.2 mg, 0.47 mmol), 4-chloro-N-(4-methoxyphenyl)pyridin-2-amine (100 mg, 0.43 mmol) and sodium 2-methylpropan-2-olate (82 mg, 0.85 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (28.4 mg, 0.05 mmol) and diacetoxypalladium (7.65 mg, 0.03 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford N4-benzyl-N2-(4-methoxyphenyl)pyridine-2,4-diamine (77 mg, 59.2 %) as an off-white solid.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=CC=C(C=C1)NC2=NC=CC(=C2)NCC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 59.17 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/01/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "687" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[K+].[K+]" - } - amount { - moles { - value: 0.0027 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.008 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C2=C(N1C)C=CC(=C2)N)Cl" - } - amount { - moles { - value: 0.000988 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NN(C=C1C=O)C2=NC(=NC=C2)Cl" - } - amount { - moles { - value: 0.000898 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 8.98e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.49e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 40 mL scintillation vial charged with 3-chloro-1,2-dimethyl-1H-indol-5-amine (192 mg, 0.99 mmol), 1-(2-chloropyrimidin-4-yl)-3-methyl-1H-pyrazole-4-carbaldehyde (200mg, 0.90 mmol), palladium(II) acetate (10.08 mg, 0.04 mmol), dicyclohexyl(2\',4\',6\'-triisopropyl-[1,1\'-biphenyl]-2-yl)phosphine (x--phos) (42.8 mg, 0.09 mmol) and Dioxane (8mL) After being degassed by nitrogen bubbling , the reaction mixture was heated 100 C for 6 hours. At this stage most of the starting material was consumed.nbsp;The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water and brine. The organic layer separated, dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography (Isco, Hexaneethyl acetate, 0-100%, 25 minutes) to give 1-(2-((3-chloro-1,2-dimethyl-1H-indol-5-yl)amino)pyrimidin-4-yl)-3-methyl-1H-pyrazole-4-carbaldehyde (221 mg, 64.6 %) as a yellow solid. LCMS (2 minute, Acid _CV10.olp method) 381 (M + 1), 1.27 minutes." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C2=C(N1C)C=CC(=C2)NC3=NC=CC(=N3)N4C=C(C(=N4)C)C=O)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 64.6 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/07/2014" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "689" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00139 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=C2C(=CC(=C1F)F)NC(=O)C=C2Cl" - } - amount { - moles { - value: 0.000464 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C[C@H]1C[C@@H](CCN1C(=O)C2=C(N(N=C2)C)Cl)N.C(=O)(C(F)(F)F)O" - } - amount { - moles { - value: 0.000464 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 4.64e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.64e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 140.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "4-chloro-6,7-difluoroquinolin-2(1H)-one (100 mg, 0.46 mmol) was taken in a microwave tube. Added ((2S,4R)-4-amino-2-methylpiperidin-1-yl)(5-chloro-1-methyl-1H-pyrazol-4-yl)methanone 2,2,2-trifluoroacetate (172 mg, 0.46 mmol), followed by the addition of Palladium (II) acetate (10.41 mg, 0.05 mmol), racemic-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (28.9 mg, 0.05 mmol), Cesium carbonate (111 mL, 1.39 mmol), N,N\'-Diisopropylethylamine (242 mL, 1.39 mmol).nbsp;toluene (10 mL) was added and jected to microwave with the following parameters.Temperaturenbsp;140 CTime 60 minutesAfter the completion of the reaction, dissolved the compound in methanol and purified by column" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@H]1C[C@@H](CCN1C(=O)C2=C(N(N=C2)C)Cl)NC3=CC(=O)NC4=CC(=C(C=C43)F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 49.46 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/28/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "690" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00835 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.06 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=C2C(=CC(=C1F)F)NC(=O)C=C2Cl" - } - amount { - moles { - value: 0.00278 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C[C@H]1C[C@@H](CCN1C(=O)C2=C(N(N=C2)C)Cl)N.C(=O)(C(F)(F)F)O" - } - amount { - moles { - value: 0.00417 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000278 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000278 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 140.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "((2S,4R)-4-amino-2-methylpiperidin-1-yl)(5-chloro-1-methyl-1H-pyrazol-4-yl)methanone 2,2,2-trifluoroacetate (1548 mg, 4.17 mmol) was taken in a 100ml single necked flask equipped with a reflux condenser connected to nitrogen source. Added 4-chloro-6,7-difluoroquinolin-2(1H)-one (600 mg, 2.78 mmol), followed by the addition of racemic-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (173 mg, 0.28 mmol), Palladium (II) acetate (62.5 mg, 0.28 mmol),nbsp;and Cesium carbonate (668 mL, 8.35 mmol). toluene (60 mL) was added followed by the addition of N,N\'-Diisopropylethylamine (1454 mL, 8.35 mmol).The contents of the flask were purged with nitrogen for 5 minutes and heate at 140 C for overnight.After the completion of the reaction, added methanol, and adsorbed on silica gel, and purified by reverse phase column." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@H]1C[C@@H](CCN1C(=O)C2=C(N(N=C2)C)Cl)NC3=CC(=O)NC4=CC(=C(C=C43)F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 23.08 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/01/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "692" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000977 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1CN)F" - } - amount { - moles { - value: 0.000537 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(4-fluorophenyl)methanamine (67.3 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford N4-(4-fluorobenzyl)-N2-phenylpyridine-2,4-diamine (86 mg, 60.0 %) as an off-white solid.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)NCC3=CC=C(C=C3)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 60.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/01/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "693" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00802 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCC1CN" - } - amount { - moles { - value: 0.00535 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC=C(C=C1)Br" - } - amount { - moles { - value: 0.00535 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000802 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000401 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium (II) acetate (0.090 g, 0.40 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.464 g, 0.80 mmol) were suspended in toluene (3 mL). The mixture was evacuated and purged with nitrogen, and warmed to 50C.In a separate vessel, 1-bromo-4-methoxybenzene (1 g, 5.35 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (0.654 mL, 5.35 mmol) and sodium-t-butoxide (0.771 g, 8.02 mmol) were suspended in toluene (7 mL). The resulting mixture was evacuated, purged with nitrogen and warmed to 50C. After ~30 mins, the catalyst mixture was transferred to the reaction vessel. The reaction was evacuated and purged with nitrogen and heated at 80C overnight. The mixture was diluted with water (250 mL), and extracted with ethyl acetate (200 mL).nbsp;The organic was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH antions were evaporated to dryness to afford 4-methoxy-N-((tetrahydro-2H-pyran-4-yl)methyl)aniline (0.270 g, 22.82 %) as a brown oil. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=CC=C(C=C1)NCC2CCOCC2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 22.82 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/29/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "694" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 5.86e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CN" - } - amount { - moles { - value: 0.000537 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 5.86e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.91e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Phenylmethanamine (57.6 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. 2-Dicyclohexylphosphino-2\',6\'-di-i-propoxy-1,1\'-biphenyl (27.4 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by preparative HPLC (Waters SunFire column, 5 silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness N4-benzyl-N2-phenyl-2,4-diamine (17.80 mg, 13.23 %) as an off-white solid. nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 13.23 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/11/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "695" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 5.86e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CN" - } - amount { - moles { - value: 0.000537 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=C(C=CC(=C2P(C3CCCCC3)C4CCCCC4)OC)OC)C(C)C" - } - amount { - moles { - value: 5.86e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.91e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Phenylmethanamine (57.6 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. Dicyclohexyl(2\',4\',6\'-triisopropyl-3,6-dimethoxy-[1,1\'-biphenyl]-2-yl)phosphine (31.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by preparative HPLC (Waters SunFire column, 5 silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing product were evaporated to dryness to afbenzyl-N2-phenylpyridine-2,4-diamine (8.50 mg, 6.32 %) as an off white solid.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 6.32 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/23/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "696" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000977 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CN" - } - amount { - moles { - value: 0.000537 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.91e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Phenylmethanamine (57.6 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by preparative HPLC (Waters SunFire column, 5 silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing product were evaporated to dryness to affordyl-N2-phenylpyridine-2,4-diamine (72.4 mg, 53.8 %) as an off-white solid.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 53.81 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/23/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "697" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000977 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CN" - } - amount { - moles { - value: 0.000782 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.91e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Phenylmethanamine (84 mg, 0.78 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by preparative HPLC (Waters SunFire column, 5 silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing product were evaporated to dryness to afford N-N2-phenylpyridine-2,4-diamine (85 mg, 63.1 %) as an off-white solid.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 63.1 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/25/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "698" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 5.86e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CN" - } - amount { - moles { - value: 0.000537 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=C(C=CC(=C2P(C3CCCCC3)C4CCCCC4)OC)OC)C(C)C" - } - amount { - moles { - value: 5.86e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.91e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Phenylmethanamine (57.6 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. Dicyclohexyl(2\',4\',6\'-triisopropyl-3,6-dimethoxy-[1,1\'-biphenyl]-2-yl)phosphine (31.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was thermally heated to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by preparative HPLC (Waters SunFire column, 5 silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing product were evaporated to dryness to afbenzyl-N2-phenylpyridine-2,4-diamine (49.6 mg, 36.9 %) as an off white solid.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 36.87 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/30/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "699" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 5.86e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CN" - } - amount { - moles { - value: 0.000537 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=C(C=CC(=C2P(C3CCCCC3)C4CCCCC4)OC)OC)C(C)C" - } - amount { - moles { - value: 5.86e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.91e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Phenylmethanamine (57.6 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. Dicyclohexyl(2\',4\',6\'-triisopropyl-3,6-dimethoxy-[1,1\'-biphenyl]-2-yl)phosphine (31.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was thermally heated to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by preparative HPLC (Waters SunFire column, 5 silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing product were evaporated to dryness to afbenzyl-N2-phenylpyridine-2,4-diamine (56.5 mg, 42.0 %) as an off white solid.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 41.99 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/08/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "700" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 5.86e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CN" - } - amount { - moles { - value: 0.000537 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 5.86e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.91e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Phenylmethanamine (57.6 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. 2-Dicyclohexylphosphino-2\',6\'-di-i-propoxy-1,1\'-biphenyl (27.4 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 1.5 hours under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by preparative HPLC (Waters SunFire column, 5 silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness N4-benzyl-N2-ridine-2,4-diamine (6.50 mg, 4.83 %) as an off-white solid. nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 4.83 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/24/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "702" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000977 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CN" - } - amount { - moles { - value: 0.000537 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.91e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Phenylmethanamine (57.6 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol)-diacetoxypalladium (8.78 mg, 0.04 mmol), (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2.00 mL) and sealed into a microwave tube. The reaction was heated thermally to 100 C for 30 minutes and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N4-benzyl-N2-phenylpyridine-2,4-diamine (66.4 mg, 49.4 %) as an off-white solid.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 49.35 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/20/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "703" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000977 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CN" - } - amount { - moles { - value: 0.000537 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.91e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Phenylmethanamine (57.6 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture in DMA (1 mL). Nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford N4-benzyl-N2-phenylpyridine-2,4-diamine (93 mg, 69.1 %) as an off-white solid.nbsp;nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 69.12 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/24/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "704" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000977 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CN" - } - amount { - moles { - value: 0.000537 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.91e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Phenylmethanamine (57.6 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol)-diacetoxypalladium (8.78 mg, 0.04 mmol), (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2.00 mL) and sealed into a microwave tube. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N4-benzyl-N2-phenylpyridine-2,4-diamine (77 mg, 57.0 %) as an off-white solid. nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 57.01 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/20/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "705" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000977 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CN" - } - amount { - moles { - value: 0.000537 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.91e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Phenylmethanamine (57.6 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford EN06208-42-01 (98 mg, 0.356 mmol, 72.8 %) as an off-white solid.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 72.84 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/24/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "706" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00244 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.0025 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CN" - } - amount { - moles { - value: 0.00134 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.00122 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 0.00015 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 9.77e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Phenylmethanamine (144 mg, 1.34 mmol), 4-chloro-N-phenylpyridin-2-amine (250 mg, 1.22 mmol)-diacetoxypalladium (21.94 mg, 0.10 mmol), (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (81 mg, 0.15 mmol) and sodium 2-methylpropan-2-olate (235 mg, 2.44 mmol) were suspended in DMA (2.50 mL) in a partially sealed tube. The reaction was heated thermally to 80 C for 1 hour, followed by 90C overnight and cooled to RT. The reaction mixture was filtered through celite using methanol, neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N4-benzyl-N2-phenylpyridine-2,4-diamine (33.0 mg, 9.81 %) as a brown gum. n" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 9.81 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/19/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "707" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000977 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CN" - } - amount { - moles { - value: 0.000537 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 5.86e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Phenylmethanamine (57.6 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol)-diacetoxypalladium (8.78 mg, 0.04 mmol), (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2.00 mL) in a partially sealed tube. The reaction was heated thermally to 100 C for 30 minutes and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20g SCX column. The crude product was purified by preparative HPLC using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N4-benzyl-N2-phenylpyridine-2,4-diamine (7.60 mg, 5.65 %) as an off-white solid.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 5.65 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/20/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "710" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00403 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0249 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2" - } - amount { - moles { - value: 0.00252 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC=CC=C1Br" - } - amount { - moles { - value: 0.00252 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000101 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 5.04e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 105.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.046 g, 0.05 mmol) and rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.063 g, 0.10 mmol) were mixed together and evacuated and purged with nitrogen 3 times. toluene (24.91 ml) was added and the resulting mixture heated to 50C for 10 minutes.In a second reaction vessel was mixed sodium tert-butoxide (0.387 g, 4.03 mmol), (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.500 g, 2.52 mmol), 1-bromo-2-methoxybenzene (0.314 ml, 2.52 mmol) and toluene (24.91 ml). The mixture was evacuated and purged with nitrogen 3 times. The solution of catalyst was added to the reaction mixture and the resulting mixture was heated at 105 C for 16 hours.The reaction mixture was cooled to RT and filtered through celite and evaporated.The crude product was purified by flash silica chromatography, elution gradient 100% DCM. Pure fractions were evaporated to dryness to afford (1S,4S)-tert-butyl 5-(2-methoxyphenyl)-2,5-diazabic.1]heptane-2-carboxylate (0.529 g, 68.9 %) as a yellow gum. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C3=CC=CC=C3OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 68.91 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/02/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "711" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00225 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CCNCC1" - } - amount { - moles { - value: 0.00225 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C=C1C(=O)O)Cl)Br" - } - amount { - moles { - value: 0.0015 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "4-bromo-3-chlorobenzoic acid (0.353 g, 1.5 mmol), piperidine (0.234 mL, 2.25 mmol), and sodium tert-butoxide (0.216 g, 2.25 mmol) were stirred together under N2 and heated to 80 C. Pd2(dba)3 (0.014 g, 0.015 mmol), and BINAP (0.031 g, 0.05 mmol) were mixed in toluene (2 mL) and then added to the mixture and stirred at 110 C overnight. LCMS showed a very small amount of desired product (~2%). The reaction mixture was degassed with N2 for 30 minutes, then addtional Pd Binap was added. The reaction was again heated to 110 C. LCMS showed a small amount of desired product (~10%) but mostly still starting material. The desired product was not isolated from this reacti" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CCN(CC1)C2=C(C=C(C=C2)C(=O)O)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/10/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "712" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "[Li+].C[Si](C)(C)[N-][Si](C)(C)C" - } - amount { - moles { - value: 0.015 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1CCOC1" - } - amount { - volume { - value: 0.015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CCNC1" - } - amount { - moles { - value: 0.00734 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC2=C(C=C1Br)NN=C2" - } - amount { - moles { - value: 0.00609 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 0.000122 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4.C1=CC=C([C-]=C1)CCN.[Cl-].[Pd+2]" - } - amount { - moles { - value: 0.00012 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 60.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "uThis reaction is done in triplicateu:6-bromo-1H-indazole (1.2 g, 6.09 mmol, 1 eq each), chloro(2-dicyclohexylphosphino-2\',6\'-di-i-propoxy-1,1\'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (RuPhos-PreCatalyst) (89 mg, 0.12 mmol, 0.02 eq each), 2-Dicyclohexylphosphino-2\',6\'-di-i-propoxy-1,1\'-biphenyl (RuPhos ligand) (57 mg, 0.12 mmol, 0.02 eq, each) were taken a stoppered bottle, flush with N2, pyrrolidine (0.60 ml, 522 mg. 7.34 mmol, 1.2 eq, each) and lithium bis(trimethylsilyl)amide (1M soln in THF, 15 ml, 15 mmol, 2.46 eq, each) were added in succession, flushed with N2, stoppered the bottle and stirred at 60 C. LC-MS, after 2 hrs, showed that all the starting material is consumed. Cooled to r.t, queched the reaction with 2M HCl (9 ml, each), combined the reaction mixture and then extracted with EtOAc (250 ml) and saturated NaHCO3 (aq) soln. The organics was collected and the aq. layer was further extracted with EtOAc (250 ml). The combined organics was fer washed with brine (250 ml). The organics was collected, dried (Na2SO4), filtered and evaporated to a brown solid (4.01 g, combined crude yield). The residue was chroamtographed (SiO2 - 100 g, Biotage-Pre-packed colum, heptane-EtOAC 5:1 to 2:1 gradiant. The appropriate fractions were combined and evaporated to a light brown solids (TLC: Rf = 15 mm63 mm, heptane-EtOAc 1:1, ucompound in TLC plate beome grey colored upon standing for few minutesu) corresponds to the required product (P1) (Starting material comes at 28 mm63 mm in the same solvent system).uEN07765-42-01 (SN1050263564; AZ13824296-001u): 3.207 g (total yield, so each batch should be 1.069 g, 94%, ca 96% pure).1H NMR (500 MHz, DMSO) d 1.94 - 2 (m, 4H), 3.27 (t, 4H), 6.34 (s, 1H), 6.56 (dd, 1H), 7.50 (d, 1H), 7.78 (s, 1H), 12.35 (s, 1H).Expected Number of Hs: 13. Assigned Hs: 13.LC-MS: ESI-MS mz: [M+H]+ 188.2. Rf = 1.59 min4 min and 1.48 min4 min in acidic (pH3) and basic (pH10) system repectively.TLC: Rf = 15 mm64 mm (SiO2-glas plate, heptane-EtOAc 1:1 vv, spots were detected by UV254 (uspot became grey colored upon standing the plate at r.tu.)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CCN(C1)C2=CC3=C(C=C2)C=NN3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 93.74 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/17/2015" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "722" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00118 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.008 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCNCC1" - } - amount { - moles { - value: 0.000619 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C(=NC(=N1)Br)Br" - } - amount { - moles { - value: 0.000589 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000177 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 8.84e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of 3,5-dibromo-1-methyl-1H-1,2,4-triazole (142 mg, 0.59 mmol), 1-methylpiperazine (62.0 mg, 0.62 mmol), tris(dibenzylideneacetone)dipalladium(0) (81 mg, 0.09 mmol), BINAP (110 mg, 0.18 mmol) and sodium tert-butoxide (113 mg, 1.18 mmol) in toluene (8 ml) was stirred at 100 C for 1.5hrs. LCMS indicated no desired product formation. Discarded." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CCN(CC1)C2=NC(=NN2C)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/04/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "723" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00362 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.008 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CC(C1)N" - } - amount { - moles { - value: 0.00249 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(N=C1)Br)Cl" - } - amount { - moles { - value: 0.00208 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 3.12e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.58e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 115.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Pd2(dba)3 (0.014 g, 0.02 mmol), 2,2\'-bis(diphenylphosphanyl)-1,1\'-binaphthalene (BINAP) (0.019 g, 0.03 mmol) and toluene (8 mL) was added to a flask. 2-bromo-3-chloropyridine (0.4 g, 2.08 mmol), cyclobutanamine (0.177 g, 2.49 mmol) and sodium 2-methylpropan-2-olate (0.348 g, 3.62 mmol) was added, the mixture bubbled with N2 for 5 min, then the reaction was heated to 115 C in an oil-bath under nitrogen. LC-MS 1h: 33% product, 21% sm left.The reaction was cooled to rt and the solvent was evaporated.The residue was purified by automated flash chromatography on a 50g column. A gradient from 0% to 50% of EtOAc in heptane over 15CV was used as mobile phase. The product was collected using the wavelength 245 and 311 nm, relevant fractions pooled and evaporated to give 95 mg clear oil.1H-NMR: OK, some extra small peaks in aromatic region (sm or dba?).1H NMR (400 MHz, CDCl3) d 1.65 - 2.01 (m, 4H), 2.45 (dtd, 2H), 4.54 (h, 1H), 6.49 (dd, 1H), 7.41 (dd, 1H), 8.01 (dd, 1H)Expected Number of Hs: 11Assigned Hs: 10, NH not assigned.LC-MS: OK, 86% product. M+1=183 found." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CC(C1)NC2=C(C=CC=N2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 25.02 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/30/2016" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "724" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "[Li+].C[Si](C)(C)[N-][Si](C)(C)C" - } - amount { - moles { - value: 0.0139 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1CCOC1" - } - amount { - volume { - value: 0.001 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCC1O" - } - amount { - moles { - value: 0.0076 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=CC=C1Br" - } - amount { - moles { - value: 0.00633 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C1=CC=CC=C1C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 0.000633 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000633 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 65.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;In a 50 ml round bottomed flask THF (1 mL) was added to a mixture of 4-bromopyridine (1 g, 6.33 mmol), pyrrolidin-3-ol (0.662 g, 7.60 mmol),2-(dimethylamino)-2\'-(dicyclohexylphosphino)biphenyl (0.249 g, 0.63 mmol)nbsp;and Pd2(dba)3 (0.580 g, 0.63 mmol). To the slurry lithium bis(trimethylsilyl)amide (13.92 mL, 13.92 mmol) was added dropwise at 0 C and the solution was refluxed at 65 C overnight for 20 hrs. The reaction mixture was passed through celite, concentrated and column purified (0-20%MeOHDCM) to obtain 0.447 mg of produ" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CN(CC1O)C2=CC=NC=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 43.01 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/22/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "725" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0013 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C=O" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1C(CN1)(F)F.Cl" - } - amount { - moles { - value: 0.000478 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)CC1=NC=CC(=C1)Br" - } - amount { - moles { - value: 0.000435 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 4.35e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 6.95e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "palladium acetate (1.561 mg, 6.95 mol) and BINAP (2.71 mg, 4.35 mol) were added to methyl 2-(4-bromopyridin-2-yl)acetate (100 mg, 0.43 mmol), 3,3 difluoroazetidine hydrochloride (61.9 mg, 0.48 mmol) and cesium carbonate (425 mg, 1.30 mmol) in DMF (5 mL) at 21Cnbsp;under nitrogen. The resulting mixture was stirred at 120 C for 2.5 hours. - lcms looks ok. Cooled to room temp.The reaction mixture was diluted with EtOAc (150 mL), and washed sequentially with water (75 mL), water (75 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness - 200mg yellow oil. Contained Pd impurities.The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 1M NH3MeOH and pure fractions were evaporated to dryness to afford methyl 2-(zetidin-1-yl)pyridin-2-yl)acetate (42.0 mg, 39.9 %) as a yellow gum. maybe better to avoid aq wu and just purify by SCX column." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC(=O)CC1=NC=CC(=C1)N2CC(C2)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 39.89 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/15/2014" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "726" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0121 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00904 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)C1=CC=C(C=C1)Br" - } - amount { - moles { - value: 0.00603 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000603 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000603 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a CEM MW vial, p-Bromoacetophenone (729 ml, 6.03 mmol),tert-Butyl 1-piperazinecarboxylate (1.684 g, 9.04 mmol),racemic-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.375 g, 0.60 mmol),Palladium (II) acetate (0.135 g, 0.60 mmol),Cesium carbonate (3.93 g, 12.06 mmol) was taken in toluene (10 ml).The RM was jected to MW power of 300W,temp 120C for 45 minutes. The LCMS was checked showed the formation of required mass.Work-up:The RM was passed through hyflow bed and filtrate was evaporated and chrmatographed using Ethyl acetate hexane to obtain tert-butyl 4-(4-acetylphenyl)piperazine-1-carboxylate (0.963 g, 52.5 %)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)C1=CC=C(C=C1)N2CCN(CC2)C(=O)OC(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 52.48 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/12/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "727" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00451 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC(=C(C(=C1)C)S(=O)(=O)N[C@H](CN)C(C)C)C" - } - amount { - moles { - value: 0.00301 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC2=C(C=NN2C3=CC=C(C=C3)F)C(=C1)Br" - } - amount { - moles { - value: 0.00301 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000694 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000262 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "BINAP (0.432 g, 0.69 mmol) and Pd2(dba)3 (0.24 g, 0.26 mmol) were dissolved in toluene (10 mL) and to this (S)-N-(1-amino-3-methylbutan-2-yl)-2,4,6-trimethylbenzenesulfonamide (0.856 g, 3.01 mmol) andnbsp;4-bromo-1-(4-fluorophenyl)-1H-indazole (0.876 g, 3.01 mmol) was added followed by sodium tert-butoxide (0.434 g, 4.51 mmol). The reaction mixture was degassed and the reaction tube was filled with nitrogen before it was heated at 110C for 2h. LCMS indicated 55% product and just a small amout of starting materials remained. The reaction was partitioned between EtOAc and water. The layers were separated and the aqueous extracted twice with EtOAc. The organic extracts were combined, filtered through a fine sinter funnel to remove a grey ppte and then dried using a phase separator cartridge. The solvent was removed in vacuo and the residuenbsp;purified by silica gel column chromatography (0-20% ethyl acetate in heptane). The product 340mg was obtained as a orange foam and was 90% clean by LCMS. The maal was dissolved in DMSO and mitted to WRAP. (S)-N-(1-((1-(4-fluorophenyl)-1H-indazol-4-yl)amino)-3-methylbutan-2-yl)-2,4,6-trimethylbenzenesulfonamide (0.169 g, 11.38 %). Final form unknown. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CC(=C(C(=C1)C)S(=O)(=O)N[C@H](CNC2=C3C=NN(C3=CC=C2)C4=CC=C(C=C4)F)C(C)C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 11.38 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/22/2015" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "730" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00295 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCNCC1" - } - amount { - moles { - value: 0.00221 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=C(C2=CC(=C(C=C2N=C1)OC)Br)NC3=C(C=C(C=C3)Cl)Cl" - } - amount { - moles { - value: 0.00148 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000148 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 7.38e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a solution of ethyl 6-bromo-4-(2,4-dichlorophenylamino)-7-methoxyquinoline-3-carboxylate (694 mg, 1.48 mmol) and 1-methylpiperazine (0.246 mL, 2.21 mmol) in dioxane (10 mL) was added cesium carbonate (962 mg, 2.95 mmol), tris(dibenzylideneacetone)dipalladium(0) (67.6 mg, 0.07 mmol) and rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (92 mg, 0.15 mmol). Reaction vessel in oil bath set to 100 C. 2.15pmon 20 hours - LCMS shows product (489) and SM (470)26 hours - ratio of product : SM looks better by MS.2 x on - small SM peak remaining in MS.Concentrated onto silica and purified on ISCO. 40g column, 4:1 H:EA, then gradient up to ~1:1 EA:MeOH.Can\'t find product by LCMS in any fractions. NMR of polar fractions may be acid from Buchwald coupling.Need to purify SM on column, repeat." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=C(C2=CC(=C(C=C2N=C1)OC)N3CCN(CC3)C)NC4=C(C=C(C=C4)Cl)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/29/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "731" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00169 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.075 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCC[C@H](C1)N" - } - amount { - moles { - value: 0.048 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(N=CC=C1)Br" - } - amount { - moles { - value: 0.0403 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00169 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000778 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 115.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Production using the conditions which were shown to work in EN07957-762016-03-0114:20; Pd2(DBA)3 (1.05 g) and BINAP (712 mg mg) was stirred in toluene (75 ml). 14:25; 2-bromo-3-methylpyridine (6.94 g), the amine (9.62 g), and sodium t-butoxide (5.43 g), was added to the mixture. 14:30; Heating at 115 C. In an attempt to degas the reaction by employing vacuum to the flask good reflux, indicating a slight exotherm, took place. HPLC after 5 minutes indicated complet reaction. The mixture was allowed to cool.2016-03-0209:00; Water (50 ml) was followowed by 0.5 M citric acid (~75 ml) to give pH 3. The aqueous phase was extracted with another 25 ml toluene and the combined extracts were washed with water. Removal of the solvent in vacuo followed by evaporation of the solvent gave a reddish brown residue, 13.3 g. The mixture was dissolved in toluene and purified on a 100 g silica column, 25-100% ethyl acetate over 6 columns, collecting at 300 nm. This h was repeated on a 340 g silica column to give 6.24 g oil with a clear orange color.nbsp;About 4 g more impure material was also isolated. It was realized that preparative HPLC was required for purifiaction of the material. The impurity was mainly the diphosphine oxide originating from the BINAP. All material was purifed by preparative HPLC, 15-65% ACN in TFA 0.1%. The eluents were neutralized with ammonia and the acetonitrile was removed in vacuo. Extraction with DCM, drying (magnesium sulfate) and removal of the solvent in vacuo (over the weekend) gave 8.21 g semicrystalline material.The 1H-NMR and 13C NMR looks slightly dubious (too many protons and a13C shift at 3.8 ppm) but probably good enough for further synthesis. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(N=CC=C1)N[C@@H]2CCCN(C2)C(=O)OC(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 69.75 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/01/2016" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "732" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 3.05e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0025 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCC[C@H](C1)N" - } - amount { - moles { - value: 0.00263 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(N=CC=C1)Br" - } - amount { - moles { - value: 0.002 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 3.05e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.53e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 115.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Test reaction using the conditions which were shown to work in EN07957-762016-02-2614:30; Pd2(DBA)3 (14 mg) and BINAP (19 mg) was stirred in toluene (2.5 ml). 14:35; 2-bromo-3-methylpyridine (344 mg), sodium t-butoxide (334 mg), and the amine (526 mg) was added to the mixture. 14:40; Heating at 115 C. 15:10; 81% product. 15:40; 81% product, No further progress was observed, probably because of lack of amine15:50; Another 0.4 ml amine was added to the mixture. 16:15; No further progress by HPLC, reaction terminated. 50 microlitres of the mixture was evaporated and the residue was dissolved in methanol-d4 and 1H NMR was recorded. By 1H NMR the starting pyridine was consumed completely, as opposed to the HPLC-MS which indicated 16% starting material. 2016-02-2910:35; Purification using 25-100% ethyl acetate in heptane over 6 column lengths on a 50 g column, detection at 300 nm and collection on threshold 50 mAU. Evaporation he fractions gave 480 mg oil. ee measurement showed 99.9% ee " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(N=CC=C1)N[C@@H]2CCCN(C2)C(=O)OC(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 82.37 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/26/2016" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "733" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00341 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCNCC1" - } - amount { - moles { - value: 0.00171 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C2C=CC(=CC2=C1NC3=C(C=C(C=C3)F)F)Br.Cl" - } - amount { - moles { - value: 0.00114 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000114 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 5.69e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a solution of ethyl 6-bromo-4-(2,4-difluorophenylamino)quinoline-3-carboxylate hydrochloride (505 mg, 1.14 mmol) and 1-methylpiperazine (0.189 mL, 1.71 mmol) in dioxane (10 mL) was added cesium carbonate (1113 mg, 3.41 mmol), tris(dibenzylideneacetone)dipalladium(0) (52.1 mg, 0.06 mmol) and rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (70.9 mg, 0.11 mmol). Reaction vessel in oil bath set to 100 C. 3pmon - 20 hours, LCMS shows mostly SM (408), trace of product (427). Heating stopped after 24 hours.8608 - Additional portions of Pd cat, BINAP and Me piperazine added, and reaction returned to oil bath at 105C.on - Reaction more advanced, but still mostly SM. From past experience, Buchwald coupling may be more successful if SM is purified on silica column first.Discarded" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C2C=CC(=CC2=C1NC3=C(C=C(C=C3)F)F)N4CCN(CC4)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/31/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "734" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00242 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00161 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC2=C(C(=C1)Br)NC=C2" - } - amount { - moles { - value: 0.00161 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 0.000161 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 8.05e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-Dicyclohexylphosphino-2\',6\'-di-i-propoxy-1,1\'-biphenyl (75 mg, 0.16 mmol) and palladium (II) acetate (18.08 mg, 0.08 mmol) were dissoved in toluene (2 mL) at ambient temperature. The mixture was degassed and purged with nitrogen and warmed to 50C for 20 mins.In a separate vessel, were mixed tert-butyl piperazine-1-carboxylate (300 mg, 1.61 mmol), 7-bromo-1H-indole (316 mg, 1.61 mmol) and sodium-t-butoxide (296 mL, 2.42 mmol) in toluene (3 mL). The mixture was degasssed and purged with nitrogen and warmed to 50C.The catalyst solution was added to the reaction vessel and the resulting mixture was degassed and purged with nitrogen and heated at 100C for overnight. UPLC analysis showed virtually no reaction (only 7% conversion to product).Reaction ab" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC=CC3=C2NC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/13/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "735" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00513 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00321 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC=CC=C1Br" - } - amount { - moles { - value: 0.00321 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000128 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 6.42e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.059 g, 0.06 mmol) and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.080 g, 0.13 mmol) were mixed innbsp;toluene (10 mL) and degessed at 90 C for 10 mins. The mixture was then cooled andnbsp;1-bromo-2-methoxybenzene (0.400 mL, 3.21 mmol), sodium 2-methylpropan-2-olate (0.493 g, 5.13 mmol) and tert-butyl piperazine-1-carboxylate (0.597 g, 3.21 mmol) were added. The resulting mixture was stirred at 100 C for 16 hours under nitrogen. The reaction mixture was filtered through celite and the filtrate concentrated. The crude product was purified by flash silica chromatography, elution gradient 20 to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(2-methoxyphenyl)piperazine-1-carboxylate (0.585 g, 62.4 %) as a yellow oil which crystallised on standi" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC=CC=C2OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 62.37 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/05/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "736" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.7 [N-arylation with Ar-X] Chloro N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0129 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H](C1)C(=O)N" - } - amount { - moles { - value: 0.00429 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1(CCN2C(=C(C=N2)C3=CC(=NC=C3F)Cl)C1)C" - } - amount { - moles { - value: 0.00429 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000858 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.[Pd]" - } - amount { - moles { - value: 0.000429 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Tetrakis(triphenylphosphine)palladium(0) (0.496 g, 0.43 mmol) was added to 3-(2-chloro-5-fluoropyridin-4-yl)-5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (1.2g, 4.29 mmol), tert-butyl ((1R,3S)-3-carbamoylcyclohexyl)carbamate (1.039 g, 4.29 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.496 g, 0.86 mmol) and Cesium carbonate (4.19 g, 12.87 mmol) innbsp;1,4-dioxane (10 mL)Degassed for 5 mins under nitrogen and the resulting suspension was stirred at 120 C for 17 hours in the microwave reactor. The reaction mixture was partitioned between water (20ml) and ethyl acetate (100ml) filtered and separated. The organics were absorbed onto silica and purified by flash silica chromatography, elution gradient 1:1 EtOAc in heptane. Pure fractions were evaporated to dryness to afford tert-butyl ((1R,3S)-3-((4-(5,5-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexyl)carbamate (1.100 g, 52.8 %) as a white solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1(CCN2C(=C(C=N2)C3=CC(=NC=C3F)NC(=O)[C@H]4CCC[C@H](C4)NC(=O)OC(C)(C)C)C1)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 52.81 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/06/2015" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "737" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000117 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CS(=O)(=O)CC1=CC(=CC(=C1)F)N" - } - amount { - moles { - value: 0.000468 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=CC(=C1)F)C2=NC(=NC=C2F)Cl" - } - amount { - moles { - value: 0.000468 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000117 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 9.35e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine (0.12 g, 0.47 mmol), 3-fluoro-5-((methylsulfonyl)methyl)aniline (0.095 g, 0.47 mmol), cesium carbonate (0.609 g, 1.87 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.068 g, 0.12 mmol)and Pd2(dba)3 (0.086 g, 0.09 mmol) were suspended in degassed 1,4-dioxane (3 mL) at ambient temperature. The resulting mixture was degassed, purged with nitrogen and heated at 100 C for 3 hours after which time reaction was shown to be complete by LC-MS. The mixture was allowed to cool overnight. The reaction mixture was diluted with water (250 mL), and extracted with DCM (250 mL).nbsp;The organic was dried over MgSO4, filtered and evaporated to afford crude product.nbsp;The crude product was purified by flash silica chromatography, elution 50% ethyl acetate in Heptane. Fractions were evaporated to dryness to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 50 mm diam0 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 5-fluoro-4-(4-fluoro-2-methoxyphenyl)-N-(3-fluoro-5-((methylsulfonyl)methyl)phenyl)pyrimidin-2-amine (0.120 g, 60.6 %) as a white solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=C(C=CC(=C1)F)C2=NC(=NC=C2F)NC3=CC(=CC(=C3)CS(=O)(=O)C)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 60.61 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/10/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "739" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.7 [N-arylation with Ar-X] Chloro N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00147 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H](C1)C(=O)N" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1(CC2=C(C=NN2C1)C3=CC(=NC=C3F)Cl)C" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 9.78e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.[Pd]" - } - amount { - moles { - value: 4.89e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Tetrakis(triphenylphosphine)palladium(0) (56.5 mg, 0.05 mmol) was added to 3-(2-chloro-5-fluoropyridin-4-yl)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (130 mg, 0.49 mmol), tert-butyl ((1R,3S)-3-carbamoylcyclohexyl)carbamate (119 mg, 0.49 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (56.6 mg, 0.10 mmol) and Cesium carbonate (478 mg, 1.47 mmol) in 1,4-dioxane (5.98 ml).nbsp;Degassed for 5 mins under nitrogen and the resulting suspension was stirred at 120 C for 2 hours in the microwave reactor. The reaction mixture was partitioned between water (20ml) and DCM (40ml) and separated using a phase separation cartridge.nbsp;The organics were absorbed onto silica and purified by flash silica chromatography, elution gradient 0 to 60% EtOAc in heptane. Pure fractions were evaporated to dryness to afford tert-butyl ((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexyl)carbamate (81 mg, 35.1 %) as a pale yellow solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1(CC2=C(C=NN2C1)C3=CC(=NC=C3F)NC(=O)[C@H]4CCC[C@H](C4)NC(=O)OC(C)(C)C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 35.11 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/18/2015" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "740" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.7 [N-arylation with Ar-X] Chloro N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00413 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H](C1)C(=O)N" - } - amount { - moles { - value: 0.00138 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1(CC2=C(C=NN2C1)C3=CC(=NC=C3F)Cl)C" - } - amount { - moles { - value: 0.00138 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000275 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.[Pd]" - } - amount { - moles { - value: 0.000138 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Tetrakis(triphenylphosphine)palladium(0) (159 mg, 0.14 mmol) was added to 3-(2-chloro-5-fluoropyridin-4-yl)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (365.4 mg, 1.38 mmol), tert-butyl ((1R,3S)-3-carbamoylcyclohexyl)carbamate (333 mg, 1.38 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos)nbsp;(159 mg, 0.28 mmol)and Cesium carbonate (1344 mg, 4.13 mmol) in 1,4-dioxane (15 mL). The resulting suspension was degassed for 10 minutes under nitrogen and then stirred at 120 C for 8 hours overnight in the microwave reactor. The reaction mixture was partioned between water (30 mL) and DCM (15 mL) and seperated.iLCMS analysis showed product in the aqueous extract. iThe aqueous layer was extracted with DCM (2 X 20 mL). LCMS analysis showed some product still within in the aqueous extract. iThe aqueous layer was extracted again with DCM (2 X 25 mL).nbsp;iThe organic extracts were combined, dried over MgSO4, filtered and evaporato afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 60% EtOAc in heptane. Pure fractions were evaporated to dryness to afford tert-butyl ((1R,3S)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexyl)carbamate (348 mg, 53.6 %) as a white solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1(CC2=C(C=NN2C1)C3=CC(=NC=C3F)NC(=O)[C@H]4CCC[C@H](C4)NC(=O)OC(C)(C)C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 53.6 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/06/2015" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "741" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00171 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CCNC(C1)C2=CC=CC=C2" - } - amount { - moles { - value: 0.000682 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)Br" - } - amount { - moles { - value: 0.000568 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 2.84e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.42e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Caesium carbonate (556 mg, 1.71 mmol) was added to bromobenzene (0.060 mL, 0.57 mmol) and 2-phenylpiperidine (110 mg, 0.68 mmol) in 1,4-dioxane (2 mL). The reaction was degassed and Tris(dibenzylideneacetone)?dipalladium(0) (13.01 mg, 0.01 mmol) and dicyclohexyl(2\',6\'-diisopropoxy-[1,1\'-biphenyl]-2-yl)phosphine (RuPhos) (13.26 mg, 0.03 mmol) were added.nbsp;The resulting solution was stirred at 100 C for 16 hours. LCMS showed The reaction mixture was diluted with EtOAc, and washed with water. The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 15% MeOH in DCM. Pure fractions were evaporated to dryness to afford 1,2-diphenylpiperidine (21.00 mg, 15.56 %) as a yellow oil. f0 = 19 mg bromobenzenef1 = 21 mg productThe reaction was abandonned." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CCN(C(C1)C2=CC=CC=C2)C3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 15.56 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/23/2015" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "742" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00478 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.025 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00341 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=CC(=C1)Br)OCC2=CC=CC=C2" - } - amount { - moles { - value: 0.00341 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000136 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000102 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Tonbsp;tert-butyl piperazine-1-carboxylate (0.635 g, 3.41 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.094 g, 0.10 mmol) and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.085 g, 0.14 mmol) andnbsp;Sodium tert-butoxide (0.459 g, 4.78 mmol) was added a solution of 1-(benzyloxy)-4-bromo-2-methoxybenzene (1 g, 3.41 mmol) in Toluene (25 mL).nbsp;The resulting solution was stirred at reflux for18 hours. The reaction was allowed to cool to room temperature and diluted with dcm (50 ml). This was washed with water (2 x 50 ml), dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The crude product was dissolved in hydrochloric acid solution in methanol (4N, 20 ml) and stirred at room temprature overnight. The solvent was removed under reduced pressure.The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness to afford 1-(4-(benzyloxy)-3-methoxyphenyl)piperazine (0.614 g, 60.3 %) as a yellow gum. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=C(C=CC(=C1)N2CCNCC2)OCC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 60.33 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/11/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "743" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0505 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.28 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)N" - } - amount { - moles { - value: 0.0433 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=CC=C1Br" - } - amount { - moles { - value: 0.0361 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00216 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000722 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "ANILINE (3.94 mL, 43.29 mmol) was added to 4-bromopyridine (5.7 g, 36.08 mmol), PALLADIUM(II) ACETATE (0.162 g, 0.72 mmol), XANTPHOS (1.252 g, 2.16 mmol) and SODIUM TERT-BUTOXIDE (4.85 g, 50.51 mmol) in toluene (280 mL) under nitrogen. The resulting mixture was stirred at 100 C for 4 hours. The reaction mixture was evaporated to dryness and redissolved in EtOAc (200 mL), and washed sequentially with water (2 x 100 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and preadsorbed onto silica. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to afford N-phenylpyridin-4-amine (1.528 g, 24.88 %) as a pink solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=CC=NC=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 24.88 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/03/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "744" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0222 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.125 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)N" - } - amount { - moles { - value: 0.019 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=CC=C1Br" - } - amount { - moles { - value: 0.0158 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000949 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000316 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "ANILINE (1.730 mL, 18.99 mmol) was added to 4-bromopyridine (2.5 g, 15.82 mmol), PALLADIUM(II) ACETATE (0.071 g, 0.32 mmol), XANTPHOS (0.549 g, 0.95 mmol) and SODIUM TERT-BUTOXIDE (2.129 g, 22.15 mmol) in toluene (125 mL) under nitrogen. The resulting mixture was stirred at 100 C for 4 hours. The reaction mixture was evaporated to dryness and redissolved in EtOAc (100 mL), and washed sequentially with water (2 x 100 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and preadsorbed onto silica. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to afford N-phenylpyridin-4-amine (1.102 g, 40.9 %) as a white solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=CC=NC=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 40.92 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/28/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "745" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0877 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.5 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)N" - } - amount { - moles { - value: 0.0752 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=CC=C1Br" - } - amount { - moles { - value: 0.0627 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00376 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00125 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "ANILINE (6.85 mL, 75.19 mmol) was added to 4-bromopyridine (9.9 g, 62.66 mmol), PALLADIUM(II) ACETATE (0.281 g, 1.25 mmol), XANTPHOS (2.175 g, 3.76 mmol) and SODIUM TERT-BUTOXIDE (8.43 g, 87.72 mmol) in toluene (500 mL) under nitrogen. The resulting mixture was stirred at 100 C for 4 hours. The reaction mixture was evaporated to dryness and redissolved in EtOAc (200 mL), and washed sequentially with water (2 x 100 mL) and saturated brine (100 mL). The organic layer was dried over MgSO4, filtered and preadsorbed onto silica. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to afford N-phenylpyridin-4-amine (2.160 g, 20.25 %) as a pale tan solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=CC=NC=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 20.25 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/06/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "746" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00253 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.006 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00169 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1C=CC2=C1C(=CC=C2)Br" - } - amount { - moles { - value: 0.00169 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 0.000338 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000169 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium (II) acetate (37.9 mg, 0.17 mmol) and 2-dicyclohexylphosphino-2\',6\'-di-i-propoxy-1,1\'-biphenyl (158 mg, 0.34 mmol) were dissolved in toluene (3 mL) and the resulting solution degassed and purged with nitrogen. The mixture was warmed to 50C for 15 mins.In a separate vessel, were mixed tert-butyl piperazine-1-carboxylate (314 mg, 1.69 mmol), tert-butyl 7-bromo-1H-indole-1-carboxylate (500 mg, 1.69 mmol) and sodium-t-butoxide (243 mg, 2.53 mmol) in toluene at ambient temperature. The mixture was degassed and purged with nitrogen. The catalyst solution was added and the resulting mixture heated at 100C under nitrogen overnight.The main product of the reaction is 7-bromoindole. Boc has been lost (high temp, base). Only small trace desired product visible in UPLC.Reaction abandoned. Try lower temps, different b" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC=CC3=C2N(C=C3)C(=O)OC(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/18/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "747" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000506 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.000338 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1C=CC2=C1C(=CC=C2)Br" - } - amount { - moles { - value: 0.000338 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 6.75e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.38e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 95.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "uTrial reactionuPalladium (II) acetate (7.58 mg, 0.03 mmol) and 2-Dicyclohexylphosphino-2\',6\'-di-i-propoxy-1,1\'-biphenyl (31.5 mg, 0.07 mmol) were suspended in 1,4-dioxane (1 mL) at ambient temperature. The mixture was degassed and purged with nitrogen and warmed to 50C for 20 mins.In a separate vessel, were mixed tert-butyl piperazine-1-carboxylate (62.9 mg, 0.34 mmol), tert-butyl 7-bromo-1H-indole-1-carboxylate (100 mg, 0.34 mmol) and cesium carbonate (165 mg, 0.51 mmol) in 1,4-dioxane (2 mL). The mixture was degassed and purged with nitrogen several times. The catalyst solution was added and the resulting mixture was heated at 95C overnight under a nitrogen atmosphere.No reaction observed by LCMS. Main component of the mixture was unreacted BOC-protected indole. No loss of BOC, but still no reacti" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC=CC3=C2N(C=C3)C(=O)OC(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/20/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "748" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0014 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=COC(=N1)N" - } - amount { - moles { - value: 0.0012 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=NC(=C1)Cl" - } - amount { - moles { - value: 0.001 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium(II) acetate (4.49 mg, 0.02 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.017 g, 0.03 mmol) were mixed together in a reaction vessel and evacuated and purged with nitrogen 3 times. Dioxane (1 mL) was added and the resulting mixture was heated to to 50C for 30 minutes.oxazol-2-amine (0.101 g, 1.20 mmol) together with 2-chloropyridine (0.094 mL, 1.00 mmol) and cesium carbonate (0.456 g, 1.40 mmol) were placed in a second vessel, evacuated and purged with nitrogen 3nbsp;times and dioxane (3 mL) was added. The catalyst solution was added and the resulting mixture heated at 100 C for 16 hours.bNo oxazol-2-amine present in proton NMR of crude reaction mixture. bThe starting material is decomposing under the reaction conditions, could be the route of the very low productivity in the C-N couplings using these strates. Only chloropyridine observed in the proton NMR and LCMS of the crude reaction mixture.Conclusion: Experiment abandoned, nhe desired product isolated. . " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=NC(=C1)NC2=NC=CO2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/12/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "749" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[K+].[K+]" - } - amount { - moles { - value: 0.0001 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=COC(=N1)N" - } - amount { - moles { - value: 0.002 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=NC(=C1)Cl" - } - amount { - moles { - value: 0.001 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C1=CC2=CC=CC=C2N1C3=CC=CC=C3)C(C)(C)C" - } - amount { - moles { - value: 0.0002 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: Comparison of the reactivity of 2-aminooxazole in the coupling with 2-chloropyridine using three different catalyst systems ( previously shown to be the best performers in a 96-well Process Research and Development Screen)To an oven-dried microwave vial was added TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.046 g, 0.05 mmol) and 2-(di-tert-butylphosphino)-1-phenyl-1H-indole (0.067 g, 0.2 mmol) and the vial was purged with nitrogen. dioxane (2 mL) (degassed) was added and the reaction mixture was heated to 50 C for 40 min followed by heating to 90 C for a further 15 min (Solution 1).nbsp;To an oven dried microwave vial was added 2-chloropyridine (0.095 mL, 1 mmol), oxazol-2-amine (0.187 g, 2.00 mmol), potassium carbonate (0.207 g, 1.50 mmol) and 4,4\'-di-tert-butylbiphenyl (0.027 g, 0.1 mmol). The vial was then capped and purged with nitrogen. To this was added the activated catalyst solution (Solution 1) . The reaction mixture was then heated to 90 C for n inert atmosphere. LCMS of the crude reaction mixture under basic conditions showed a peak which had the mass of the desired product, however, the chloropyridine starting material co-elutes under these conditions. Under acidic conditions none of the desired product mass was observed at Rt= 0.25 min (whereas for EN05378-80 and EN05378-81, the product mass was observed at this retention time). A product of mass corresponding to homo-coupled product was observed under basic conditions. Reaction not progressed.Conclusion: The \'t-Butyl Beller ligand\' was not efficent for the coupling of these strates under the above conditions." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=NC(=C1)NC2=NC=CO2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "12/20/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "750" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[K+].[K+]" - } - amount { - moles { - value: 0.0001 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=COC(=N1)N" - } - amount { - moles { - value: 0.002 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=NC(=C1)Cl" - } - amount { - moles { - value: 0.001 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=C(C=CC(=C2P(C3CCCCC3)C4CCCCC4)OC)OC)C(C)C" - } - amount { - moles { - value: 0.0002 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: Comparison of the reactivity of 2-aminooxazole in the coupling with 2-chloropyridine using three different catalyst systems ( previously shown to be the best performers in a 96-well Process Research and Development Screen)To an oven-dried microwave vial was added TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.046 g, 0.05 mmol) and dicyclohexyl(2\',4\',6\'-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.107 g, 0.2 mmol) and the vial was capped and purged with nitrogen. dioxane (2 mL) (degassed) was added and the reaction [Reactants]mixture was heated to 50 C for 40 min followed by heating to 90 C for a further 15 min (Solution 1).To an oven dried microwave vial was added 2-chloropyridine (0.095 mL, 1 mmol), oxazol-2-amine (0.187 g, 2.00 mmol), potassium carbonate (0.207 g, 1.50 mmol) and 4,4\'-di-tert-butylbiphenyl (0.027 g, 0.1 mmol). The vial was then capped and purged with nitrogen. To this was added the activated catalyst solution (Solution 1). The reaction mixture wheated to 90 C for 16 h under an inert atmosphere.LCMS of the crude reaction mixture (Base) showed the mass peak for the desired product, however, this peak co-elutes with the Cl-pyridine starting material. LCMS of the crude reaction mixture using an acidic method showed no peak in the UV which had a mass corresponding to that of the product, however, the desired mass was observed in the MS at Rt= 0.27 min. A peak in the UV of a mass corresponding to the homocoupled bipyridine product was observed under both acidic and basic methods. Dichloromethane was added to the crude reaction mixture together with silica (2 g). The solvent was removed under reduced pressure and the resulting residue was placed in a dry-load tube prior to chromatography. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% methanolic ammonia (7 M) in DCM. 2-aminooxazole (103 mg) was recovered. The fraction containing the mass of the desired product produced 33 mg of impure materiale attached proton NMR, the desired product bumayub be present (but it\'s hard to say). If this sample was to be pure it would correspond to an isolated yield of ~ 20% of the desired product, due to the fact that this is a really impure sample the real value is probably less than 10%.Conclusion: Reaction not progressed. nbsp;nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=NC(=C1)NC2=NC=CO2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "12/20/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "752" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.1 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.2 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.1 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CNC2=NC=C(C=C21)Br" - } - amount { - moles { - value: 0.0502 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 0.00251 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00502 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (9.9 g, 50.25 mmol), morpholine (7.96 mL, 100.49 mmol), sodium 2-methylpropan-2-olate (19.32 g, 200.98 mmol),dicyclohexyl(2\',6\'-diisopropoxy-[1,1\'-biphenyl]-2-yl)phosphine (1.172 g, 2.51 mmol) in degassed dioxane (200 mL) was added diacetoxypalladium (1.128 g, 5.02 mmol) and the reaction mixture was heated under nitrogen at 90 C for 17 hours, then evaporated and partitioned between DCM (150 ml) and saturated aqueous sodium bicarbonate solution (150 mL). The aqueous phase was extracted further with DCM (70 ml) and the combined organics were evaporated, redissolved in a mixture of methanol and DCM and purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-(1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine (8.54 g, 84 %) as a yellow solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1COCCN1C2=CN=C3C(=C2)C=CN3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 83.63 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/11/2014" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "754" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0518 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.1 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.0518 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CNC2=NC=C(C=C21)Br" - } - amount { - moles { - value: 0.0259 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 0.00129 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00259 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (5.1 g, 25.88 mmol), morpholine (4.10 mL, 51.77 mmol), sodium 2-methylpropan-2-olate (9.95 g, 103.54 mmol),dicyclohexyl(2\',6\'-diisopropoxy-[1,1\'-biphenyl]-2-yl)phosphine (0.604 g, 1.29 mmol) in degassed dioxane (100 mL) was added diacetoxypalladium (0.581 g, 2.59 mmol) and the reaction mixture was heated under nitrogen at 90 C for 17 hours, then evaporated and partitioned between DCM (80ml) and saturated aqueous sodium bicarbonate solution (80ml). The aqueous phase was extracted further with DCM (50ml) and the combined organics were evaporated, redissolved in a mixture of methanol and DCM and purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-(1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine (3.40 g, 64.6 %) as a yellow solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1COCCN1C2=CN=C3C(=C2)C=CN3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 64.63 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/27/2014" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "755" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.1 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.2 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.1 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CNC2=NC=C(C=C21)Br" - } - amount { - moles { - value: 0.0502 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 0.00502 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00251 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (9.9 g, 50.25 mmol), morpholine (7.96 mL, 100.49 mmol), sodium 2-methylpropan-2-olate (19.32 g, 200.98 mmol),dicyclohexyl(2\',6\'-diisopropoxy-[1,1\'-biphenyl]-2-yl)phosphine (2.345 g, 5.02 mmol) in degassed dioxane (200 mL) was added diacetoxypalladium (0.564 g, 2.51 mmol) and the reaction mixture was heated under nitrogen at 90 C for 17 hours, then evaporated and partitioned between DCM (150 mL) and saturated aqueous sodium bicarbonate solution (150 mL). The aqueous phase was extracted further with DCM (70 mL) and the combined organics were concentrated. The crude material was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-(1H-pyrrolo[2,3-b]pyridin-5-yl)morpholine (9.28 g, 91 %) as a yellow solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1COCCN1C2=CN=C3C(=C2)C=CN3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 90.87 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/18/2014" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "756" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00178 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.1 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[Si](C)(C)OCCN" - } - amount { - moles { - value: 0.0178 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" - } - amount { - moles { - value: 0.0178 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.00178 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00178 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "PdOAc2 (0.399 g, 1.78 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.848 g, 1.78 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (5.00 g, 17.79 mmol), 2-(tert-butyldimethylsilyloxy)ethanamine (4.16 g, 17.79 mmol) and cesium carbonate (8.69 g, 26.68 mmol) in toluene (100 mL) at 20C in a microwave vial. The microwave vial was sealed and the reaction was heated to 120 C for 10 hours in the microwave reactor and cooled to RT.b bnbsp;uSplit into 5 x 20 ml mw vials such as in each was:uPdOAc2 (0.080 g, 0.36 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.170 g, 0.36 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (1.000 g, 3.56 mmol), 2-(tert-butyldimethylsilyloxy)ethanamine (0.832 g, 3.56 mmol) and cesium carbonate (1.739 g, 5.34 mmol) in toluene (20 mL) at 20C in a microwave vial. The microwave vial was sealed and thes heated to 120 C for 10 hours in the microwave reactor and cooled to RT.b bThe reaction mixtures were combined and diluted with EtOAc (150 mL), and washed sequentially with water (200 mL) and saturated brine (200 mL). The organic layer was filtered and dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was evaporated and was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)ethyl)-3-fluoroaniline (3.62 g, 54.2 %) as a yellow oil. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)[Si](C)(C)OCCNC1=CC(=C(C=C1)OCC2=CC=CC=C2)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 54.2 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/21/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "757" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000189 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[Si](C)(C)OCCN" - } - amount { - moles { - value: 0.00189 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)COC2=C(C=C(C=C2)Br)F" - } - amount { - moles { - value: 0.00189 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.000189 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000189 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "PdOAc2 (42.3 mg, 0.19 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (90 mg, 0.19 mmol) were added in one portion to a degassed solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (530 mg, 1.89 mmol), 2-(tert-butyldimethylsilyloxy)ethanamine (441 mg, 1.89 mmol) and cesium carbonate (921 mg, 2.83 mmol) in toluene (15 mL) at 20C in a microwave vial. The microwave vial was sealed and the reaction was heated to 120 C for 12 hours in the microwave reactor and cooled to RT. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was filtered and dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 4-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)ethyl)-3-fluoroaniline (312 mg, 44.1 %) as a yellow o" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)[Si](C)(C)OCCNC1=CC(=C(C=C1)OCC2=CC=CC=C2)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 44.07 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/13/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "759" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00324 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.016 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC1=CC=C(C=C1)F" - } - amount { - moles { - value: 0.00278 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC(=NC=C1)Br" - } - amount { - moles { - value: 0.00231 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 0.000347 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000116 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 105.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 100 mL round-bottomed flask (t=g) was methyl 2-bromoisonicotinate (.5 g, 2.31 mmol), 4-fluoro-N-methylaniline (0.348 g, 2.78 mmol), and CS2CO3 (1.056 g, 3.24 mmol) in toluene (16 mL) to give a yellow suspension. Pd2dba3 (0.106 g, 0.12 mmol) and biphenyl-2-yldicyclohexylphosphine (0.122 g, 0.35 mmol) were added. Reaction was allowed to stir overnight. LCMS in the morning revealed little product had formed. Something with mass 272 dominated.Reaction was discarded." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(C1=CC=C(C=C1)F)C2=NC=CC(=C2)C(=O)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/09/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "763" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000648 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CNC1=CC=C(C=C1)F" - } - amount { - moles { - value: 0.000555 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC(=NC=C1)Br" - } - amount { - moles { - value: 0.000463 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 6.94e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.31e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 85.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 100 mL round-bottomed flask (t=g) was biphenyl-2-yldicyclohexylphosphine (0.024 g, 0.07 mmol), methyl 2-bromoisonicotinate (.1 g, 0.46 mmol), and 4-fluoro-N-methylaniline (0.070 g, 0.56 mmol) in toluene (3 mL) to give a purple suspension. Pd2dba3 (0.021 g, 0.02 mmol) and CS2CO3 (0.211 g, 0.65 mmol) were added. Flask was placed in an oil bath at 85 C.LCMS taken at 1, 2 and 4 hours indicated reaction was not progressing. Reaction was discarded." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(C1=CC=C(C=C1)F)C2=NC=CC(=C2)C(=O)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/10/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "764" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00119 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC1=NC(=NC=C1Br)N" - } - amount { - moles { - value: 0.00099 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)I)C(F)(F)F" - } - amount { - moles { - value: 0.00119 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 4.95e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.95e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "repeat of uEN06995-58\\Reactionu but using XantphosbuAim:-u prepare target for further use.b1-iodo-3-(trifluoromethyl)benzene (0.171 ml, 1.19 mmol), 5-bromo-4-methoxypyrimidin-2-amine (0.202 g, 0.99 mmol), PALLADIUM(II) ACETATE (0.011 g, 0.05 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) - Xantphos (0.029 g, 0.05 mmol) and cesium carbonate (0.387 g, 1.19 mmol)nbsp;were mixed in toluene (5ml), purged with nitrogen and stirred in a sealed tube at 90 C overnight.nbsp;LCMS: pH = 3, 2 minute run time, shows sign of product at Rt = 1.41 minThe reaction mixture was diluted with EtOAc (20 ml), filtered through a celite pad and concentrated to give 477 mg yellow solid.TLC (1:1 - EtOAc : n-heptane) see diagram UV onlyThis was disolved in DCM, absorbed onto a samplet and purified on a 10 g Biotage SNAP column (approx column volume = 7 ml), eluting with a step-wise gradient from 0 : 10 to 4 : 6 EtOAc : n-heptane using a Thomson pcollecting 12 ml fractions. F1 - y = 149 mg - GCMS (Steep_10 min), Rt = 7.88 min (100%) mz: 3468.LCMS of F2 did not show anything of interest!buConclusion:u- bSeems like xanphos works but could be better - used in EN06995-68" - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=NC(=NC=C1Br)NC2=CC=CC(=C2)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 43.23 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/07/2014" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "765" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.009 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C(=CC=N1)N" - } - amount { - moles { - value: 0.00099 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN=C(N=C1C2=CN3C[C@H](N(C(=O)C3=N2)CC4=CC(=C(C=C4)F)F)COC)Cl" - } - amount { - moles { - value: 0.00119 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.0003 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.0003 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "18-mar-2014 17:15:52 +0100, blandar allt, add toluen, N2 flushar - rr 110 gCnN2. Nsta em kl 16, ftt svalna - LCMS ser bra ut, 17:49:27 - nu hydrolysrt, klart efter 90 min ca, slr p 600 uL HoAc, evap. Till SSL, 24-mar-2014 190 mg ter frn SSL. Jonbyt ( 1 g CBA prekond MeOH, lser inbsp;ngra ml ACN, eluerar mha 2.5 verkolonn vol, spder med avjonat " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)CN(C1=CC(=C(N=C1)C(=O)[C@H]2C[C@@H]2C(=O)O)OC)C3=C(C=CC(=C3)C(F)(F)F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 15.7 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/18/2014" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "766" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0003 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.03 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)CNC1=C(C=CC(=C1)C(F)(F)F)F" - } - amount { - moles { - value: 0.006 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1CC1C(=O)C2=C(C=C(C=N2)Br)OC" - } - amount { - moles { - value: 0.006 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.0003 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.0003 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "P vanligt stt (allt satsas i Toluen, N2 bubblar) start 09-jun-2014 19:51:32 +0200. LCMS-1 1600 nsta em ser bra ut, hittar inga SM, fr svalna - bryter. Spder med 30 ml etoac, filtrerar genom SiO plugg, evap. evap tv gnger ur 30 ml THF, LCMS-2 visar P10-jun-2014 19:15:25 +0200 lser i 20 ml THF, 10 ml MeOH, adderar LiOH(758 mg lst i 20 ml aq) - lsning, rr rt. Kl 1951 kr LCMS-3, ser riktigt bra ut, inga SM kvar ser det ut som. Ser ingen stitution F mot MeO. Kl 20.20 quench med 2 ml HOAc, evap hrt, m=5.0 g - till SSL.16-jun-2014 11:32:38 +0200 nu ftt ter 1.4 g dygt frn SSL samt ven dess enantiomer. Tar det via pulvret och kr HNMR (3.5 mg i DMSO). Visar rester frn upprening, stter kl 12.07 p indunstaren med fullt vakuum 60 grC badT samt kolsyreisaceton kylning f frlaget. Gr fram till 1335, sedan rt 10 min.Gr ver till PARD med hela batchen.en R.R isomeren i betydlig mngd frn SSL, anvndes frst fr att trna krist med 9010nbsp;aqetoh enligt Hkans recept, ser ok ut men mycket skumning. Dag senare slr p ngra ml iPrOH ser svrlsligt ut, add aning aq uppskattningsvis 80 iPrOH 20 aq, ser lite dimmigt utvrmer 70 gRC olja under omrn 5 min, mindre dimma?, str ngot litet faller ut sanbbt men kommer ej lngre evap, faller vits - kristallin? Vrmer 60 grC med CO2 aceton frlag 1 h.Fr ihop 128 mg ser bra ut (krist). Fr Jonas Bergare fr mrkning oc" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)CN(C1=CC(=C(N=C1)C(=O)[C@H]2C[C@@H]2C(=O)O)OC)C3=C(C=CC(=C3)C(F)(F)F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 29.09 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/09/2014" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "767" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0101 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1CCCO1" - } - amount { - volume { - value: 1.3 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1C(=CC=N1)N" - } - amount { - moles { - value: 0.00761 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN=C(N=C1C2=CN3C[C@H](N(C(=O)C3=N2)CC4=CC(=C(C=C4)F)F)COC)Cl" - } - amount { - moles { - value: 0.00507 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C1=CC=CC=C1C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 0.000406 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000203 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2016-05-18btimenbsp;tempnbsp;commentb114:20nbsp;21nbsp;(S)-2-(2-chloro-5-methylpyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one (2.2 g, 5.07 mmol), 1-methyl-1H-pyrazol-5-amine (0.754 g, 7.61 mmol) and cesium carbonate (3.30 g, 10.14 mmol) was charged to a 100mL reactor. 2-methyl tetrahydrofuran (1.2 L) and water (0.120 L) was charged. Degassed (6x vacN2)14:25nbsp;21nbsp;2\'-(dicyclohexylphosphanyl)-N,N-dimethyl-[1,1\'-biphenyl]-2-amine (dave phos) (0.160 g, 0.41 mmol) and Pd2dba3 (0.186 g, 0.20 mmol)nbsp;was added. degassed (6x vacN2).14:25nbsp;21nbsp;heated to 80 magnetic stirrer under nitrogen.nbsp;nbsp;nbsp;IPC1 (1,5h) SFC-MS indicates 9.5% conversion.2016-05-1908:00nbsp;reflux nbsp;IPC2 (18h) SFC-MS indicates 66% conversion. 14.00nbsp;refluxnbsp;IPC3 (23h) SFC-MS indicates 72% conversion.The reaction mixture was cooled to 40C and 1 eq. of catalysd ligand was added, 0.17g Pd and 0.15g Davefos. degassed 6 times. Jacket to 80C , stirred over night.2016-05-2007:45nbsp;reflux nbsp;IPC4 42h complete conversion.1.19 g of silicycle was added and the temperature was set to ambient..10:18:07nbsp;rtnbsp;the mixture was filtered through a celite filter (25). the filter cake was washed with EtOAc (2x 10 ml).10:30:44nbsp;rtnbsp;the filtrate was transfered to a sep funnel and washed with aq citric acid (0,5M, 15 ml) and water (5 ml). Unfortunately when washing with water some diluted HCl was used, so the reaction mixture was basified with bicarbonate solution prior to the final water wash. The organic layer was evaporated to a solid, 2.7g Material sent to SSL for separation 2016-05-23.Yield after chromatography: 1" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN=C(N=C1C2=CN3C[C@H](N(C(=O)C3=N2)CC4=CC(=C(C=C4)F)F)COC)NC5=CC=NN5C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 55.03 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/18/2016" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "769" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "[Li+].C[Si](C)(C)[N-][Si](C)(C)C" - } - amount { - moles { - value: 0.00119 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1CCOC1" - } - amount { - volume { - value: 0.001 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C(CN)C(=O)N.Cl" - } - amount { - moles { - value: 0.000622 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1C(=O)O)Br" - } - amount { - moles { - value: 0.000497 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 50.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium (II) acetate (0.011 g, 0.05 mmol) was added to(R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (0.027 g, 0.05 mmol) in THF (1 mL) in a reaction vessel evacuated and purged with nitrogen. The resulting catalyst mixture was stirred and under nitrogen at 50 C for 30 minutes. 04-Dec-2013 10:52:28 AM -0500LiHMDS (1.194 mL, 1.19 mmol), 3-aminopropanamide, HCl (0.077 g, 0.62 mmol) and 4-bromobenzoic acid (0.1 g, 0.50 mmol) was added to a second reaction vessel and purged with nitrogen. were added at 20 C.nbsp;The catalyst solution was added to the reaction mixture and the resulting mixture was stirred at 120 C for 16 hours. nbsp;LCMS showed starting material only. Desired product not isolated from this re" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1C(=O)O)NCCC(=O)N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "12/04/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "770" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0056 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.012 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1C2=CN=C(C=C2)N" - } - amount { - moles { - value: 0.00269 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN2C=C(C=C(C2=N1)Br)Cl" - } - amount { - moles { - value: 0.00224 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000448 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000336 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 105.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of 8-bromo-6-chloroimidazo[1,2-a]pyridine, HCl (600mg, 2.24 mmol),nbsp;5-morpholinopyridin-2-amine (482 mg, 2.69 mmol), BINAP (279 mg, 0.45 mmol),nbsp;cesium carbonate (1824 mg, 5.60 mmol)nbsp;in Toluene (12 mL) was spargednbsp;with nitrogen while stirring for 10 minutes. palladium(II) acetate (87 mg, 0.39 mmol) was then added and the reaction stirred at 105 Cnbsp;for overnight.nbsp;At ths stage LCMS indicated that formation of the product. After this time, the reaction was cooled to room temperature, dilutednbsp;with mixture of 1:1 methanolDCM ( 100 mL) and filtered through celite. The filtrated concentrated under reduced pressure and the resulting residue purified by flash chromatography (silicagel,nbsp;0-10%nbsp;DCMMethanol, 25 minutes) to afford 6-chloro-N-(5-morpholinopyridin-2-yl)imidazo[1,2-a]pyridin-8-amine (482 mg, 65.3 %)nbsp;as a solid. LCMS (2 minute, Acid _CV10.olp methodnbsp;330 (M + 1), 0.66 minutes.1H NMR (400 MHz, DMSO-idi6) d ppm 9.16 (sH) 8.30 - 8.34 (m, 1 H) 8.25 - 8.29 (m, 1 H) 7.98 - 8.03 (m, 1 H) 7.88 - 7.92 (m, 1 H) 7.54 - 7.57(m, 1 H) 7.36 - 7.47 (m, 2 H) 3.72 - 3.79 (m, 4 H) 3.05 - 3.12 (m, 4 H)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1COCCN1C2=CN=C(C=C2)NC3=CC(=CN4C3=NC=C4)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 65.27 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/12/2014" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "771" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00181 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1C[C@H](C(=O)NC1)N" - } - amount { - moles { - value: 0.00104 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(N=C1)Br)Cl" - } - amount { - moles { - value: 0.00104 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 1.56e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 7.9e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 115.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 5 ml MW vial,nbsp;Pd2((dba)3 (7.23 mg, 7.90 mol), 2,2\'-bis(diphenylphosphanyl)-1,1\'-binaphthalene (BINAP) (9.71 mg, 0.02 mmol),nbsp;sodium 2-methylpropan-2-olate (174 mg, 1.81 mmol), (R)-3-aminopiperidin-2-one (119 mg, 1.04 mmol) and 2-bromo-3-chloropyridine (200 mg, 1.04 mmol) mixed in toluene (2 mL) to give a brown suspension. The mixture was degassed with N2 bubbling for 5 min, then the vial was capped and the reaction stirred at 115C in an oil-bath over night.The reaction was cooled to rt, DCM and aq NaHCO3 were added, the mixture stirred, filtered through a phase separator and evaporated.LC-MS crude: Traces of product, mainly starting bromide left.Reaction discar" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1C[C@H](C(=O)NC1)NC2=C(C=CC=N2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/10/2016" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "772" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000977 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C(=C1)F)CN)F" - } - amount { - moles { - value: 0.000537 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.91e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(2,6-difluorophenyl)methanamine (77 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford N4-(2,6-difluorobenzyl)-N2-phenylpyridine-2,4-diamine (93 mg, 61.1 %) as a purple gum.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)NCC3=C(C=CC=C3F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 61.13 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/04/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "773" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000977 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C(=C1)F)CN)F" - } - amount { - moles { - value: 0.000635 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.91e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol), (2,6-difluorophenyl)methanamine (91 mg, 0.64 mmol),nbsp;(R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol),sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were suspended in DME (2.0 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 20 minutes in the microwave reactor and cooled to RT. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH andnbsp;fractions were evaporated to dryness to afford crude product. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford N4-(2,6-difluorobenzyl)-N2-phenylpyridiiamine (32.0 mg, 21.04 %) as a yellow gum. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)NCC3=C(C=CC=C3F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 21.04 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/17/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "774" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00222 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000887 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C[C@@H](OC2=C(C1)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.000739 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 7.39e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 7.39e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.213 g, 0.89 mmol), Palladium(II) acetate (0.017 g, 0.07 mmol), 2-(Dicyclohexylphosphino)biphenyl (0.026 g, 0.07 mmol) and Cesium carbonate (0.722 g, 2.22 mmol) were put in a 20 mL microwave vial and sealed. The vial was flushed with argon. (S)-8-chloro-4-methyl-2-phenyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (0.203 g, 0.74 mmol) in DME (5 mL) was added and additional 5 mL was added to the vial. The reaction mixture was run in the microwave at 100C for 80 minutes. Reaction still not complete. Additional palladium(II)acetate (0.1 eq) and 2-(dicyclohexylphosphino)biphenyl (0.1 eq) were added and the reaction was run again in the microwave for 60 minutes. Have about 14% oxazepine left. Heated for additional 45 minutes. 10% oxazepine left. Added 0.1 eq palladium(II)acetate, 0.1 eq 2-(dicyclohexylphosphino)biphenyl and 0.3 eq of 3-methoxy-4-(4-methyl-1Himidazol-1-yl)aniline andnbsp;let the reaction run in the microwave for additional 60 minutes. Thection mixture was filtrated through celite, concentrated and purified first by silica flash chromatography using methanol in dichlorometane (0 to 4%). The productcontaining fractions were pooled and purified further by preparative chromatography. The productcontaining fractions were pooled, concentrated and partitioned between sat. NaHCO3 (aq) and dichloromethane. The organic layer was washed with brine, dried (MgSO4) and concentrated giving 0.091 g of the product." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(CN(C[C@@H](O4)C5=CC=CC=C5)C)C=C3)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 27.89 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/20/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "775" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000101 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3)OC(=CC2=O)N4CCOCC4" - } - amount { - moles { - value: 6.73e-05 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=C(C=C1F)Br)F" - } - amount { - moles { - value: 7.4e-05 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.37e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)[PH+](C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5[PH+](C6=CC=CC=C6)C7=CC=CC=C7)C.C1=[C-]C=C(C=C1F)F.Br[Pd+]" - } - amount { - moles { - value: 3.37e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Pd complexe (2.96 mg, 3.37 mol) was added to a stirred mixture of N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (25 mg, 0.07 mmol), 1-bromo-3,5-difluorobenzene (8.53 l, 0.07 mmol) and cesium carbonate (32.9 mg, 0.10 mmol) dissolved in 1,4-dioxane (0.5 ml) under argon. The resulting suspension was degased with argon and then stirred at 80 C for 3.5 hours.Lcms showed complete reaction.The reaction mixture was allowed to cool to room temperature, filtered and concentrated.The crude product was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (11.00 mg, 33.8 %) as a pale beige foam.LCMS and NM" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(C)C(=O)C1=CC2=C(C(=C1)C3CCCN3C4=CC(=CC(=C4)F)F)OC(=CC2=O)N5CCOCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 33.8 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/04/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "776" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000216 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCNCC1" - } - amount { - moles { - value: 0.000324 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)C2=NC=CN2)NC(=O)C3=CC=C(C=C3)OCC4=C(C=CC=N4)Br" - } - amount { - moles { - value: 0.000108 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 4.32e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.16e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of N-(5-(1H-imidazol-2-yl)-2-methylphenyl)-4-((3-bromopyridin-2-yl)methoxy)benzamide (50 mg, 0.11 mmol), 1-methylpiperazine (32.4 mg, 0.32 mmol), Pd2(dba)3 (19.76 mg, 0.02 mmol) and BINAP (26.9 mg, 0.04 mmol), CS2CO3 (70.3 mg, 0.22 mmol) in DMA (5 mL) was stirred at 100 C for overnight. LCMS didn\'t mornitor the desired product." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)C2=NC=CN2)NC(=O)C3=CC=C(C=C3)OCC4=C(C=CC=N4)N5CCN(CC5)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/06/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "777" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.7 [N-arylation with Ar-X] Chloro N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00238 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H](C1)C(=O)N" - } - amount { - moles { - value: 0.000954 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CCN2C(=C(C=N2)C3=CC(=NC=C3F)Cl)C1" - } - amount { - moles { - value: 0.000795 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000159 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.[Pd]" - } - amount { - moles { - value: 7.95e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Tetrakis(triphenylphosphine)palladium(0) (0.092 g, 0.08 mmol) was added to 3-(2-chloro-5-fluoropyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (0.200 g, 0.79 mmol), tert-butyl ((1R,3S)-3-carbamoylcyclohexyl)carbamate (0.231 g, 0.95 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.092 g, 0.16 mmol) and Cesium carbonate (0.777 g, 2.38 mmol) in 1,4-dioxane (5.98 ml).nbsp;Degassed for 5 mins under nitrogen and the resulting suspension was stirred at 120 C for 2 hours in the microwave reactor. The reaction mixture was partitioned between water (20ml) and DCM (40ml) and separated using a phase separation cartridge.nbsp;The organics were absorbed onto silica and purified by flash silica chromatography, elution gradient 0 to 60% EtOAc in heptane. Still impure but telescoped through to next stage without further purification. (136mg)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H](C1)C(=O)NC2=NC=C(C(=C2)C3=C4CCCCN4N=C3)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 37.41 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/18/2015" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "779" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00497 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.00473 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C1=NC=C(C=N1)F)N.Cl" - } - amount { - moles { - value: 0.00142 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(N=C1)NC2=C3C=CN(C3=NC(=N2)Cl)C4CC4" - } - amount { - moles { - value: 0.00071 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 0.00011 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 7e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of 1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (252 mg, 1.42 mmol), 2-chloro-7-cyclopropyl-N-(1-methyl-1H-imidazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (205 mg, 0.71 mmol), palladium(II) acetate (15.94 mg, 0.07 mmol) and palladium(II) acetate (15.94 mg, 0.07 mmol) (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (62.1 mg, 0.11 mmol) and CS2CO3 (1619 mg, 4.97 mmol)nbsp;in 1,4-dioxane (4733 l) was heatd to 150 oC for 20 min with well-stirring. Reaction was diluted with DCMMeOh (10%) the organic layer was washed with water. And concntraction provided product. Reaction is clean and 70% contaminated with hydroxy product (P3). Reaction was purified on gilsen (5 to 45%) provide product 40 mg. Compound was mitted to chiral purification. Chiral sepreation:En02021-65-2 (P2, E1) : EN02021-65-3 (P3, E2) = 4:96There is no racemization observed in reaction." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C1=NC=C(C=N1)F)NC2=NC(=C3C=CN(C3=N2)C4CC4)NC5=CN(C=N5)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 37.23 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "12/04/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "780" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000977 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC=CC(=C1)CN" - } - amount { - moles { - value: 0.000537 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(3-methoxyphenyl)methanamine (73.7 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford N4-(3-methoxybenzyl)-N2-phenylpyridine-2,4-diamine (80 mg, 53.6 %) as an off-white gum.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=CC=CC(=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 53.61 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/02/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "781" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.7 [N-arylation with Ar-X] Chloro N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0101 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.007 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCC[C@H](C1)N" - } - amount { - moles { - value: 0.00605 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=NC(=C1)Cl" - } - amount { - moles { - value: 0.00504 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 3.78e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.92e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Vial 1)Pd2(dba)3 (0.018 g, 0.02 mmol) and BINAP (0.024 g, 0.04 mmol) were mixed in toluene (1mL) under N2 and stirred at rt for 5min. Vial 2)sodium tert-butoxide (0.999 g, 10.08 mmol), tert-butyl (R)-3-aminopiperidine-1-carboxylate (1.249 g, 6.05 mmol) and 2-chloropyridine (0.477 mL, 5.04 mmol) were mixed in toluene (6mL) under N2. Added the catalyst solution from vial 1. The mixture was heated at 110C in an oil-bath.LCMS (3h): product, no SM left.The reaction was cooled to rt and the solvent was evaporated. Added EtOAc, washed with water.Purified by column chromatography (using SP4 TM HPFC system, KP-Sil (50g) column, A=heptane, B=EtOAc2M NH3 in MeOH (91), 27mLfr, (0% B 2CV, 0-30% B 10CV, 30% B 2CV)) to yield tert-butyl (R)-3-(pyridin-2-ylamino)piperidine-1-carboxylate (1.306 g, 93 %) as yellow solid.[M+H]+ 278.1H NMR (400 MHz, CDCl3) d 1.42 (s, 9H), 1.51 - 1.64 (m, 2H), 1.68 - 1.8 (m, 1H), 1.93 - 2.0, 1H), 2.81 - 3.36 (m, 2H), 3.45 - 4.16 (m, 3H), 4.50 (d, 1H), 6.42 (d, 1H), 6.5 - 6.62 (m, 1H), 7.36 - 7.45 (m, 1H), 8.02 - 8.13 (m, 1H).nbsp;br Expected Number of Hs: 23nbsp;br Assigned Hs: 23." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCC[C@H](C1)NC2=CC=CC=N2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 93.42 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/26/2016" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "782" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000977 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=CC=C1CN" - } - amount { - moles { - value: 0.000537 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.91e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Pyridin-4-ylmethanamine (58.1 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by preparative HPLC (Waters SunFire column, 5 silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated ts N2-phenyl-N4-(pyridin-4-ylmethyl)pyridine-2,4-diamine (39.8 mg, 29.5 %) as an off white gum.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)NCC3=CC=NC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 29.48 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/23/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "783" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000977 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=CC=C1CN" - } - amount { - moles { - value: 0.000537 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.91e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Pyridin-4-ylmethanamine (58.1 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford impure product. Impure product was purified by flash silica chromatography, elution gradient 3 to 8% MeOH in. Fractions containing product were evaporated to dryness to afford impure product. Impure product was purified by preparative HPLC (Waters SunFire column, 5 silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to drynessnbsp;N2-phenyl-N4-(pyridin-4-ylmethyl)pyridine-2,4-diamine (31.2 mg, 23.11 %) as an off white solid.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)NCC3=CC=NC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 23.11 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/05/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "784" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0124 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0198 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC1CCNCC1" - } - amount { - moles { - value: 0.00743 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)Br)[N+](=O)[O-]" - } - amount { - moles { - value: 0.00495 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000495 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000248 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 95.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 100 mL round bottom flask was charged with a magnetic stir bar, 1-bromo-3-nitrobenzene (1.000 g, 4.95 mmol), [Reactants], Pd2dba3 (0.227 g, 0.25 mmol), BINAP (0.308 g, 0.50 mmol), Cs2CO3 (4.03 g, 12.38 mmol), and toluene (19.80 ml).nbsp;The vessel was capped with a septum, placed under an atmosphere of argon, and placed in an oil bath heated to 95 C.nbsp;The reaction was allowed to stir at this temperature for 16 h before being allowed to cool to rt.nbsp;The reaction mixture was poured into a separatory funnel containing water (~100 mL) and extracted with ethyl acetate ( 2 x 100 mL).nbsp;The combined organic extract was dried with MgSO4, filtered, and conc.i in vacuoi to yield the crude product which was purified via silica gel chromatography (80 g) using ethyl acetatehexanes (1:5) as eluent to provide pure tert-butyl 1-(3-nitrophenyl)piperidin-4-ylcarbamate (0.901 g, 56.6 %) as a light yellow solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC1CCN(CC1)C2=CC(=CC=C2)[N+](=O)[O-]" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 56.63 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "12/13/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "785" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000643 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@@H]1CNCCN1" - } - amount { - moles { - value: 0.000643 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)OCC1=C2C(=CC=C1)C(=O)C=C(O2)C3=CC=C(C=C3)Br" - } - amount { - moles { - value: 0.000536 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 4.02e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (6.02 mg, 0.03 mmol) was added to a degassed mixture ofnbsp;(2-(4-bromophenyl)-4-oxo-4H-chromen-8-yl)methyl acetate (200 mg, 0.54 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthalene (25.03 mg, 0.04 mmol) and cesium carbonate (244 mg, 0.75 mmol) in toluene (5 mL). The resulting suspension was stirred at 110 C for 3 hours under nitrogen (see note 1).nbsp;More diacetoxypalladium (6.02 mg, 0.03 mmol) was added and the reaction mixture was heated to 110C for 1 hour and again could see no product.nbsp;TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (4.91 mg, 5.36 mol) and 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthalene (25.03 mg, 0.04 mmol) were added and the reaction mixture was heated to 110C for 1 hour and again could see no product.nbsp;sodium 2-methylpropan-2-olate (61.8 mg, 0.64 mmol) was added and the reaction mixture was heated to 110C for 1 hour where a small amount of product could be detected by LCMS and significant dehalogenation.nbsp;The reaction mixtuol to room temperature The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and fractions were evaporated to dryness to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% 7N NH3MeOH in DCM.nbsp;Fractions were evaporated to dryness to afford product that was not pure.nbsp;The sample was dissolved in DMF (4ml) and the crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (R)-8-(hydroxymethyl)-2-(4-(3-methylpiperazin-1-yl)phenyl)-4H-chromen-4-one (25.00 mg, 13.31 %) as a yellow solid. nbsp;br " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@@H]1CN(CCN1)C2=CC=C(C=C2)C3=CC(=O)C4=CC=CC(=C4O3)CO" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 13.31 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/15/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "789" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00257 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.008 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC(=C(C=C1NC(=O)C)N)F" - } - amount { - moles { - value: 0.000899 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.000856 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C(C)(C)C)C(C)(C)C)C(C)C" - } - amount { - moles { - value: 8.56e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 4.28e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In 20 ml microwave vial were addednbsp;5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (200 mg, 0.86 mmol), N-(5-amino-4-fluoro-2-methylphenyl)acetamide (164 mg, 0.90 mmol), Pd2dba3 (39.2 mg, 0.04 mmol), di-tert-butyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (37.5 mg, 0.09 mmol) and Cs2CO3 (837 mg, 2.57 mmol). The vessel was fitted with septum, gas inlet and dioxane (8 mL) was added via syringe. The resulting suspension was stirred for 5 min. under N2. The septum and gas inlet quickly replaced with microwave vial cap and the mixture was heated to 150oC under microwave irradiation for 30 min.The reaction mixture filtered through celite, filtrate concentrated, combined with EN02368-53 experiment and purified by ISCO column (0-5% MeOH-CH2Cl2). The obtained compound triturated with CH3CN, filtered and dried to give light brown color solid.Conclusion: product isolated" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CC(=C(C=C1NC(=O)C)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 20.63 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/29/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "790" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00131 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.00048 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC(=CC=C1)Br" - } - amount { - moles { - value: 0.000437 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 8.73e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.18e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of ethyl 3-bromobenzoate (0.070 mL, 0.44 mmol), cesium carbonate (427 mg, 1.31 mmol), diacetoxypalladium (4.90 mg, 0.02 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (5.44 mg, 8.73 mol) and morpholine (0.042 mL, 0.48 mmol) in toluene (2 mL) was refluxed for 1h. The reaction mixture was cooled and filtered through celite. The celite was washed with EtOAc. The solvent was removed under reduced pressure. The residue was purified by automated flash chromatography on a SNAP 25 gnbsp;column. A gradient from 0% to 50% of EtOAc in Heptane over 10CV was used as mobile phase. The product was collected using the wavelength 254 nm." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CC(=CC=C1)N2CCOCC2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 79.84 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/14/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "792" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00483 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0114 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00322 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CN=C1)Br" - } - amount { - moles { - value: 0.00322 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 0.000644 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000322 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "diacetoxypalladium (0.072 g, 0.32 mmol) and RuPhos (0.301 g, 0.64 mmol) were stirred in 1,4-dioxane (11.36 ml) for 10 mins at 50 C.tert-butyl piperazine-1-carboxylate (0.6 g, 3.22 mmol), 3-bromopyridine (0.310 ml, 3.22 mmol) and sodium tert-butoxide (0.464 g, 4.83 mmol) were added and the reaction mixture was stirred at 100 C for 64 h. The reaction mixture was filtered through celite. The crude product was purified by flash silica chromatography, elution gradient 20 to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(pyridin-3-yl)piperazine-1-carboxylate (0.322 g, 38.0 %) as a yellow oil which crystallised on standing. This was then combined with EN06111-39-01.n" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CN=CC=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 37.96 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/10/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "793" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00484 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0316 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00322 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CN=C1)Br" - } - amount { - moles { - value: 0.00322 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000129 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 6.44e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 85.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.059 g, 0.06 mmol) and rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.080 g, 0.13 mmol) were mixed together and evacuated and purged with nitrogen 3 times. toluene (31.6 ml) was added and the resulting mixture heated to 90C for 10 minutes then cooled to room temperature. sodium tert-butoxide (0.465 g, 4.84 mmol), 3-bromopyridine (0.310 ml, 3.22 mmol) and tert-butyl piperazine-1-carboxylate (0.6 g, 3.22 mmol) were added and the resulting mixture was heated at 85 C for 64 hours. The reaction mixture was cooled to RT and filtered through celite and concentrated to give an orange solid. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(pyridin-3-yl)piperazine-1-carboxylate (0.248 g, 29.2 %) as a yellow oil which crystallised on standi" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CN=CC=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 29.23 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/03/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "794" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0065 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1CCOC1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)N)CO" - } - amount { - moles { - value: 0.00325 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)Br" - } - amount { - moles { - value: 0.0039 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000487 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000195 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 65.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A solution of Tris(dibenzylideneacetone)dipalladium(0) (0.178 g, 0.19 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.282 g, 0.49 mmol) in THF (20 mL) (degassed) was heated to 50 C under a nitrogen atmosphere for 30 min. (3-(phenylamino)phenyl)methanol (0.072 g, 11.13 %) (0.4 g, 3.25 mmol) and cesium carbonate (2.117 g, 6.50 mmol) were added followed by bromobenzene (0.409 mL, 3.90 mmol) and the mixture stirred at 65 C over two days. The reaction mixture was cooled to room temperature then diluted with DCM and filtered. stirred with SiliCycle SiliMet-SH (1 g) for 3 h at 60 C. The mixture was filtered through an acrodisc glassfiber filter, 25 mm, 1.0 m. The filtrate (clear) wasnbsp;concentrated to give crude product (1,00 g). The crude was dissolved in DMSO and the product was purified by prep-HPLC on a Kromasil C8 column (10 m 250x50 ID mm) using a gradient of 5-65% acetonitrile in H2OACNHOAc 9550.2 buffer over 30 minutes with a flow of 100 s were collected on UV at 303 nm, threshold 1000. The product containing fractions were pooled and concentrated on the rotavapor. Toluene was added and evaporated to get rid of residue of water to give the product (3-(phenylamino)phenyl)methanol (0.072 g, 11.13 %) as a transparent oil." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=CC=CC(=C2)CO" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 11.13 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/26/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "795" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00149 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC1=NC(=NC=C1Br)N" - } - amount { - moles { - value: 0.00124 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)I)C(F)(F)F" - } - amount { - moles { - value: 0.00149 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 8.71e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 6.22e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "cfnbsp;uEN06995-11\\Reactionu and many othersbuAim:-u prepare target for further use.b1-iodo-3-(trifluoromethyl)benzene (0.215 ml, 1.49 mmol), 5-bromo-4-methoxypyrimidin-2-amine (0.254 g, 1.24 mmol), PALLADIUM(II) ACETATE (0.014 g, 0.06 mmol), rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthalene (0.054 g, 0.09 mmol) and cesium carbonate (0.487 g, 1.49 mmol)nbsp;were mixed in toluene (5ml), purged with nitrogen and stirred in a sealed tube at 80 C overnight.nbsp;LCMS: pH = 3, 2 minute run time, Rt = 0.66 min (32% by UV),nbsp;mz: 204 (MH+)nbsp;- 316 (M-H-) - ?; Rt = 1.10 min (15% by UV),nbsp;mz: 257, 306 (MH+) - 316nbsp;(M-H-) - ?; Rt = 1.28 min (25% by UV),nbsp;mz: 350,nbsp;(MH+) product ?.The reaction mixture was diluted with EtOAc (20 ml), filtered through a celite pad and concentrated to give 902 mg yellow oil.TLC (1:1 - EtOAc : n-heptane) see diagram UV onlyThis was disolin DCM, absorbed onto a samplet and purified on a 10 g Biotage SNAP column (approx column volume = 7 ml), eluting with a step-wise gradient from 0 : 10 to 4 : 6 EtOAc : n-heptane using a Thomson pump collecting 12 ml fractions.nbsp;F1 - y = 38 mg - GCMS and NMR - show it to be productF2 - y = 229 mgnbsp;- GCMS and NMR - show it to be bromo SMbuConclusion:u- bAbandoned - to be repeated with xanphos" - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=NC(=NC=C1Br)NC2=CC=CC(=C2)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 8.77 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "12/04/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "796" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000818 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.00625 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CCNCC1" - } - amount { - moles { - value: 0.000273 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1CCN(CC1)C2=C3CN(CCC3=C(C=C2)OC)C(=O)CC4=CC=C(C=C4)Br" - } - amount { - moles { - value: 0.000273 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 1.64e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.64e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-(4-bromophenyl)-1-(5-methoxy-8-(4-methylpiperazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (125 mg, 0.27 mmol),[Reactants],piperidine (23.22 mg, 0.27 mmol) was taken in a mixture of DME (5 mL):water (1.250 mL) under N2.The reaction mixture was purged under N2 for 10 min.Tris(dibenzylideneacetone)dipalladium (0) (14.98 mg, 0.02 mmol) was added to the above reaction.The resulting reaction was stirred for 3 hrs at reflux tempt.LCMS profile showed formation of required product.Reaction was cooled to rt,solvents was evapourated to dryness.Crude was diluted with DCM and water (min) and organic layer separated and concentrated .Purification was done on RP systme to get product 1-(5-methoxy-8-(4-methylpiperazin-1-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-(4-(piperidin-1-yl)phenyl)ethanone as a solid.but the product was not mitted due to very less ammount." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CCN(CC1)C2=C3CN(CCC3=C(C=C2)OC)C(=O)CC4=CC=C(C=C4)N5CCCCC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/16/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "797" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00547 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C2C(=C1)C(=CN=N2)Cl" - } - amount { - moles { - value: 0.00182 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C(=C(C=N1)C(=O)N2CCC(CC2)N)Cl" - } - amount { - moles { - value: 0.00182 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000182 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000182 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 140.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(4-aminopiperidin-1-yl)(5-chloro-1-methyl-1H-pyrazol-4-yl)methanone (442 mg, 1.82 mmol) was taken in a microwave tube. Added racemic-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (113 mg, 0.18 mmol) followed by the addition of Palladium (II) acetate (40.9 mg, 0.18 mmol), racemic-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (113 mg, 0.18 mmol), Cesium carbonate (1782 mg, 5.47 mmol) and diisopropylethyl amine(1ml). toluene (10 mL) was added and stirred at 140 C for 8h.After the completon of the reaction adsorbed the reaction mass on silica gel and purified by silica gel column." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1C(=C(C=N1)C(=O)N2CCC(CC2)NC3=CN=NC4=CC=CC=C43)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 8.14 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/18/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "798" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000203 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CC(OC2=C(C1=O)C=CC(=N2)Cl)C3=CC=CC=C3" - } - amount { - moles { - value: 0.000203 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)N)OC.Cl" - } - amount { - moles { - value: 0.000304 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 2.03e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.03e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: " were placed in a microwave vial equipped with a stirring bar. The vial was capped and flushed with argon. DME (2 mL) and Et3N (0.028 mL, 0.20 mmol) were added via a syringe and the mixture was stirred at room temperature for 30 min and then heated to 100C in a microwave apparatus for 1h. The reaction mixture was diluted with dichloromethane and ethyl acetate, fitered and concentrated. The residue was purified by reversed phase HPLC to give 37 mg of the product as a solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(C=C(C=C2)NC3=NC4=C(C=C3)C(=O)N(CC(O4)C5=CC=CC=C5)C)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 40.02 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/19/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "800" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0154 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)NC1=C(C=CC(=C1)N)N(C)CCN(C)C" - } - amount { - moles { - value: 0.00565 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.00514 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C(C)(C)C)C(C)(C)C)C(C)C" - } - amount { - moles { - value: 0.000514 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000257 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Two reactions setup, each 600 mg scale.A 20 mL microwave reactor vial was charged with 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (1.2 g, 5.14 mmol), N-(5-amino-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acetamide (1.414 g, 5.65 mmol), 2-Di-t-butylphosphino-2\',4\',6\'-tri-i-propyl-1,1\'-biphenyl (0.218 g, 0.51 mmol), Pd2dba3 (0.235 g, 0.26 mmol) and CS2CO3 (5.02 g, 15.41 mmol). The vessel was fitted with a septum and gas inlet andnbsp;dioxane (20 mL) was added via syringe. The resulting suspension was stirred for 5 min under nitrogen. The septum and gas inlet was quickly replaced with a microwave vial cap and the mixture was heated at 150 degrees under microwave irradiation for 1h. Two reactions combined and filtered through celite. The filtrate concentrated and mitted for purification (report attached). bReceived a 3 different set up fractions:bFirst set up fractions (EN02868-04-1), LC-MS looks clean but 1H NMR shows acetate peak, couldn\'t getrid of it even longer time on lyohillizer.Second setup fractions combined, lyophllized, purified by ISCO column (0 - 20% MeOH-CH2Cl2 + 0.05% TEA). The obtained compound is a gum. It was triturated with 2 ml of EtOAc, formed a nice solid, it was filtered, washed with Et2O and dried to give 230 mg of white solid. 1H NMR showed slight shift of couple of peaks, it may be due to the protonation. 63 mg of this compound registered and mitted (EN02868-04-2). Third setup fractions showed no required product peaks, was discarded.EN02868-04-1, the remaining material after mission (EN02868-04-2), the filtrate of EN02868-04-2 combined, concentrated, treated with 3 g of MP-carbonate in THF (30 ml). After 1 h stirring, it was filtered washed with THF, concentrated, triturated with CH3CN, filtered and dried to give white color solid (EN02868-04-3). Conclusion: Product isolated" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)NC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)N(C)CCN(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 15.62 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/31/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "801" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00455 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0151 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.00565 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC2=NC=CN2C=C1Br" - } - amount { - moles { - value: 0.00152 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 7.59e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "Cl[Pd+].C1=CC=C(C=C1)C2=CC=CC=C2N" - } - amount { - moles { - value: 8e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "6-bromoimidazo[1,2-a]pyridine (299 mg, 1.52 mmol), dicyclohexyl(2\',6\'-diisopropoxy-[1,1\'-biphenyl]-2-yl)phosphine (35.4 mg, 0.08 mmol), RuPhos 2nd generation (58.9 mg, 0.08 mmol), morpholine (0.159 ml, 1.82 mmol) and cesium carbonate (1483 mg, 4.55 mmol) were dissolved in degassed 1,4-dioxane (15.100 ml).nbsp;Reaction mixture was purged with nitrogen for 2-3 minutes before heating to 90 C and stirred under nitrogen overnight. The reaction was incomplete, therefore additional morpholine (0.159 ml, 1.82 mmol), RuPhos 2nd generation (58.9 mg, 0.08 mmol) and dicyclohexyl(2\',6\'-diisopropoxy-[1,1\'-biphenyl]-2-yl)phosphine (35.4 mg, 0.08 mmol) were added and the reaction mixture washeated for a further 6.5 hours at 105C.nbsp;The reaction was still only ~20% complete therefore additional morpholine (0.318 ml), RuPhos 2nd generation (117.8 mg) and dicyclohexyl(2\',6\'-diisopropoxy-[1,1\'-biphenyl]-2-yl)phosphine (70.8 mg) were added and the reaction heated for a further 24 hours at 105C and then all to RT. The residue partitioned between EtOAc and water, the organic phase was separated and the aq. rextracted with more EtOAc.nbsp;The combined organic extracts were washed with brine, dried over magnesium sulfate filtered and evaporated.nbsp;The crude material was purified by flash silica (12g, grace) chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 4-(imidazo[1,2-a]pyridin-6-yl)morpholine (98 mg, 31.8 %) as a white solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1COCCN1C2=CN3C=CN=C3C=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 31.84 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/20/2014" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "802" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0253 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0165 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)N" - } - amount { - moles { - value: 0.0145 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(N=CC=C1)Br" - } - amount { - moles { - value: 0.0145 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000218 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.00011 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 115.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Ref: EN07957-77nbsp;BIS(DIBENZYLIDENEACETONE)PALLADIUM(Pd2((dba)3) (0.101 g, 0.11 mmol) and 2,2\'-bis(diphenylphosphanyl)-1,1\'-binaphthalene (BINAP) (0.136 g, 0.22 mmol) was was stirred in toluene (16.5 mL) under N2. Then 2-bromo-3-methylpyridine (1.619 mL, 14.53 mmol), cyclohexanamine (1.662 mL, 14.53 mmol) and sodium 2-methylpropan-2-olate (2.430 g, 25.29 mmol) was added to the above reaction mixture under N2.The reaction mixture was degasssed by reapeated 3 times with N2 and vaccum before the reaction mixture was heated at 115 C for 1.5h LCMS indicated no SM left.nbsp;The reaction mixture was cooled to rt, and then diluted with EtOAcnbsp;and H2O. and neutralized by citric acid to PH ca 5. The aqoeus phase was extracted with EtOAc (4 x). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified automated flash chromatography on 100 g column. A gradient from 0 %nbsp;tonbsp;30 % of EtOAc in heptane over 1800 mL was used as mobile phase. product was collected using the wavelength 249 nm.Collect:F10, 0.231 g, light yellowish solid. LCMS ok, NMR okF11-13: 1.398 g, light yellowish solid, LCMS ok, NMR okF14-16, 79 mg, light yellowish solid, LCMS ok, NMR okNMR of F11-131H NMR (500 MHz, DMSO) d 1.09 - 1.2 (m, 1H), 1.2 - 1.37 (m, 4H), 1.61 (d, 1H), 1.71 (d, 2H), 1.90 (d, 2H), 2.01 (s, 3H), 3.86 (ddd, 1H), 5.28 (d, 1H), 6.39 (dd, 1H), 7.09 - 7.22 (m, 1H), 7.83 (dd, 1H).Expected Number of Hs: 18Assigned Hs: 18.[M + H]+ 191.2" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(N=CC=C1)NC2CCCCC2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 61.83 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/01/2016" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "803" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 2.83e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CC(NC1)C2=CC=CC=C2" - } - amount { - moles { - value: 0.000679 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)Br" - } - amount { - moles { - value: 0.000566 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 2.83e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.42e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Caesium carbonate (553 mg, 1.70 mmol) was added to bromobenzene (0.059 mL, 0.57 mmol) and 2-phenylpyrrolidine (100 mg, 0.68 mmol) in 1,4-dioxane (2 mL). The reaction was degassed and Tris(dibenzylideneacetone)?dipalladium(0) (12.96 mg, 0.01 mmol) and dicyclohexyl(2\',6\'-diisopropoxy-[1,1\'-biphenyl]-2-yl)phosphine (RuPhos) (13.21 mg, 0.03 mmol) were added.nbsp;The resulting solution was stirred at 100 C for 16 hours. LCMS showed the formation of the product.The reaction mixture was diluted with EtOAc, and washed with water. The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. NMR confirmed the presence of the product.The crude product was purified by flash silica chromatography, elution gradient 0 to 15% DCM in MeOH. Pure fractions were evaporated to dryness to afford 1,2-diphenylpyrrolidine (114 mg, 90 %) as a brown oil. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CC(N(C1)C2=CC=CC=C2)C3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 90.18 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/19/2015" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "805" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00187 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CN" - } - amount { - moles { - value: 0.000933 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CSC(=N1)Cl" - } - amount { - moles { - value: 0.000933 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 0.00011 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00011 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "phenylmethanamine (100 mg, 0.93 mmol), 2-chloro-4-methylthiazole (125 mg, 0.93 mmol) and sodium 2-methylpropan-2-olate (179 mg, 1.87 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (62.1 mg, 0.11 mmol) and diacetoxypalladium (16.76 mg, 0.07 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. No reaction. abandoned." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CSC(=N1)NCC2=CC=CC=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/18/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "808" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.002 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)N" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=NC=C1C(F)(F)F)Cl" - } - amount { - moles { - value: 0.000999 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 160.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Objective: Test of scope in the coupling of ester stituted aminooxazoleTo an oven-dried microwave vial was added ethyl 2-aminooxazole-5-carboxylate (156 mg, 1.00 mmol), 2-chloro-5-(trifluoromethyl)pyridine (181 mg, 1.00 mmol), cesium carbonate (651 mg, 2.00 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (22.87 mg, 0.02 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (43.4 mg, 0.075 mmol) and the vial was capped and purged with nitrogen. dioxane (4 mL) (degassed) was added and the reaction mixture was heated to 160 C for 1 h under microwave irradiation.LCMS of the crude reaction mixture indicated that the desired product had been formed with very small amounts of side products apparent.DCM (20 mL) was added to the crude reaction mixture together with silica (2 g) and the solvent was removed from the reaction mixture under reduced pressure. The resulting residue was then placed in a dry-load tube prior to chromatography. The crude product was purified by h silica chromatography, elution gradient 0 to 5% methanolic ammonia in DCM. Pure fractions were evaporated to dryness to afford the desired product in 74% yield and 92% purity by LCMS. The product was triturated with MeCN to give a solid which was collected by filtration and dried under vacuum to give ethyl 2-(5-(trifluoromethyl)pyridin-2-ylamino)oxazole-5-carboxylate (185 mg, 61.5 %) as a cream solid. This material was shown to be gt; 95% pure based on proton NMR strength.Conclusion: The desired product was formed in moderate yield and high purity." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1=CN=C(O1)NC2=NC=C(C=C2)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 61.47 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/13/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "809" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000977 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C(=C1)CN)F" - } - amount { - moles { - value: 0.000537 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(2-fluorophenyl)methanamine (67.3 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford N4-(2-fluorobenzyl)-N2-phenylpyridine-2,4-diamine (89 mg, 62.1 %) as a white solid.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)NCC3=CC=CC=C3F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 62.09 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/01/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "810" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000947 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN(C=N1)C2=C(N=C(C=C2)N)OC" - } - amount { - moles { - value: 0.000521 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN=C(S1)C2CN(CC3=C(O2)N=C(C=C3)Cl)C" - } - amount { - moles { - value: 0.000473 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 4.73e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.73e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "8-chloro-4-methyl-2-(5-methylthiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine (140 mg, 0.47 mmol), 6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-amine (106 mg, 0.52 mmol), 2-(DICYCLOHEXYLPHOSPHINO)BIPHENYL (16.59 mg, 0.05 mmol), PALLADIUM(II) ACETATE (10.63 mg, 0.05 mmol) and Cs2CO3 (308 mg, 0.95 mmol) were weighed into a microwave vial, the vial was capped and DME (4 mL) was added. The vial was flushed with argon and heated to 100C in a microwave reactor for 1 h. The reaction mixture was diluted with dichloromethane and filtered and the solvents were evaporated. The residue was purified by column chromatography on Silica using gradient elution with methanol in dichloromethane (0-6 %) to give N-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methyl-2-(5-methylthiazol-2-yl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepin-8-amine (162 mg, 73.8 %)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN=C(S1)C2CN(CC3=C(O2)N=C(C=C3)NC4=NC(=C(C=C4)N5C=C(N=C5)C)OC)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 73.84 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/01/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "812" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.7 [N-arylation with Ar-X] Chloro N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 6.1e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)C(=O)N" - } - amount { - moles { - value: 0.00061 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(N=C1)Cl)Cl" - } - amount { - moles { - value: 0.000671 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 6.1e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.05e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 5 mL vial were added Pd(OAc)2 (6.85 mg, 0.03 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (35.3 mg, 0.06 mmol), N-(3-chloropyridin-2-yl)benzamide (15.30 mg, 10.78 %) and cesium carbonate (477 mg, 1.46 mmol) in dioxane (2 mL) to give a yellow solution. The flask was evacuated and filled with Nitrogen three times. Then, 2,3-dichloropyridine (99 mg, 0.67 mmol) was added. The reaction mixture was stirred overnight at 80C.The reaction mixture was diluted with EtOAc (3 mL) and filtered. The solid was washed with EtOAc and the collected organic layers were evaporated to dryness, to give the crude product.The compound was purified by preparative HPLC on a Kromasil C8 column (10 m 250x20 ID mm) using a gradient of 10-50% acetonitrile in H2OACNFA 9550.2 buffer, over 20 minutes with a flow of 19 mLmin. The compounds were detected by UV at 230nm. (15,3 mg pure product).The reaction was repeated at 80C, RT and 110C on microwave, overnight and a weekend: d remains very low for all conditions except for the reaction at RT (no product at all). " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)C(=O)NC2=C(C=CC=N2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 10.78 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/26/2016" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "815" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00121 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1C(F)(F)F)Cl" - } - amount { - moles { - value: 0.00121 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000101 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 5.04e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 105.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 2.0-5.0 mL microwave vial was charged with (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (200 mg, 1.01 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (62.8 mg, 0.10 mmol), Sodium tert-butoxide (116 mg, 1.21 mmol), 2-Chloro-4-(trifluoromethyl)pyridine (0.156 mL, 1.21 mmol) and a mixture of toluene (2.5 mL) and DMF (.5 mL). The reaction mixture was degassed for 10 minutes with nitrogen, and then Tris(dibenzylideneacetone)dipalladium(0) (46.2 mg, 0.05 mmol) was added. The reaction mixture was stirred at 105C in an oil bath 12h.nbsp;The solution was diluted with EtOAc and washed with saturated NaHCO3 solution, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was loaded on a 24g silica gel column and purified on a Teledyne Isco instrument, eluting with 10% to 40% ethyl acetate in heptane to provide (1S,4S)-tert-butyl 5-(4-(trifluoromethyl)pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (254 mg, 73.3 %) as a solp1H NMR (400MHz ,CHLOROFORM-d) d 8.26 (d, J = 5.5 Hz, 1 H), 6.75 (d, J = 5.1 Hz, 1 H), 6.48 (s, 1 H), 4.99 - 4.83 (m, 1 H), 4.76 - 4.52 (m, 1 H), 3.56 (t, J = 8.4 Hz, 1 H), 3.49 - 3.32 (m, 3 H), 2.04 - 1.91 (m, 2 H), 1.45 (d, J = 18.0 Hz, 9 H); MS mz 344.2 [M+H]+ (ESI)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C3=NC=CC(=C3)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 73.34 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/29/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "816" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000908 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2" - } - amount { - moles { - value: 0.000757 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1C(F)(F)F)Cl" - } - amount { - moles { - value: 0.000908 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 7.57e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 3.78e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 2.0-5.0 mL microwave vial was charged with (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (150 mg, 0.76 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (47.1 mg, 0.08 mmol), Sodium tert-butoxide (87 mg, 0.91 mmol), 2-Chloro-4-(trifluoromethyl)pyridine (0.117 mL, 0.91 mmol) and and mixture of toluene (2.5 mL) and DMF (.5 mL). The reaction mixture was degassed for 10 minutes with nitrogen, and then Tris(dibenzylideneacetone)dipalladium(0) (34.6 mg, 0.04 mmol) was added. The reaction mixture was stirred at 120C under microwave irradiation for 30 minutes. The solution was then irradiated for another 30 min at 120C.nbsp;The solution was diluted with EtOAc and washed with saturated NaHCO3 solution, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was loaded on a 24g silica gel column and purified on a Teledyne Isco instrument, eluting with 10% to 40% ethyl acetate in heptane to provide (1S,4S)-tert-butyl 5-(4-(trifluorpyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (88 mg, 33.9 %) as a solid.MS mz 344.2 [M+H]+ (ESI)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C3=NC=CC(=C3)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 33.88 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/22/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "817" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00271 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CC(CCC1=O)N" - } - amount { - moles { - value: 0.00156 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(N=C1)Br)Cl" - } - amount { - moles { - value: 0.00156 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 2.34e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.18e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 115.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 10 ml MW vial,nbsp;Pd2((dba)3 (10.85 mg, 0.01 mmol), 2,2\'-bis(diphenylphosphanyl)-1,1\'-binaphthalene (BINAP) (14.56 mg, 0.02 mmol),nbsp;sodium 2-methylpropan-2-olate (261 mg, 2.71 mmol), 5-amino-1-methylpiperidin-2-one (200 mg, 1.56 mmol) and 2-bromo-3-chloropyridine (300 mg, 1.56 mmol) mixed in toluene (3 mL) to give a brown suspension. The mixture was degassed with N2 bubbling for 5 min, then the vial was capped and the reaction stirred at 115C in an oil-bath for 1h then to rt for 2h.LC-MS 1h: 15% product.LC-MS on: 19% product.The reaction was cooled to rt and the solvent was evaporated.The residue was purified by automated flash chromatography on a 50g column. A gradient from 20% to 100% of EtOAc in heptane over 20CV was used as mobile phase. The product was collected using the wavelength 307 and 241 nm.Product was not found in any of the fractions, reaction discarded." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CC(CCC1=O)NC2=C(C=CC=N2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/21/2016" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "819" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.012 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1C(CO1)N.Cl" - } - amount { - moles { - value: 0.004 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)[N+](=O)[O-])Br" - } - amount { - moles { - value: 0.004 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 4e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.0004 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2-bromo-1-methyl-4-nitrobenzene (864 mg, 4mmol), oxetan-3-amine hydrochloride (438 mg, 4 mmol), CS2CO3 (3910 mg, 12.00 mmol), palladium(II) acetate (44.9 mg, 0.20 mmol), (R)-(-)-1-[(S)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (224 mg, 0.40 mmol) in 1,4-doxane was degased, inflated with Ar and heated at 90 oC for 5h. LCMS showed some product peak. Silica gel 2g was added to the mixture, evaporated all solvents in GeneVac. The sample was dry loaded for purification by ISCO (HexaneEtOAc=10010-10050)N-(2-methyl-5-nitrophenyl)oxetan-3-amine (240 mg, 28.8 %)1H NMR (400 MHz, CD2Cl2) d: 7.47 (dd, 1H),nbsp;7.14 (d, 1H), 6.98 (s, 1H), 4.99 (t, 2H),nbsp;4.63 (m, 1H), 4.46 (t, 2H),nbsp;4.20(m, 1H), 2.18 (s, 3H).nbsp;LCMS: 209 [M+H]+." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)[N+](=O)[O-])NC2COC2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 28.82 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/14/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "820" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000898 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CN" - } - amount { - moles { - value: 0.000494 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1NC2=NC=CC(=C2)Cl)F" - } - amount { - moles { - value: 0.000449 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Phenylmethanamine (52.9 mg, 0.49 mmol), 4-chloro-N-(4-fluorophenyl)pyridin-2-amine (100 mg, 0.45 mmol) and sodium 2-methylpropan-2-olate (86 mg, 0.90 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (29.9 mg, 0.05 mmol) and diacetoxypalladium (8.07 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford N4-benzyl-N2-(4-fluorophenyl)pyridine-2,4-diamine (98 mg, 74.4 %) as an off-white solid.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=C(C=C3)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 74.38 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/01/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "821" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000905 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=CC(=C1)N2CCN(CC2)CCO)N" - } - amount { - moles { - value: 0.000754 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC2=C(C=NN2C=C1)C3=NC(=NC=C3Cl)Cl" - } - amount { - moles { - value: 0.000754 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 8e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 8e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 140.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "3-(2,5-dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (200 mg, 0.75 mmol), 2-(4-(4-amino-3-methoxyphenyl)piperazin-1-yl)ethanol (190 mg, 0.75 mmol), cesium carbonate (295 mg, 0.91 mmol), diacetoxypalladium (13.55 mg, 0.06 mmol)nbsp;and (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (41.8 mg, 0.08 mmol) were suspended in DME (5 mL) and sealed into a microwave tube. The reaction was degased, purged with nitrogen and heated to 140 C over a period of 30 minutes in the microwave reactor. The reaction mixture was filtratet and the fitrate was evaporated. The crude product was purified by flash chromatography on silica gel eluting with 0 to 5% methanol in dichloromethane. The solvent was evaporated to dryness to afford 2-(4-(4-(5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-ylamino)-3-methoxyphenyl)piperazin-1-yl)ethanol (60mg) 1H NMR 01570-55-03 as anbsp;red gum.The gum was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microilica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford 2-(4-(4-(5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-ylamino)-3-methoxyphenyl)piperazin-1-yl)ethanol (40.0 mg, 11.05 %) as a yellow foam.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=C(C=CC(=C1)N2CCN(CC2)CCO)NC3=NC=C(C(=N3)C4=C5C=CC=CN5N=C4)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 11.05 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/11/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "822" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00824 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1CCOC1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00275 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1C#N)Br" - } - amount { - moles { - value: 0.00275 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.000275 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000275 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To 4-bromobenzonitrile (.5 g, 2.75 mmol)nbsp;dissolved in dry THF (10nbsp;mL) was added tert-butyl piperazine-1-carboxylate (0.512 g, 2.75 mmol), Sodium-t-butoxide (0.792 g, 8.24 mmol) and purged with N2 gas for 10 min followed by the addition of 2-(Dicyclohexylphosphino)-2\',4\',6\'-tri-i-propyl-1,1\'-biphenyl (0.131 g, 0.27 mmol)and Palladium II acetate (0.062 g, 0.27 mmol).nbsp;The contents were further purged with N2 gas for further 10 min and heated at 85 C for 2 h. The reaction mass was concentrated and the reside diluted with water and extracted with ethyl acetate . The combined organic extracts were washed with brine solution and dried over anhydrous sodium sulphate.nbsp;The organic layer was evaporated under reduced pressure to obtain the crude product which was purified by 60-120 mesh silica gel column chromatography usingnbsp;25% Ethyl acetate : Hexanes mixture to obtain tert-butyl 4-(4-cyanophenyl)piperazine-1-carboxylate (0.650 g, 82 %) as a white solid.nbsp;z (ES+), M+ = 288.4" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC=C(C=C2)C#N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 82.34 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/03/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "823" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.001 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCNCC1" - } - amount { - moles { - value: 0.0015 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC(=CC(=C1)[N+](=O)[O-])Br" - } - amount { - moles { - value: 0.0005 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "1-bromo-3-methoxy-5-nitrobenzene (116 mg, 0.5 mmol), 1-methylpiperazine (167 l, 1.50 mmol), Palladium(II) acetatenbsp;(11.23 mg, 0.05 mmol), BINAP (31.1 mg, 0.05 mmol), Cs2CO3 (326 mg, 1.00 mmol) and PhCH3 (10 mL) were added to a 100ml rb flask and heated at 150 C for 1h.LCMS showed rxn done with desired product formed.Rxn was filtered and concentrated. The residue was purified by Gilson (CH3CNWater 0-50% + 0.1%TFA) to get the desired product 1-(3-methoxy-5-nitrophenyl)-4-methylpiperazine (130 mg, 71.2" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CCN(CC1)C2=CC(=CC(=C2)OC)[N+](=O)[O-]" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 71.17 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/10/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "824" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0023 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1C(CO1)N" - } - amount { - moles { - value: 0.00192 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=CC(=C1)I)Br" - } - amount { - moles { - value: 0.00192 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000192 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 4.79e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A solution of 1-bromo-4-iodo-2-methoxybenzene (0.60 g, 1.92 mmol) dissolved in toluene (15 mL) was treated with oxetan-3-amine (0.140 g, 1.92 mmol), SODIUM TERT-BUTOXIDE (0.221 g, 2.30 mmol), XANTPHOS (0.111 g, 0.19 mmol)nbsp;and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.044 g, 0.05 mmol)nbsp;under nitrogen. The resulting mixture was stirred at 80 C in a sealed tube for 2 hours. The reaction mixture was diluted with water (10 mL), and extracted with ethyl acetate (3x 20 mL).nbsp;The organic was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution 0-30% EtOAc in Heptane. Pure fractions were evaporated to dryness to afford N-(4-bromo-3-methoxyphenyl)oxetan-3-amine (0.177 g, 35.8 %) as a beige solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=C(C=CC(=C1)NC2COC2)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 35.77 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/17/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "825" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CCC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000495 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCNC1=CC=CC=C1" - } - amount { - moles { - value: 0.000248 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=NC(=NC=C1Br)I" - } - amount { - moles { - value: 0.000272 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 1.24e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.24e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "5-bromo-2-iodo-4-methoxypyrimidine (0.086 g, 0.27 mmol), diacetoxypalladium (2.78 mg, 0.01 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) - XantPhos (7.16 mg, 0.01 mmol) and sodium 2-methylbutan-2-olate (0.055 g, 0.50 mmol) andnbsp;di((3S,5S,7S)-adamantan-1-yl)(butyl)phosphine (8.88 mg, 0.02 mmol) were added to a micro vial. Then N-ethylaniline (0.031 mL, 0.25 mmol) innbsp;toluene (1.5 mL) was added to the reaction mixture. The vial was sealed and evacuated and flushed with nitrogen and then stirred at 100C on. LCMS showed product formation. The reaction mixture was cooled to rt and then filtered over celite. The crude product was diluted with 25 ml of DCM and then washed with sat. NaHCO3 followed by brine. The organic phase was dried over a phase separator and then concentrated to dryness.bNo LCMS data due to database failure over three months and was only saved locally on LCMS computer and pdf-files seems to be deleted on machine. Not used in further reactions.b" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCN(C1=CC=CC=C1)C2=NC=C(C(=N2)OC)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 70.78 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/17/2014" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "826" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CCC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000297 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCNC1=CC=CC=C1" - } - amount { - moles { - value: 0.000248 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=NC(=NC=C1Br)I" - } - amount { - moles { - value: 0.000272 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CCCCP(C12CC3CC(C1)CC(C3)C2)C45CC6CC(C4)CC(C6)C5" - } - amount { - moles { - value: 2.48e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.24e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 60.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "5-bromo-2-iodo-4-methoxypyrimidine (0.086 g, 0.27 mmol), diacetoxypalladium (2.78 mg, 0.01 mmol), di((3S,5S,7S)-adamantan-1-yl)(butyl)phosphine (8.88 mg, 0.02 mmol) and sodium 2-methylbutan-2-olate (0.033 g, 0.30 mmol) were added to a micro vial. Then N-ethylaniline (0.031 mL, 0.25 mmol) in toluene (1.5 mL) was added to the reaction mixture. The vial was sealed and evacuated and flushed with nitrogen and then stirred at 60C on. LCMS showed product formation. The reaction mixture was cooled to rt and then filtered over celite. The crude product was diluted with 25 ml of DCM and then washed with sat. NaHCO3 followed by brine. The organic phase was dried over a phase separator and then concentrated to dryness.bNo LCMS data due to database failure over three months and was only saved locally on LCMS computer and pdf-files seems to be deleted on machine. Not used in further reactions.b" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCN(C1=CC=CC=C1)C2=NC=C(C(=N2)OC)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 53.74 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/20/2014" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "827" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00489 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCCN1" - } - amount { - moles { - value: 0.0321 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC1=C(C=CC(=C1)Br)Cl" - } - amount { - moles { - value: 0.00391 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000391 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "palladium(II) acetate (0.110 g, 0.49 mmol), BINAP (0.244 g, 0.39 mmol) and CS2CO3 (1.594 g, 4.89 mmol) were added to a mixture of [Reactants] and piperazine (2.76 g, 32.10 mmol) innbsp;toluene (10 mL), The suspension were heated to 110 C for 16 hours, LCMS showed product mass [M+1]:312.0 at retention time RT=1.69 min (polar short purity method). Workup reaction by additional of water (10mL), extracted with EtOAc (3x20 mL), washed with brine, dried with Na2SO4, evaporated off solvent to give a residue, which was purified by isco chromatographer, eluting with 0-10% MeOH in DCM to give as a yellow solid. LCMS confirmed the target compound." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC1=C(C=CC(=C1)N2CCNCC2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 57.11 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/29/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "828" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00436 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.035 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CN=C1)C2=NC(=NC=C2)N" - } - amount { - moles { - value: 0.00291 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=N1)[N+](=O)[O-])Br" - } - amount { - moles { - value: 0.0032 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000581 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000291 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium(II) acetate (65.3 mg, 0.29 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (336 mg, 0.58 mmol) were mixed together in a reaction vessel and evacuated and purged with nitrogen 3 times. Toluene (35 ml) was added and the resulting mixture was heated to to 50C for 45 minutes.To this mixture was added 3-bromo-2-methyl-5-nitropyridine (694 mg, 3.20 mmol), then 4-(pyridin-3-yl)pyrimidin-2-amine (500 mg, 2.91 mmol) and cesium carbonate (1421 mg, 4.36 mmol), andthe resulting mixture heated at 90 Cnbsp;for 16 hours.The reaction mixture was cooled to RT, 50ml EtOAc was added and the mixture was filtered. The filtrate was concentrated, diluted with EtOAc (200 mL), and washed sequentially with water (150 mL) and saturated brine (150 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product, ~2g brown wet solid.The crude product was purified by flash silica chromatography, elution gradient 0 to 4% MeOH in DCM. Pure fractiing at 3% were evaporated to dryness to afford N-(2-methyl-5-nitropyridin-3-yl)-4-(pyridin-3-yl)pyrimidin-2-amine (169 mg, 18.86 %) as a colourless solid. . " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=N1)[N+](=O)[O-])NC2=NC=CC(=N2)C3=CN=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 18.86 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/27/2014" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "829" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0131 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0871 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CN=C1)C2=NC(=NC=C2)N" - } - amount { - moles { - value: 0.00871 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=N1)[N+](=O)[O-])Br" - } - amount { - moles { - value: 0.00828 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00174 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000871 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium(II) acetate (65.3 mg, 0.29 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (336 mg, 0.58 mmol) were mixed together in a reaction vessel and evacuated and purged with nitrogen 3 times. Toluene (35 ml) was added and the resulting mixture was heated to to 50C for 45 minutes, then cooled to r.t.To this mixture at r.t was added 3-bromo-2-methyl-5-nitropyridine (694 mg, 3.20 mmol), then 4-(pyridin-3-yl)pyrimidin-2-amine (500 mg, 2.91 mmol) and cesium carbonate (1421 mg, 4.36 mmol), and the resulting mixture heated at 90 Cnbsp;for 16 hours under N2.The reaction mixture was cooled to RT, 150ml EtOAc was added and the mixture was filtered. The filtrate was concentrated, diluted with EtOAc (500 mL), and washed sequentially with water (300 mL) and saturated brine (150 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product, ~2g brown wet solid.The crude product was purified by flash silica chromatography, elution gradient 0 OH in DCM. Pure fractions eluting at 3% were evaporated to dryness to afford N-(2-methyl-5-nitropyridin-3-yl)-4-(pyridin-3-yl)pyrimidin-2-amine (169 mg, 18.86 %) as a cream solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=N1)[N+](=O)[O-])NC2=NC=CC(=N2)C3=CN=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 21.22 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/27/2014" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "830" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[K+].[K+]" - } - amount { - moles { - value: 0.00422 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0075 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)N" - } - amount { - moles { - value: 0.00187 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=NC(=C1)Cl)Cl" - } - amount { - moles { - value: 0.00154 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 3.05e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 2.67e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 160.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "2,6-dichloropyridine (228 mg, 1.54 mmol) was dissolved in toluene (7.5 ml) and diacetoxypalladium (6 mg, 0.03 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthalene (19 mg, 0.03 mmol),nbsp;aniline (0.170 ml, 1.87 mmol) and potassium carbonate (583 mg, 4.22 mmol) were added added. The reaction mixture was sparged with notrogen for 3-4 minutes before being sealed into a microwave tube and heated to 160 C over ~3 minutes, before holding at that temperature for 30 minutes.nbsp;After cooling to ambient temperature the reaction mixture was diluted to ~40 mL with ethyl acetate and insoluble material removed by filtration. The filtrate was evaporated and purification attempted by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. Product containing fractions were evaporated to dryness to afford 6-chloro-N-phenylpyridin-2-amine (167 mg, 53.0 %) as a waxy pale yellow solid" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC(=CC=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 52.97 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/05/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "831" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00244 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=C2C(=CC(=C1F)F)NC(=O)C=C2Cl" - } - amount { - moles { - value: 0.000812 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C[C@H]1C[C@@H](CCN1C(=O)C2=C(N(N=C2)C)Cl)N" - } - amount { - moles { - value: 0.000812 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 8.12e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 8.12e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 140.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 25ml Biotage microwave vial, 4-chloro-6,7-difluoroquinolin-2(1H)-one (0.175 g, 0.81 mmol), ((2S,4R)-4-amino-2-methylpiperidin-1-yl)(5-chloro-1-methyl-1H-pyrazol-4-yl)methanone (0.208 g, 0.81 mmol) ,racemic-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.051 g, 0.08 mmol), Cesium carbonate (0.793 g, 2.44 mmol), Palladium (II) acetate (0.018 g, 0.08 mmol)nbsp;were taken were taken in toluene (10 mL) to give brown suspension. The reaction mass was jected to microwave irradiation at 140 oC for 1 hour. The reaction ws monitored by LCMS, indicated required product formation.Workup: The reaction mixture was concentrated to dryness and purified by silica gel column chromatography using 0 to 20% Methanol in DCM and then purified by reverse phase chromatography to obtain 4-(((2S,4R)-1-(5-chloro-1-methyl-1H-pyrazole-4-carbonyl)-2-methylpiperidin-4-yl)amino)-6,7-difluoroquinolin-2(1H)-one (0.030 g, 8.48 %) as white solid.The compound was mitted for biological testing." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@H]1C[C@@H](CCN1C(=O)C2=C(N(N=C2)C)Cl)NC3=CC(=O)NC4=CC(=C(C=C43)F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 8.48 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/23/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "832" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00181 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1(COC1)CN" - } - amount { - moles { - value: 0.00125 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(N=C1)Br)Cl" - } - amount { - moles { - value: 0.00104 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 1.56e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 7.9e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 115.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 5 MW vial,nbsp;Pd2((dba)3 (7.23 mg, 7.90 mol), 2,2\'-bis(diphenylphosphanyl)-1,1\'-binaphthalene (BINAP) (9.71 mg, 0.02 mmol),nbsp;sodium 2-methylpropan-2-olate (174 mg, 1.81 mmol), (3-methyloxetan-3-yl)methanamine (126 mg, 1.25 mmol) and 2-bromo-3-chloropyridine (200 mg, 1.04 mmol) mixed in toluene (2 mL) to give a brown suspension. The mixture was degassed with N2 bubbling for 5 min, then the vial was capped and the reaction stirred at 115C in an oil-bath for 1h then to rt for 2h.LC-MS: 61% product, 28% sm left.The reaction was cooled to rt and the solvent was evaporated.The residue was purified by automated flash chromatography on a 25g column. A gradient from 5% to 50% of EtOAc in heptane over 15CV was used as mobile phase. The product was collected using the wavelength 315 nm, relevant fractions pooled and evaporated to give 27 mg suryp.LC-MS: M+1=213 found.1H-NMR: OK, traces of sm and solvents left.1H NMR (400 MHz, CDCl3) d 1.37 (s, 3H)d, 2H), 4.42 (d, 2H), 4.58 (d, 2H), 5.25 (s, 1H), 6.53 (dd, 1H), 7.44 (dd, 1H), 8.00 (dd, 1H).Expected Number of Hs: 13Assigned Hs: 13." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1(COC1)CNC2=C(C=CC=N2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 12.22 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/26/2016" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "834" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00484 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0297 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2" - } - amount { - moles { - value: 0.00303 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CN=C1)Br" - } - amount { - moles { - value: 0.00333 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00012 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 85.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.055 g, 0.06 mmol) and rac-2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.075 g, 0.12 mmol) were mixed together and evacuated and purged with nitrogen 3 times. toluene (29.7 ml) was added and the resulting mixture heated to 90C for 10 minutes then cooled to room temperature.In a second reaction vessel was mixed sodium tert-butoxide (0.465 g, 4.84 mmol), 3-bromopyridine (0.321 ml, 3.33 mmol) and (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.601 g, 3.03 mmol) and toluene (29.7 ml). The mixture was evacuated and purged with nitrogen 3 times. The solution of catalyst was added to the reaction mixture and the resulting mixture was heated at 85 C for 64 hours.The reaction mixture was cooled to RT and filtered through celite and concentrated to give an orange solid.The crude product was purified by flash silica chromatography, elution gradient 30 to 50% EtOAc in heptane. Then 100% MeOH.nbsp;Pure fractions porated to dryness to afford (1S,4S)-tert-butyl 5-(pyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.823 g, 99 %) as a pale yellow dry film. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C3=CN=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 98.65 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/29/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "835" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00014 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.000103 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C(=CC=C1)C)C(=O)NC(C2=CC(=CC=C2)Br)C34CCC(N3C)CC4" - } - amount { - moles { - value: 9.36e-05 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 9.36e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.68e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a suspension of N-((3-bromophenyl)(7-methyl-7-azabicyclo[2.2.1]heptan-1-yl)methyl)-2,6-dimethylbenzamide (0.040 g, 0.09 mmol), MORPHOLINE (8.97 L, 0.10 mmol), BINAP (5.83 mg, 9.36 mol), and sodium tert-butoxide (0.013 g, 0.14 mmol) in toluene (2 mL) was added palladium(II) acetate (1.051 mg, 4.68 mol).nbsp;Nitrogen was passed through the solution for 15 min prior to being heated at 80 C overnight.nbsp;Crude LC shows starting material still present.nbsp;Heated to 110oC for 2 days.nbsp;Reaqction no longer progressing.Reaction mixture was concentrated in vacuo.nbsp;Material was diluted with ethyl acetate, filtered thru celite and concentrated in vacuo.Submitted to purification group (52 mg in 1.6 mL DMSO).nbsp;Received back dried-down fractions.nbsp;Diluted with DCM, combined and concentrated to afford 2,6-dimethyl-N-((7-methyl-7-azabicyclo[2.2.1]heptan-1-yl)(3-morpholinophenyl)methyl)benzamide (7.30 mg, 17.99 %)Submitted 4.5 mgVial # 26243972 545 g" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C(=CC=C1)C)C(=O)NC(C2=CC(=CC=C2)N3CCOCC3)C45CCC(N4C)CC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 17.99 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/13/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "836" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000977 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC=C(C=C1)CN" - } - amount { - moles { - value: 0.000537 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(4-methoxyphenyl)methanamine (73.7 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford N4-(4-methoxybenzyl)-N2-phenylpyridine-2,4-diamine (101 mg, 67.7 %) as a white solid.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=CC=C(C=C1)CNC2=CC(=NC=C2)NC3=CC=CC=C3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 67.69 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/01/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "837" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000498 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0493 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1C2=CC=CC=C2CN1" - } - amount { - moles { - value: 0.00498 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1Br)I" - } - amount { - moles { - value: 0.00498 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000498 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000498 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "palladium(II) acetate (0.112 g, 0.50 mmol) and XANTPHOS (0.288 g, 0.50 mmol) were added to a degassed solution of isoindoline (0.566 ml, 4.98 mmol), 1-bromo-4-iodobenzene (1.41 g, 4.98 mmol) and SODIUM TERT-BUTOXIDE (1.197 g, 12.46 mmol) in toluene (49.3 ml) under nitrogen. The resulting solution was stirred at 100 C for 18 hours. The reaction mixture was allowed to cool to RT and was partitioned between EtOAc and H2O, filtered and the organic layer separated and dried over MgSO4, filtered and evaporated to dryness to give crude product.nbsp;The crude product preabsorbed onto SiO2 and was purified by flash silica (40g, grace) chromatography, elution gradient 0 to 10% DCM in heptane. Pure fractions were evaporated to dryness to afford 2-(4-bromophenyl)isoindoline (0.660 g, 48.3 %) as an orange solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1C2=CC=CC=C2CN1C3=CC=C(C=C3)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 48.3 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/14/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "838" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.6 [N-arylation with Ar-X] Bromo N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0065 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CC(C1)N.Cl" - } - amount { - moles { - value: 0.00338 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(N=C1)Br)Cl" - } - amount { - moles { - value: 0.0026 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 3.9e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.97e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 115.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Pd2(dba)3 (0.018 g, 0.02 mmol), 2,2\'-bis(diphenylphosphanyl)-1,1\'-binaphthalene (BINAP) (0.024 g, 0.04 mmol) and toluene (4 mL) was added to a flask. 2-bromo-3-chloropyridine (0.5 g, 2.60 mmol), 1-methylazetidin-3-amine hydrochloride (0.414 g, 3.38 mmol) and sodium 2-methylpropan-2-olate (0.624 g, 6.50 mmol) was added, the mixture bubbled with N2 for 5 min, then the reaction was heated to 115 C in an oil-bath under nitrogen for 2h, then to rt over night.The reaction was cooled to rt and the solvent was evaporated.The residue was purified by automated flash chromatography on a 100g column. A gradient from 10% to 100% of EtOAc (with 2% TEA) in heptane over 25CV was used as mobile phase. The product was collected using the wavelength 243 and 308 nm.No product found in any fractions.Reaction discarded." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CC(C1)NC2=C(C=CC=N2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/31/2016" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "840" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0193 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1CCOC1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00644 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC(=CC(=C1)Br)F" - } - amount { - moles { - value: 0.00644 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.000644 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000644 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To methyl 3-bromo-5-fluorobenzoate (1.5 g, 6.44 mmol)nbsp;dissolved in dry THF (20nbsp;mL) was added tert-butyl piperazine-1-carboxylate (1.199 g, 6.44 mmol), Sodium-t-butoxide (1.856 g, 19.31 mmol) and purged with N2 gas for 10 min followed by the addition of2-(Dicyclohexylphosphino)-2\',4\',6\'-tri-i-propyl-1,1\'-biphenyl (0.307 g, 0.64 mmol), Palladium II acetate (0.145 g, 0.64 mmol) .nbsp;The contents were further purged with N2 gas for further 10 min and heated at 85 C for overnight. The reaction mass was concentrated and the reside diluted with water and extracted with ethyl acetate . The combined organic extracts were washed with brine solution and dried over anhydrous sodium sulphate.nbsp;The organic layer was evaporated under reduced pressure to obtain the crude product which was purified by 60-120 mesh silica gel column chromatography usingnbsp;25% Ethyl acetate ; hexanes mixture to obtain 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-fluorobenzoic acid (1.500 g, 71.8 % oil. mz (ES-), M- = 323" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC(=CC(=C2)C(=O)O)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 71.85 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/12/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "841" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.7 [N-arylation with Ar-X] Chloro N-arylation" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00243 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.0072 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N[C@@H]1CCC[C@H](C1)C(=O)N" - } - amount { - moles { - value: 0.000971 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1(CC2=C(C=NN2C1)C3=CC(=NC=C3F)Cl)C" - } - amount { - moles { - value: 0.000809 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000162 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=CC=CC=C3.[Pd]" - } - amount { - moles { - value: 8.09e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Tetrakis(triphenylphosphine)palladium(0) (0.094 g, 0.08 mmol) was added to Racemic tert-butyl ((1R,3R)-3-carbamoylcyclohexyl)carbamate (0.235 g, 0.97 mmol),3-(2-chloro-5-fluoropyridin-4-yl)-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (0.215 g, 0.81 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (0.094 g, 0.16 mmol) and cesium carbonate (0.791 g, 2.43 mmol) in 1,4-dioxane (6 mL) and water (1.200 mL).nbsp;The resulting suspension was degassed for 10 minutes under nitrogen and then stirred at 100 C for 48 hours. LCMS is complete, it needs this long. The mixture was cooled, diluted with water (40 ml), and extracted with EtOAc (3 x 20 ml). The combined organics were evaporated to crude material. The crude product was purified by flash silica chromatography, elution gradient 0 to 60% EtOAc in heptane. Pure fractions were evaporated to dryness to afford Racemic tert-butyl ((1R,3R)-3-((4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-5-fluoropyridin-2-yl)carbamoyl)cyclohexarbamate (0.322 g, 84 %) as a white foam. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1(CC2=C(C=NN2C1)C3=CC(=NC=C3F)NC(=O)[C@@H]4CCC[C@H](C4)NC(=O)OC(C)(C)C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 84.39 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/09/2015" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "842" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00127 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0127 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00127 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC1=C(C=C(C=C1)Br)Cl" - } - amount { - moles { - value: 0.00127 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000127 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 6.37e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 50 mL round-bottomed flask, PALLADIUM ACETATE (0.014 g, 0.06 mmol) was treated with BINAP (0.079 g, 0.13 mmol) under nitrogen in degassed Toluene (12.74 ml). The reaction was heated to 80 C and was stirred for 10 min. To the flask was then added tert-butyl piperazine-1-carboxylate (0.237 g, 1.27 mmol), cesium carbonate (0.208 g, 0.64 mmol), potassium carbonate (0.176 g, 1.27 mmol), and 18-CROWN-6 (0.034 g, 0.13 mmol). The reaction was then treated with 4-bromo-2-chloro-1-ethoxybenzene (0.300 g, 1.27 mmol) and was allowed to stir at 80C 5 h.bLCMS High pH:bNo reaction obse" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC1=C(C=C(C=C1)N2CCN(CC2)C(=O)OC(C)(C)C)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/25/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "843" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00242 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0157 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN(C)CCN" - } - amount { - moles { - value: 0.00201 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=CC(=C1)I)Br" - } - amount { - moles { - value: 0.00201 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000201 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 5.03e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A solution of 1-bromo-4-iodo-2-methoxybenzene (0.63 g, 2.01 mmol) dissolved in toluene (15.73 ml) was treated with N1,N1-dimethylethane-1,2-diamine (0.177 g, 2.01 mmol), SODIUM TERT-BUTOXIDE (0.232 g, 2.42 mmol), XANTPHOS (0.116 g, 0.20 mmol)nbsp;and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.046 g, 0.05 mmol)nbsp;under nitrogen. The resulting mixture was stirred at 80 C in a sealed tube for 2 hours. The reaction mixture was diluted with water (200 mL), and extracted with ethyl acetate (200 mL).nbsp;The organic was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution 0-10% methanol in dcm. Pure fractions were evaporated to dryness to afford N1-(4-bromo-3-methoxyphenyl)-N2,N2-dimethylethane-1,2-diamine (0.251 g, 45.6 %) as a brown oil. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN(C)CCNC1=CC(=C(C=C1)Br)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 45.64 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/13/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "844" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0102 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.03 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)N" - } - amount { - moles { - value: 0.00732 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC(=NC(=C1)Cl)Cl" - } - amount { - moles { - value: 0.00732 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000219 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 7.32e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "SODIUM TERT-BUTOXIDE (0.984 g, 10.24 mmol) was added to 2,6-dichloro-N-methylisonicotinamide (1.5 g, 7.32 mmol), ANILINE (0.667 mL, 7.32 mmol), PALLADIUM(II) ACETATE (0.016 g, 0.07 mmol) and XANTPHOS (0.127 g, 0.22 mmol) in toluene (30 mL) under nitrogen. The resulting mixture was stirred at 80 C for 4 hours. The reaction mixture was evaporated to dryness and redissolved in EtOAc (100 mL), and washed sequentially with water (2 x 50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and preadsorbed onto silica. The crude product was purified by flash silica chromatography, elution gradient 30 to 80% EtOAc in heptane. Pure fractions were evaporated to dryness to afford 2-chloro-N-methyl-6-(phenylamino)isonicotinamide (1.012 g, 52.9 %) as a cream solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CNC(=O)C1=CC(=NC(=C1)Cl)NC2=CC=CC=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 52.86 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/23/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "845" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000977 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)F)CN" - } - amount { - moles { - value: 0.000537 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)Cl" - } - amount { - moles { - value: 0.000489 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(3-fluorophenyl)methanamine (67.3 mg, 0.54 mmol), 4-chloro-N-phenylpyridin-2-amine (100 mg, 0.49 mmol) and sodium 2-methylpropan-2-olate (94 mg, 0.98 mmol) were suspended in DMA (2 mL) and sealed into a microwave tube. Nitrogen was bubbled through the reaction mixture for 5 minutes. (R)-(-)-1-[(S)-2-(DICYCLOHEXYLPHOSPHINO)FERROCENYL]ETHYLDI-T-BUTYLPHOSPHINE (32.5 mg, 0.06 mmol) and diacetoxypalladium (8.78 mg, 0.04 mmol) were added to the reaction mixture and nitrogen was bubbled through the reaction mixture for a further 5 minutes. The reaction was heated thermally to 100 C for 30 mins under nitrogen and cooled to RT. The reaction mixture was neutralised with HCl and purified by ion exchange chromatography, using a 20 g SCX column. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Fractions containing product were evaporated to dryness to afford N4-(3-fluorobenzyl)-N2-phenylpyridine-2,4-diamine (84 mg, 58.6 %) as an off-white solid.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)NC2=NC=CC(=C2)NCC3=CC(=CC=C3)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 58.6 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/02/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "846" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000353 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CCN(CC1)C2CCNCC2" - } - amount { - moles { - value: 0.00353 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1Br)I" - } - amount { - moles { - value: 0.00353 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000353 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000177 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.162 g, 0.18 mmol) was added to 1,4\'-bipiperidine (0.595 g, 3.53 mmol), 1-bromo-4-iodobenzene (1.000 g, 3.53 mmol),nbsp;(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.205 g, 0.35 mmol) and sodium 2-methylpropan-2-olate (0.408 g, 4.24 mmol) in toluene (10 mL). The resulting mixture was degassed again and was stirred at 80 C for 18 hours under nitrogen. The reaction mixture was cooled to room temperature and filtered then the filtrate was diluted with EtOAc (50 mL), and washed sequentially with water (50 mL), water (50 mL), and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 1\'-(4-bromophenyl)-1,4\'-bipiperidine (0.736 g, 64.4 %) as a pale brown oil. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CCN(CC1)C2CCN(CC2)C3=CC=C(C=C3)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 64.41 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/13/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "847" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00649 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@@H]1CNCCN1C(=O)OC(C)(C)C" - } - amount { - moles { - value: 0.00433 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CCOC1=C(C=C(C=C1)Br)OC" - } - amount { - moles { - value: 0.00433 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000173 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000216 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium(II) acetate (0.049 g, 0.22 mmol)and (R)-(+)-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.108 g, 0.17 mmol) were added to 4-bromo-1-ethoxy-2-methoxybenzene (1 g, 4.33 mmol),(R)-1-N-Boc-2-methyl piperazine (0.867 g, 4.33 mmol)nbsp;and Sodium tert-butoxide (0.624 g, 6.49 mmol) in anhydrous Toluene (20 mL) under argon. The resulting solution was stirred at reflux for18 hours. The reaction was allowed to cool to room temperature and diluted with dcm (50 ml). This was washed with water (2 x 50 ml), dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The crude product was dissolved in hydrochloric acid solution in methanol (4N, 20 ml) and stirred at room temprature overnight. The solvent was removed under reduced pressure.The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3MeOH and pure fractions were evaporated to dryness to afford (R)-1-(4-ethoxy-3-methoxyphenyl)-3-methylpiperazine (0.550 g, 50.8 %) as a yellow gum. nbsp;nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC1=C(C=C(C=C1)N2CCN[C@@H](C2)C)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 50.77 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/11/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "848" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0045 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.003 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C1=CC=CC=C1Br" - } - amount { - moles { - value: 0.003 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 0.0006 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.0003 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium (II) acetate (67.3 mg, 0.30 mmol) and 2-dicyclohexylphosphino-2\',6\'-di-i-propoxy-1,1\'-biphenyl (280 mg, 0.60 mmol) were dissolved in toluene (7 mL) and purged with nitrogen. The mixture was warmed to 50C for 15 mins.In a separate vessel, were mixed 2-bromo-N,N-dimethylaniline (600 mg, 3.00 mmol), tert-butyl piperazine-1-carboxylate (559 mg, 3.00 mmol) and sodium-t-butoxide (432 mg, 4.50 mmol) in toluene (8 mL). The mixture was degassed and purged with nitrogen. The catalyst solution was added and the resulting mixture heated at 100C overnight. The reaction mixture was filtered through celite, washing with MeOHEtOAc. The filtrate was concentrated and purified by flash silica chromatography, elution gradient 0 to 70% EtOAc in heptane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(2-(dimethylamino)phenyl)piperazine-1-carboxylate (293 mg, 32.0 %) as a colourless gum.Difficult column; three spots with same Rf, but clearly different retention timuct present, but purity low. Carry through and de-BOC. See if can purify at that stage." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC=CC=C2N(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 31.99 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/17/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "849" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00105 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.000701 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC=CC=C1Cl" - } - amount { - moles { - value: 0.000701 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 7.01e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 7.01e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "RuPhos (32.7 mg, 0.07 mmol) and palladium (II) acetate (15.75 mg, 0.07 mmol) were suspended in toluene (1 mL) at ambient temperature. The mixture was degassed and purged with nitrogen several times and warmed to 50C for 20 mins.In a separate vessel were mixed 1-chloro-2-methoxybenzene (100 mg, 0.70 mmol), tert-butyl piperazine-1-carboxylate (131 mg, 0.70 mmol), sodium tertbutoxide (101 mg, 1.05 mmol) and toluene (2 mL). The suspension was degassed and purged with nitrogen then warmed to 50C.The solution of catalyst was added to the reaction vessel and the resulting mixture was degassed and purged with nitrogen. The reaction was heated to 110C (ext T) under nitrogen for 6 hours then allowed to cool to ambient temperature overnight.The reaction mixture was filtered and concentrated and the crude material purified by flash silica chromatography, elution gradient 20 to 60% EtOAc in heptane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(2-methoxyphene-1-carboxylate (23.00 mg, 11.22 %) as a colourless dry film. Yield not good....if this route followed maybe try different catalyst - pepsi? " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC=CC=C2OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 11.22 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/20/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "851" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00238 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.025 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@H]1CNCCN1C" - } - amount { - moles { - value: 0.00106 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC(=NC=C1C2=CC=C(C=C2)C3=NC4=C(C=CC=C4C(=O)N3)CO)Cl" - } - amount { - moles { - value: 0.000529 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 0.000106 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4.CC(C)(C)OC.C1=CC=C([C-]=C1)CCN.Cl[Pd+]" - } - amount { - moles { - value: 0.000106 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of CHLORO(2-DICYCLOHEXYLPHOSPHINO-2\',6\'-DI-I-PROPOXY-1,1\'-BIPHENYL)[2-(2-AMINOETHYLPHENYL)]PALLADIUM(II), METHYL-T-BUTYLETHER ADDUCT (Ru Phos Pd cycle) (43.2 mgs, 0.1eq), sodium tert-butoxide (229 mg, 2.38 mmol),nbsp;2-(4-(6-chloro-4-methylpyridin-3-yl)phenyl)-8-(hydroxymethyl)quinazolin-4(3H)-one (250 mg, 0.53 mmol)nbsp;, (S)-1,2-dimethylpiperazine (198 mg, 1.06 mmol) in dioxane (25ml) was stirred at 105C for 1hr, LCMS only detected a small peak as product. 2 more equivalent of sodium tert-butoxide was added to the mixture and stirred for overnight under N2,nbsp;LCMS indicated major peak as starting material; another batch of Ru phos pd cycle was added to the mixture, and the mixture was stirred at 120C for 1.5hrs. LCMS indicated the completion of reaction. The solvent was removed by concentration, taken into 2ml of DMSO, filtered, the filtrate was purified with reverse phase chromatography column (eluted with 5% to 50% 0.1%TFA in ACN0.1%TFA in water) and repurified with basic co(eluted with 5% to 95% ACN10MM ammonium acetate and 10MM ACN in water), still not pure enough for mission.Repurified again by analytical group, to yield (S)-2-(4-(6-(3,4-dimethylpiperazin-1-yl)-4-methylpyridin-3-yl)phenyl)-8-(hydroxymethyl)quinazolin-4(3H)-one (64.0 mg, 26.5 %) as a light yellow solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@H]1CN(CCN1C)C2=NC=C(C(=C2)C)C3=CC=C(C=C3)C4=NC5=C(C=CC=C5C(=O)N4)CO" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 26.54 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/10/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "852" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00254 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@H]1CNCCN1C" - } - amount { - moles { - value: 0.00106 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC(=NC=C1C2=CC=C(C=C2)C3=NC4=C(C=CC=C4C(=O)N3)CO)Cl" - } - amount { - moles { - value: 0.000423 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 0.000212 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(C)OC1=C(C(=CC=C1)OC(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4.CC(C)(C)OC.C1=CC=C([C-]=C1)CCN.Cl[Pd+]" - } - amount { - moles { - value: 0.000212 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 115.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of CHLORO(2-DICYCLOHEXYLPHOSPHINO-2\',6\'-DI-I-PROPOXY-1,1\'-BIPHENYL)[2-(2-AMINOETHYLPHENYL)]PALLADIUM(II), METHYL-T-BUTYLETHER ADDUCT (Ru Phos Pd cycle) (69.2 mgs, 0.2eq), sodium tert-butoxide (244 mg, 2.54 mmol) ,2-(4-(6-chloro-4-methylpyridin-3-yl)phenyl)-8-(hydroxymethyl)quinazolin-4(3H)-one (200 mg, 0.42 mmol)nbsp;, (S)-1,2-dimethylpiperazine (198 mg, 1.06 mmol) in dioxane (20ml) was stirred at 115C for 1hr,nbsp;LCMS indicated the completion of reaction. The solid was filtered off through a pad of celite, washed with DCM. The solvent of the filtrate was removed by concentration, taken into 2ml of DMSO, purified with reverse phase chromatography column (eluted with 5% to 50% 0.1%TFA in ACN0.1%TFA in water), the fractions were combined and lyphlized, to yield 117mgs of product. LCMS indicated 9% of TFA coupled side product. The solid was taken into 10ml sat. NaHCO3 aq, sonicated, until the disapearance of the side product, filtered, washed with water, dried to yield (S)-2-(4-(6--dimethylpiperazin-1-yl)-4-methylpyridin-3-yl)phenyl)-8-(hydroxymethyl)quinazolin-4(3H)-one (67.0 mg, 34.7 %) as a yellow solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@H]1CN(CCN1C)C2=NC=C(C(=C2)C)C3=CC=C(C=C3)C4=NC5=C(C=CC=C5C(=O)N4)CO" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 34.73 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/14/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "853" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.3 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00176 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.2 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCN1" - } - amount { - moles { - value: 0.0176 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=NC=C1I)Br" - } - amount { - moles { - value: 0.0176 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00176 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000616 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 20.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Pd2(dba)3 (0.564 g, 0.62 mmol) was added to 2-bromo-5-iodopyridine (5.00 g, 17.61 mmol), morpholine (1.541 mL, 17.61 mmol), sodium tert-butoxide (4.23 g, 44.03 mmol) and Xantphos (1.019 g, 1.76 mmol) in toluene (200 mL) at 20C. The resulting solution was stirred at r.t. for 3 days (as the reaction was started on a Friday). Complete.The reaction mixture was diluted with EtOAc (100 mL), and washed sequentially with water (100 mL) and saturated brine (100 mL). The organic layer was dried with MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100%nbsp;(EtOAc:MeOH - 10:1)nbsp;in heptane. Pure fractions were evaporated to dryness LCMS indicated some di-stituted product present. Triturated in heptane:EtOAc, filtered and dried to afford 4-(6-bromopyridin-3-yl)morpholine (2.400 g, 56.1 %) as a beige solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1COCCN1C2=CN=C(C=C2)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 56.05 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/08/2015" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "855" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000415 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.006 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1N)F" - } - amount { - moles { - value: 0.000831 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=NC(=C(N2CCN1C(=O)CNC(=O)OC(C)(C)C)Br)C3=CC=C(C=C3)F)C" - } - amount { - moles { - value: 0.000415 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 4.15e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.08e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a microwave vial, cesium carbonate (135 mg, 0.42 mmol), 4-fluoroaniline (92 mg, 0.83 mmol), tris(dibenzylideneacetone)dipalladium(0) (19.02 mg, 0.02 mmol), Xantphos (24.04 mg, 0.04 mmol) and dry 1,4-dioxane (6 mL) were stirred for 5 minutes at room temperature. tert-butyl (2-(3-bromo-2-(4-fluorophenyl)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethyl)carbamate (200 mg, 0.42 mmol) was added to the reaction mixture after which the reaction mixture was degassed for 15 mins and then stirred at 120 C under N2 for 20 h. The reaction was monitored by LCMS. The profile showed formation of title product.nbsp;The reaction mixture was filtered through a pad opf celite and the filtrate was concentrated to give a residue. The residue was purified by silica gel followed by reverse phase HPLC to givenbsp;tert-butyl (2-(2-(4-fluorophenyl)-3-((4-fluorophenyl)amino)-8,8-dimethyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)-2-oxoethyl)carbamate (177 mg, 83 %) as a white solipConclusion:The product was used for the next step." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1(C2=NC(=C(N2CCN1C(=O)CNC(=O)OC(C)(C)C)NC3=CC=C(C=C3)F)C4=CC=C(C=C4)F)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 83.27 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/07/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "857" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000541 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC=CC=C1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC1=CC=CC(=C1)N" - } - amount { - moles { - value: 0.000447 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)Br)C(F)(F)F" - } - amount { - moles { - value: 0.000358 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 6.91e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.56e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 50.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "PdOAc2 (8 mg, 0.04 mmol) andnbsp;(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (40 mg, 0.07 mmol) were added to a dried vial. The vial was caped with a septa-cap and inerted with nitrogen. Degassed anisole (2 mL)was added and the catalyst mixture was heated to 50C for 30 minutes, then cooled down to rt.A dry 2ml microwave vial was charged with sodium 2-methylpropan-2-olate (52 mg, 0.54 mmol). It was caped and inerted with nitrogen.nbsp;A degassed mixture of 1-bromo-3-(trifluoromethyl)benzene (50 L, 0.36 mmol) and 3-methoxyaniline (50 L, 0.45 mmol) innbsp;anisole (2 mL) wad addednbsp;at rt. The catalyst solution was added to the reaction mixture. The nitrogen inlet was removed and the vial was inserted into an alumina block at 100C. The reaction was stirred over night.After 19h, the reaction was cooled down and filtered through celite. The filtrate was concentrated. Large amounts of anisole was present. No product was detected by LCMS.The sampl" - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=CC=CC(=C1)NC2=CC=CC(=C2)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/14/2013" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "859" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00575 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.006 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2" - } - amount { - moles { - value: 0.00144 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)Br)C(F)(F)F" - } - amount { - moles { - value: 0.00216 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000345 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000144 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 50 ml round bottom equipped with stir bar was charged with binap (0.219 g, 0.34 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.132 g, 0.14 mmol)nbsp;dissolved in dioxane (6 mL).nbsp;This was degassed and purged with nitrogen and stirred at RT for 10 mins.nbsp;1-bromo-3-(trifluoromethyl)benzene (0.301 mL, 2.16 mmol) followed by tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.3 g, 1.44 mmol) andnbsp;SODIUM TERT-BUTOXIDE (0.570 g, 5.75 mmol) were added, and the reaction was stirred at 180 C for 5 min (see notes).nbsp;The solution was filtered trough celite, diluted with EtOAc and washed with saturated NaHCO3 solution. The aqueous phase was extracted with EtOAc (3X20mL), combined, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude material was loaded on a Snap KP-SIL 25g column and purified on a Biotage SP4 instrument, eluting with 10% to 35% ethyl acetate in heptane to provide tert-butyl 5-(3-(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]hee-2-carboxylate (0.489 g, 99 %) as an oil. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CC2CC1CN2C3=CC=CC(=C3)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 99.36 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/04/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "860" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00383 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2" - } - amount { - moles { - value: 0.000958 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)Br)C(F)(F)F" - } - amount { - moles { - value: 0.00144 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00023 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 9.58e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 50 ml round bottom equipped with stir bar was charged with binap (0.146 g, 0.23 mmol) and TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0) (0.088 g, 0.10 mmol)nbsp;dissolved in dioxane (5 mL).nbsp;This was degassed and purged with nitrogen and stirred at RT for 10 mins.nbsp;1-bromo-3-(trifluoromethyl)benzene (0.323 g, 1.44 mmol) followed by tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.2 g, 0.96 mmol) andnbsp;SODIUM TERT-BUTOXIDE (0.380 g, 3.83 mmol) were added, and the reaction was stirred at 80 C for 2 hrs. The solution was diluted with EtOAc and washed with saturated NaHCO3 solution. The aqueous phase was extracted with EtOAc (3X20mL), combined, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude material was loaded on a Snap KP-SIL 25g column and purified on a Biotage SP4 instrument, eluting with 10% to 35% ethyl acetate in heptane to provide tert-butyl 5-(3-(trifluoromethyl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.305 g, 93 %) as an op" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CC2CC1CN2C3=CC=CC(=C3)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 92.96 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/18/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "862" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00405 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.15 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC(=NC=C1)N" - } - amount { - moles { - value: 0.0338 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.0338 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00405 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.0027 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium(II) acetate (0.607 g, 2.70 mmol) was added to 2,4-dichloropyridine (5.00 g, 33.79 mmol), 4-methylpyrimidin-2-amine (3.69 g, 33.79 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (2.346 g, 4.05 mmol) and Cesium carbonate (22.02 g, 67.57 mmol) in dioxane (150 mL) at 20C under nitrogen. The resulting suspension was stirred at 100 C for 90 minutes. Complete reaction by LCMS, cooled to room temperature. The reaction mixture was then filtered, washed with DCM and filtrate concentrated iin vacuoi to give a yellow gum. This was then dissolved in DCM (200 mL), washed with water (200 mL) and brine (200 mL). The organic layer was passed through phase separating cartridge and concentrated under reduced pressure. The crude product was suspended in DCM, isolubles filtered off and dried to give EN01580-50-1, N-(4-chloropyridin-2-yl)-4-methylpyrimidin-2-amine (2.859 g, 38.3 %), as a yellow solid. The fltrate was then purified by flash silica chromatography, elution gradient 0 to 5% MeOH io separation acheived so all fractions containing product concentrated iin vacuoi. The residue was suspended in acetonitilewater, insolubles filtered off and dried to give EN01580-50-2, N-(4-chloropyridin-2-yl)-4-methylpyrimidin-2-amine (0.934 g, 12.5 %), as a yellow solid. The filtrate was then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford EN01580-50-3, N-(4-chloropyridin-2-yl)-4-methylpyrimidin-2-amine (0.511 g, 6.85 %), as a white solid. nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=NC(=NC=C1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 57.73 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/05/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "863" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[K+]" - } - amount { - moles { - value: 0.000275 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1CCOC1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@@H]1CN(CCN1)C(=O)OC(C)(C)C" - } - amount { - moles { - value: 0.000125 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC=C1O)Br" - } - amount { - moles { - value: 0.00025 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" - } - amount { - moles { - value: 1.25e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C.[Pd]" - } - amount { - moles { - value: 1.25e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of (R)-tert-butyl 3-methylpiperazine-1-carboxylate (0.025 g, 0.12 mmol), 4-bromophenol (0.043 g, 0.25 mmol), bis(tri-t-butylphosphine)palladium(0) (6.38 mg, 0.01 mmol) and [Reactants] in THF (2 mL) was flushed with nitrogen and sealed into a microwave tube.nbsp;The reaction was heated to 100 C for 20 minutes in the microwave reactor and cooled to RT.nbsp;No trace of desired product by LCMS.The reaction was not progressed further.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@@H]1CN(CCN1C2=CC=C(C=C2)O)C(=O)OC(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/26/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "864" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0028 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.017 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC1=NC(=NC=C1Br)N" - } - amount { - moles { - value: 0.00251 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C=C1C(F)(F)F)I)F" - } - amount { - moles { - value: 0.00338 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=COC(=C1)P(C2=CC=CO2)C3=CC=CO3" - } - amount { - moles { - value: 0.000543 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000245 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a microwave vial was added a mixture of 5-bromo-4-methoxypyrimidin-2-amine (0.513 g, 2.51 mmol), diacetoxypalladium (0.055 g, 0.245 mmol), tri(furan-2-yl)phosphine (0.126 g, 0.54 mmol), 1-fluoro-2-iodo-4-(trifluoromethyl)benzene (0.98 g, 3.38 mmol) and toluene (17 mL) under inert atmosphere.The reaction mixture was sealed and heated at 90 C under 15h.The LCMS indicated no reaction ???The sample discarded." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=NC(=NC=C1Br)NC2=C(C=CC(=C2)C(F)(F)F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/20/2014" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "866" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.3 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00223 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCNCC1" - } - amount { - moles { - value: 0.00112 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=CC(=C1)Cl)I" - } - amount { - moles { - value: 0.00112 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000559 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000112 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium II acetate (25.09 mg, 0.11 mmol) was added to 4-chloro-1-iodo-2-methoxybenzene (300 mg, 1.12 mmol), 1-methylpiperazine (0.124 ml, 1.12 mmol), sodium 2-methylpropan-2-olate (215 mg, 2.23 mmol) and 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (323 mg, 0.56 mmol) in toluene (4 ml) at room temperture under nitrogen. The resulting mixture was stirred at 100oC overnight. The reaction mixture was filtered through celite and then concentrated under reduced pressure. The crude product was then taken up in DCM and washed with water. The crude product was purified by chromatography in DCM:MeOH 0--gt;10% to afford 1-(4-chloro-2-methoxyphenyl)-4-methylpiperazine (171 mg, 63.6 %) as yellow oil. This was carried through to the next reaction immediately as it is a controlled stance." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CCN(CC1)C2=C(C=C(C=C2)Cl)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 63.57 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/10/2016" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "869" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 9.54e-06 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)O" - } - amount { - volume { - value: 0.0017 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C2C(=C1)C=C(C=N2)N" - } - amount { - moles { - value: 0.000668 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CN(CC2=C1C(=NC=C2)Cl)S(=O)(=O)C3=CC=CO3" - } - amount { - moles { - value: 0.000191 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 9.54e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 4.58e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "The yellow residue containing 5-chloro-2-(furan-2-ylsulfonyl)-1,2,3,4-tetrahydro-2,6-naphthyridine (0.057 g, 0.19 mmol) and quinolin-3-amine (0.096 g, 0.67 mmol) from 02910-38 was dissolved in toluene (1 mL) and tert-butanol (0.170 mL).nbsp;The resulting yellow solution was degassed (vacuum) and then tris(dibenzylideneacetone)dipalladium(0) (4.19 mg, 4.58 mol), Xantphos (5.52 mg, 9.54 mol), and sodium tert-butoxide (0.026 g, 0.27 mmol) were added.nbsp;Another 2 mL of toluene and 0.340 mL of tert-butanol were also added.nbsp;The resulting mixture was jected to microwave conditions for 30 min (300W, 110C) and then cooled.nbsp;The biphasic red-brownbrown-black mixture was poured into saturated aqueous sodium chloride and extracted with ethyl acetate.nbsp;The combined organic layers were dried over sodium sulfate, filtered, and concentrated.nbsp;The resulting residue was purified by falsh column chromatography (SiO2, 0-100% ethyl acetate in hexanes) and then preparative Lhanol in water containing ammonium carbonate, pH 10).nbsp;The resulting white solid was repurified a third time via preparative HPLC (C18, acetonitrile in water containing ammonium carbonate, pH 10)nbsp;to afford 6-(furan-2-ylsulfonyl)-N-(quinolin-3-yl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine (7.60 mg, 9.80 %) of 95% purity as a white solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CN(CC2=C1C(=NC=C2)NC3=CC4=CC=CC=C4N=C3)S(=O)(=O)C5=CC=CO5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 9.8 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/07/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "870" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.007 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "COCCOC" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=NC(=C1)N" - } - amount { - moles { - value: 0.006 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CN=C1)Br" - } - amount { - moles { - value: 0.005 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C1CCCC1P(C2CCCCC2)C3CCCCC3)P(C(C)(C)C)C(C)(C)C.C1CCCC1.[Fe]" - } - amount { - moles { - value: 4.86e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.86e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Stock solution: 0.01 mmol Pd and ligand were dissolved in 2 mL DME.3-bromopyridine (0.482 mL, 5.00 mmol) was dissolved in DME (10 mL). To the solution was added the stock solution, and sodium tert-butoxide (0.673 g, 7.00 mmol). To the mixture was added a solution of pyridin-2-amine (0.565 g, 6.00 mmol) in DME (10 mL). The mixture was heated at 90 C overnight. The mixture was filtered. The filtrate was concentrated, and the compound was purified by preparative HPLC on a XBridge C18 column (10 m 250x50 ID mm) using a gradient of 0-50% acetonitrile in H2OACNNH3 9550.2 buffer over 15 minutes with a flow of 100 mLmin. The compounds were detected by UV at 254nm. To the fractions (ca. 60mL) were added 5 mL of HOAc. The product was freezing-dried to give the product N-(pyridin-3-yl)pyridin-2-amine (0.190 g, 22.20" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=NC(=C1)NC2=CN=CC=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 22.2 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/30/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "871" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000395 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C1=CC2=C(C=C1)C=CN2" - } - amount { - moles { - value: 0.00036 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.00036 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.8e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In microwave tube, added 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (84mg), N-(1H-indol-6-yl)-N-methylacetamide (67 mg), Pd2(dba)3 (16 mg), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (20mg) cesium carbonate(129 mg) in anhydrous DMA (0.5mL). under microwave 150C for 30 min.the mixture was filtered. washed with MeOH. combinde organic solvent, dried to dryness. The residue solid was washed with MeOH to give about 22mg offwhite solid (product." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)N(C)C1=CC2=C(C=C1)C=CN2C3=NC4=C(C=NN4C(=C3)NC5CC5)C#N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 15.88 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/18/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "876" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000414 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.000377 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CS(=O)(=O)CC1=C(C=CC(=C1)N)Cl" - } - amount { - moles { - value: 0.000377 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.77e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.88e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 40mL vialnbsp;(t=g) was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (88 mg, 0.38 mmol), [Reactants], and cesium carbonate (135 mg, 0.41 mmol) in DMA (0.5 mL) ([VOLUME]),Pd2(dba)3 (17.24 mg, 0.02 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (21.79 mg, 0.04 mmol) were added.to give a brown suspension. The vial was filled with N2,150C microwave for 30 min. LCMS showed completion.added DMF(3 mL), filtered through celite. concentrated. The residue was washed with EtOAc and water, MeoH to give about 55mg light brown solid" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CS(=O)(=O)CC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 35.03 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/30/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "877" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00762 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CCNC1" - } - amount { - moles { - value: 0.00305 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C=C1F)C=O)Br" - } - amount { - moles { - value: 0.00305 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000152 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000152 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 95.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Tonbsp;a mixture of pyrrolidine (328 mg, 3.05 mmol), 2-bromo-4-fluorobenzaldehyde (619 mg, 3.05nbsp;mmol) in toluene (10 ml) was added Cs2CO3 (2.48g, 7.62 mmol), BINAP (95 mg ) and palladium(II) acetate (35 mg) was added. The mixture was purged with Ar for 5 min, then heated at 95 oC for 4 hrs.nbsp;After cooled to RT, EtOAc (30 mL) was added.nbsp;The organic layer was washed with water (3 x 30 mL), brine (30 mL), dried over MgSO4, filetred and concentrated. The residue was purified via combiflush (0 - 20% EtOAcHexane; 40 g column) to give the desired product as a clear reddish liquid. LCMS and H-NMR look good. 290 mgConclusion: reaction progressed to give desired productnbsp;in 49% yield." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CCN(C1)C2=C(C=C(C=C2)F)C=O" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/14/2014" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "878" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0188 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCC(=O)N1" - } - amount { - moles { - value: 0.00989 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=NC(=C1)Br)Br" - } - amount { - moles { - value: 0.0148 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00198 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000989 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "biSeptember 10 2015ibmorpholin-3-one (1g, 9.89 mmol), 2,6-dibromopyridine (3.51 g, 14.84 mmol), PdOAc2 (0.222 g, 0.99 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.145 g, 1.98 mmol) and CS2CO3 (6.12 g, 18.79 mmol) in 1,4-dioxane (20 mL) were heated at 80 C for 12 hours.biSeptember 11 2015ibLCMS showed no precursor and 37% of the desired mass MH+ 257259 @ 0.86 min along with lots of unknowns on a 2-min basic run.The reaction was cooled to RT, and filtered off the solid (Cs2CO3).nbsp;The filter was concentrated, re-dissolved in EtOAc, washed with waster, dried through MgSO4, and evaporated to give an orange gum.biSeptember 14 2015ibThe orange gum was added to a Biotage column and was eluted with 10-100%EtOAc in Heptane.nbsp;Collected fractions.The column was stuck as 37% EtOAc in Heptane.nbsp;A lot of CH2Cl2 was pushed through the column manually, and then continued the elution with 0-100% Etin DCM. Collected fractions.The product fractions were identified, combined based on LCMS and TLC, and evaporated to give a white solid as the desired product (EN07946-27-001).nbsp;Based on LCMS, it was 98% pure; based on NMR in DMSO, it was gt; 95%pure; uhowever, based on NMR in CDCl3, there were ~30% impurity in the aromatic proton region.unbsp;The product was used for next step without further purification." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1COCC(=O)N1C2=NC(=CC=C2)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 68.82 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/10/2015" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "879" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000377 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)NC1=CC=CC(=C1)N" - } - amount { - moles { - value: 0.000342 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.000342 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.42e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.71e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "in microwave tube was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (80 mg, 0.34 mmol), N-(3-aminophenyl)acetamide (51.4 mg, 0.34 mmol), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (19.81 mg, 0.03 mmol) in DMA (0.5 mL).Pd2(dba)3 (15.68 mg, 0.02 mmol) and cesium carbonate (123 mg, 0.38 mmol) were added.degassed, filled with N2.capped. then microwave 150C for 30 min.added 2 mL of MeOH, filtered through celite. concentrated. The residue was purified by ISCO (Hex to Hex:EtOAc=1:4 to 1:1 to EtOAc), collected prod fractions. concentrated to brown semi-solid" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)NC1=CC=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 67.26 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/25/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "880" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000377 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CC(C1)N2CCN(CC2)C(=O)C3CC4(C3)CCNCC4" - } - amount { - moles { - value: 0.000343 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)Br" - } - amount { - moles { - value: 0.00036 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 6.86e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.43e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "cesium carbonate (123 mg, 0.38 mmol) was added to a solution of (4-cyclobutylpiperazin-1-yl)(7-azaspiro[3.5]nonan-2-yl)methanone (100 mg, 0.34 mmol), PdOAc2 (7.70 mg, 0.03 mmol), BINAP (42.7 mg, 0.07 mmol) and bromobenzene (56.6 mg, 0.36 mmol)nbsp;in toluene (5 mL). The reaction mixture was heated to 110C for 18hrs. The room temperature cooled down mixture was filtered over celite. The solvent was concentrated. The product was purified by preparative HPLC using a low pH shallow gradient method (Mobile phase: 20-40% B; A: H2O with 0.05% TFA , B: CH3CN,nbsp;25 min. run) on Luna 15 m, C8 (2), 21.2x250 mm Phenomenex reverse phase column to provide (4-cyclobutylpiperazin-1-yl)(7-phenyl-7-azaspiro[3.5]nonan-2-yl)methanone (59.0 mg, 46.8 %) as white solid.1H NMR (400 MHz, CHLOROFORM-idi) d ppm 1.60 - 1.75 (m, 4 H) 1.75 - 1.81 (m, 2 H) 1.81 - 1.95 (m, 2 H) 1.96 - 2.10 (m, 4 H) 2.10 - 2.20 (m, 2 H) 2.21 - 2.35 (m, 4 H) 2.71 (dq, iJi=8.01, 7.75 Hz, 1 H) 3.00 - 3.11 (m,) 3.11 - 3.26 (m, 3 H) 3.31 - 3.42 (m, 2 H) 3.56 - 3.70 (m, 2 H) 6.82 (t, iJi=7.23 Hz, 1 H) 6.93 (d, iJi=7.81 Hz, 2 H) 7.18 - 7.29 (m, 2 H)HRMS imzi calcd for C23H33N3O 368.26964 [M+H]+, found 368.26981.nbsp;MS imzi 368.3 [M+H]+ (ES+)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CC(C1)N2CCN(CC2)C(=O)C3CC4(C3)CCN(CC4)C5=CC=CC=C5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 46.78 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/09/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "881" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000856 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.001 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)NC1=C(C=CC(=C1)N)N2CC[C@@H](C2)N(C)C" - } - amount { - moles { - value: 0.000471 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.000428 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 4.28e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.14e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "in microwave tube was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (100mg, 0.43 mmol), [Reactants], and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (24.76 mg, 0.04 mmol) in DMA (1.0 mL).Pd2(dba)3 (19.60 mg, 0.02 mmol) and cesium carbonate (279 mg, 0.86 mmol) were added.degassed, filled with N2.capped. then microwave 150C for 30 min.filtered, then concentrated. The crude material was purified by ISC(Hex to Hex:EtOAc=1;1 to EtOAc to EtOAc:MeOH=10:1 to EtOAc:MeOH:Et3N=10:1:0.1)) to give no very pure product.collect the product fraction, concentrated to dryness. no pure enough, tried to form solid. it failedsent to ananlytic group for purification.came back. it was OK 1TFA salt. NMR LCMS are OK" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)NC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)N5CC[C@@H](C5)N(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 36.66 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "01/29/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "882" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000476 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N" - } - amount { - moles { - value: 0.000381 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC(=CC(=N1)Cl)CO" - } - amount { - moles { - value: 0.000317 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 2.54e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 3.17e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 2.0-5.0 mL microwave vial was charged with XANTPHOS (14.66 mg, 0.03 mmol), Pd2(dba)3 (29.1 mg, 0.03 mmol), CESIUM CARBONATE (155 mg, 0.48 mmol),(2-chloro-6-methylpyridin-4-yl)methanol (50 mg, 0.32 mmol), tert-butyl carbamate (44.6 mg, 0.38 mmol)nbsp;and dioxane (3 mL). The reaction mixture was degassed for 2 minutes with nitrogen, and then the reaction mixture was stirred at 80C under microwave irradiation for 30 min. Water (5 mL) was added and the mixture was washed using EtOAc (3 x 10 mL). The organic layers were combined, dried using MgSO4, filtered and concentrated. The crude material was loaded on a 12g silica gel column and purified on a Teledyne Isco instrument, eluting with 0% to 20% EtOAc in DCM. The product that seems to be the compound was collected. Unfrtunately NMR showed that this compound is dba. The compound was not isolated." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CC(=CC(=N1)NC(=O)OC(C)(C)C)CO" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/26/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "884" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000899 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=C(C=C(C=C1)N)NC(=O)C" - } - amount { - moles { - value: 0.0003 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.0003 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 140.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 5 mL microwave reactor vial was charged with 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (0.070 g, 0.30 mmol), N-(5-amino-2-isopropylphenyl)acetamide (0.058 g, 0.30 mmol), Pd2(dba)3 (0.014 g, 0.01 mmol), Pd2(dba)3 (0.014 g, 0.01 mmol) and cesium carbonate (0.293 g, 0.90 mmol), the vessel was sealed with a microwave cap, and degassed and refilled with argon for 3 times. DMA (0.5 mL)was added via syringe. The resulting suspension heated at 140C for 30mins in microwave.nbsp;LCMS analysis showed product mass and byproduct.The reaction mixture was concentrated. 10% MeOH in DCM was added to the resulting residue to generate a brown suspension. This brown suspension was filtered to remove inorganic impurity. The filtrate was concentrated to give a brown crude product. This material was loaded on isco column (12g, DCM to 10% MeCNin DCM to 25% MeCN in DCM to 50%MeCN to 100% MeCM) and purified. Only 3mg of product was isolated.The ISCO column was saved. Some solis presented on the top of the column. This solid was recovered, washed with water and dried under high vacuum at 60C to give N-(5-(3-cyano-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)-2-isopropylphenyl)acetamide (0.012 g, 10.29 %) as an offwhite solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)C1=C(C=C(C=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)NC(=O)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 10.29 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/04/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "885" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 7.45e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CSC(=N1)N" - } - amount { - moles { - value: 0.000745 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CN(C(=O)OC1)C2=NC(=CC=C2)Br" - } - amount { - moles { - value: 0.000745 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 7.45e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" - } - amount { - moles { - value: 3.72e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "biSeptember 21 2015ib4-methylthiazol-2-amine (85 mg, 0.74 mmol), 3-(6-bromopyridin-2-yl)-1,3-oxazinan-2-one (191 mg, 0.74 mmol), 3-(6-bromopyridin-2-yl)-1,3-oxazinan-2-one (191 mg, 0.74 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (43.1 mg, 0.07 mmol) and cesium carbonate (291 mg, 0.89 mmol) in toluene (5 mL) were microwaved at 120 C under N2 for one hour.LCMS showed no precursors and 51% of the desired mass MH+291 @ 0.86 min on a 2-min basic run.The reaction mixture was diluted with EtOAc, washed with water, filtered, and evaporated to give a brown solid as the crude product.nbsp;The crude product was added to a Biotage column, and was eluted with 15-100%EtOAc in Heptane.nbsp;Collected fractions.biSeptember 22 2015ibBased on TLC and LCMS, the product fractions were combined, and evpoarated to give an yellow-brown solid (94 mg).nbsp;Based on LCMS, it was only 89% pure.Based on LCMS, it was 96% pure; based on NMt was gt; 95% pure." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CSC(=N1)NC2=NC(=CC=C2)N3CCCOC3=O" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 43.95 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/17/2015" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "886" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00315 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CSC(=N1)N" - } - amount { - moles { - value: 0.00263 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CN(C(=O)OC1)C2=NC(=CC=C2)Br" - } - amount { - moles { - value: 0.00263 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000263 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" - } - amount { - moles { - value: 0.000131 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 115.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "biSeptember 28 2015ib4-methylthiazol-2-amine (300 mg, 2.63 mmol), 3-(6-bromopyridin-2-yl)-1,3-oxazinan-2-one (676 mg, 2.63 mmol), 3-(6-bromopyridin-2-yl)-1,3-oxazinan-2-one (676 mg, 2.63 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (152 mg, 0.26 mmol) and cesium carbonate (1027 mg, 3.15 mmol) in toluene (13 mL)DMF (2.00 mL) were microwaved at 115 C under N2 for one hour.(Note: Based on the observation in EN07946-41, iDMF was added to improve the heating due to the low thremal absorbance of toluene.)iOne hour later, LCMS showed 13% of the precursor MH+257259 @ 0.84 min and 36% of the desired mass MH+291 @ 0.86 min along with some unknowns on a 2-min basic run.The reaction seemed not complete.nbsp;The reaction was microwaved at 115 C for another 45 min.One hour and 45 min later, LCMS showed 7% of the precursor MH+257259 @ 0.84 min and 37% of the desired mass MH+291 @ 0.86 min along with some unknowns on a 2-min basic r;The reaction seemed stuck, and was cooled to RT.biSeptember 29 2015ibThe reaction mixture was diluted with EtOAc, washed with water, filtered, and evaporated to give a brown solid as the crude product.nbsp;The crude product was added to a Biotage column, and was eluted with 15-100%EtOAc in Heptane.nbsp;Collected fractions.biSeptember 30 2015ibBased on TLC and LCMS, the product fractions were combined, and evpoarated to give an yellow-brown solid, which was vacuumed overnight at 40 CbiOCtober 1 2015ibBased on LCMS, it was 100% pure; based on NMR, it was 90~95% pure, and contained 0.1eq of DMF." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CSC(=N1)NC2=NC(=CC=C2)N3CCCOC3=O" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 57.15 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/28/2015" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "889" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0275 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.157 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCCN1" - } - amount { - moles { - value: 0.0495 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC(=C(C=C1)NC2=C(N=NC3=C2C=CC(=C3)Br)C#N)F" - } - amount { - moles { - value: 0.011 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.00165 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.00088 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 1L flask was charged with 7-bromo-4-(2-fluoro-4-methylphenylamino)cinnoline-3-carbonitrile (3.93 g, 11.00 mmol), Piperazine (3.88 ml, 49.51 mmol), Tris(dibenzylideneacetone)dipalladium (0) (0.806 g, 0.88 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (0.787 g, 1.65 mmol) and Sodium tert-butoxide (3.37 ml, 27.51 mmol).nbsp;The atmosphere was evacuated and replaced with N2(g) and DMA (157 ml) was added to the mixture.nbsp;The reaction mixture was stirred at 100 C for 1h.nbsp;The reaction mixture was cooled to rt, adsorbed on silica gel and flash chromatography using DCM to DCMMeOHNH4OH (10:1:0.1) provided the desired adduct as a light brown solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CC(=C(C=C1)NC2=C(N=NC3=C2C=CC(=C3)N4CCNCC4)C#N)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 50.66 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/21/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "890" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00448 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.0256 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCCN1" - } - amount { - moles { - value: 0.00806 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC(=C(C=C1)NC2=C(N=NC3=C2C=CC(=C3)Br)C#N)F" - } - amount { - moles { - value: 0.00179 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.000269 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000143 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 100 mL flask was charged with 7-bromo-4-(2-fluoro-4-methylphenylamino)cinnoline-3-carbonitrile (0.64 g, 1.79 mmol), Piperazine (0.631 ml, 8.06 mmol), Tris(dibenzylideneacetone)dipalladium (0) (0.131 g, 0.14 mmol), 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (0.128 g, 0.27 mmol) and Sodium tert-butoxide (0.548 ml, 4.48 mmol).nbsp;The mixture was suspended in DMA (25.6 ml) and the reaction mixture was stirred at 100 C for 30min.nbsp;The reaction mixture was cooled to rt, diluted with DCMMeOH (10:1) and filtered over a pad of celite.nbsp;The filterate was concentrated under reduced pressure, adsorbed onto silica gel and flash chromatography using DCM to DCMMeOHNH4OH (10:1:0.1) provided the desired compound as a light orange solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CC(=C(C=C1)NC2=C(N=NC3=C2C=CC(=C3)N4CCNCC4)C#N)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 84.7 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/16/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "891" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00405 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.15 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC(=NC(=N1)C)N" - } - amount { - moles { - value: 0.0338 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.0338 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00405 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.0027 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium(II) acetate (0.607 g, 2.70 mmol) was added to 2,4-dichloropyridine (5.00 g, 33.79 mmol), 2,6-dimethylpyrimidin-4-amine (4.16 g, 33.79 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (2.346 g, 4.05 mmol) and Cesium carbonate (22.02 g, 67.57 mmol) in dioxane (150 mL) at 20C under nitrogen. The resulting suspension was stirred at 100 C for 90 minutes. Complete reaction by LCMS, cooled to room temperature. The reaction mixture was then filtered, washed with DCM and filtrate concentrated iin vacuoi to give a yellow gum. This was then dissolved in DCM (200 mL), washed with water (200 mL) and brine (200 mL). The organic layer was passed through phase separating cartridge and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford N-(4-chloropyridin-2-yl)-2,6-dimethylpyrimidin-4-amine (4.86 g, 61.2 %) as a yellow solid. n" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CC(=NC(=N1)C)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 61.24 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/09/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "892" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00221 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCCC1=O" - } - amount { - moles { - value: 0.00111 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C=C1F)Cl)Br" - } - amount { - moles { - value: 0.00122 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 5.53e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 5.53e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a round bottom flask was added palladium(II) acetate (0.012 g, 0.06 mmol), dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.026 g, 0.06 mmol), and sodium tert-butoxide (0.213 g, 2.21 mmol).nbsp;Added 5 mL toluenet-butanol mix and purged with nitrogen.nbsp;Added piperidin-4-one (0.15 g, 1.11 mmol), in 3 mL toltbuoh (slurry), followed by 1-bromo-2-chloro-4-fluorobenzene (0.255 g, 1.22 mmol), in 2 mL toltbuoh.nbsp;Flushed with additional nitrogen and then heated to 120oC overnight.Let reaction mixture cool to room temperature and filtered through Celite.nbsp;Rinsed repeatedly with EtOAc and concentrated in vacuo.Purified via ISCO 12g SiO2 column using 0-20% hexanesethyl acetate.nbsp;Fractions 19 and 20 were combined and concentrated to afford a white solid.nbsp;NMR (I200805922.42) shows a mess.nbsp;Discarded.nbsp;Will try another way." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CN(CCC1=O)C2=C(C=C(C=C2)F)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/14/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "893" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000377 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CC(C1)N2CCN(CC2)C(=O)C3CC4(C3)CCNCC4" - } - amount { - moles { - value: 0.000343 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=NC(=C1)Br" - } - amount { - moles { - value: 0.00036 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 6.86e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.43e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "cesium carbonate (123 mg, 0.38 mmol) was added to a solution of (4-cyclobutylpiperazin-1-yl)(7-azaspiro[3.5]nonan-2-yl)methanone (100 mg, 0.34 mmol), PdOAc2 (7.70 mg, 0.03 mmol), BINAP (42.7 mg, 0.07 mmol) and 2-bromopyridine (56.9 mg, 0.36 mmol) in toluene (2 mL). The reaction mixture was heated to 110C for 18hrs. The room temperature cooled down mixture was filtered over celite. The solvent was concentrated. The product was purified by preparative HPLC using a low pH shallow gradient method (Mobile phase: 20-40% B; A: H2O with 0.05% TFA , B: CH3CN,nbsp;25 min. run) on Luna 15 m, C8 (2), 21.2x250 mm Phenomenex reverse phase column to provide (4-cyclobutylpiperazin-1-yl)(7-(pyridin-2-yl)-7-azaspiro[3.5]nonan-2-yl)methanone (54.1 mg, 42.8 %) as white solid.1H NMR (400 MHz, CHLOROFORM-idi) d ppm 1.62 - 1.75 (m, 4 H) 1.75 - 1.81 (m, 2 H) 1.81 - 1.94 (m, 2 H) 1.98 - 2.10 (m, 4 H) 2.12 - 2.21 (m, 2 H) 2.23 - 2.32 (m, 4 H) 2.71 (quin, iJi=7.91 Hz, 1 H) 3.05 - 3.14 ( H) 3.14 - 3.26 (m, 3 H) 3.33 - 3.40 (m, 2 H) 3.58 - 3.68 (m, 2 H) 7.09 - 7.15 (m, 1 H) 7.16 - 7.21 (m, 1 H) 8.06 (dd, iJi=4.49, 1.37 Hz, 1 H) 8.31 (d, iJi=2.73 Hz, 1 H)HRMS imzi calcd for C22H32N4O 369.26489 [M+H]+, found 369.26461 .MS imzi 369.2 [M+H]+ (ES+)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CC(C1)N2CCN(CC2)C(=O)C3CC4(C3)CCN(CC4)C5=CC=CC=N5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 42.78 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/16/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "895" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00111 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)NC1=C(C=CC(=C1)N)N(C)CCN(C)C" - } - amount { - moles { - value: 0.000856 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.000856 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 8.56e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 4.28e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 40mL vialnbsp;(t=g) was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (200 mg, 0.86 mmol), N-(5-amino-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acetamide (214 mg, 0.86 mmol), and cesium carbonate (363 mg, 1.11 mmol) in DMA (0.5 mL) ([VOLUME]),Pd2(dba)3 (39.2 mg, 0.04 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (49.5 mg, 0.09 mmol) were added.to give a brown suspension. The vial was filled with N2,150C microwave for 30 min. LCMS showed completion.concentrated. loaded on ISCO (Hex to Hex:EtOAc To EtOAc:MeOH=10:1 to EtOAc:MeOH:Et3N=10:1:0.1) to give yellow sticky oil. tried to use EtOAc(1 mL) as solvent to make the product to form crys. finally the solid was formed and washed with EtOA (1mL) and Et2O(2mL) to give 86mg white solidNMR LCMS are OK" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)NC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)N(C)CCN(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 22.45 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/04/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "896" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000445 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)NC1=C(C=CC(=C1)N)N(C)CCN(C)C" - } - amount { - moles { - value: 0.000342 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.000342 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.42e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.71e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 40mL vialnbsp;(t=g) was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (80 mg, 0.34 mmol), [Reactants], and cesium carbonate (145 mg, 0.45 mmol) in DMA (0.5 mL) ([VOLUME]),Pd2(dba)3 (15.68 mg, 0.02 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (19.81 mg, 0.03 mmol) were added.to give a brown suspension. The vial was filled with N2,150C microwave for 30 min. LCMS showed completion.concentrated. loaded on ISCO (Hex to Hex:EtOAc To EtOAc:MeOH=10:1 to EtOAc:MeOH:Et3N=10:1:0.1) to give yellow solid.This yellow solid was washed with EtOAc(1mL) and Et2O(2mL) to give 50 mg pure compound.NMR, 1H,HPLC are OK, see attachment" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)NC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)N(C)CCN(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 29.37 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/15/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "897" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00342 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)N)NC(=O)C" - } - amount { - moles { - value: 0.00171 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.00171 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000171 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 8.56e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "in microwave tube was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (400 mg, 1.71 mmol), N-(5-amino-2-methylphenyl)acetamide (281 mg, 1.71 mmol), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (99 mg, 0.17 mmol) in DMA (0.5 mL).Pd2(dba)3 (78 mg, 0.09 mmol) and cesium carbonate (1116 mg, 3.42 mmol) were added.degassed, filled with N2.capped. then microwave 150C for 30 min.The reaction was divided by 4, run 100mg scale four time.combined all of crude mixture, filtered and washed with MeOH.the organic solvent was removed. The black residue was tried to purifed by ISCO. impurity and prod came out together too quickly.purified by glass-clumn (150g silica, Hex to EtOAc:Hex =1:1 to EtOAc), colleceted product fraction. concentrated to give offwhite solid. LCMS showed about 10% impurity.The solid was washed with hot EtOAc(5 mL), filtered.The solild was washed with water (1mL) and EtOAc(1 mL) to give about 110mg white solid.LCMS and NMR are OK, see attachment.low yield was due to hot EtOAc wash, lost some prod." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)NC(=O)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 18.09 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/16/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "898" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000377 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)N)NC(=O)C" - } - amount { - moles { - value: 0.000342 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.000342 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.42e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.71e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "in microwave tube was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (80 mg, 0.34 mmol), N-(5-amino-2-methylphenyl)acetamide (56.2 mg, 0.34 mmol), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (19.81 mg, 0.03 mmol) in DMA (0.5 mL).Pd2(dba)3 (15.68 mg, 0.02 mmol) and cesium carbonate (123 mg, 0.38 mmol) were added.degassed, filled with N2.capped. then microwave 150C for 30 min.added 2 mL of MeOH, filtered through celite. concentrated. The residue was purified by ISCO (Hex to Hex:EtOAc=1:4 to 1:1 to EtOAc), collected prod fractions. concentrated to give offwhite solid. This solid was washed with 0.5 mL of EtOAc to give pure prod" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)NC(=O)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 18.59 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/25/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "900" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00428 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.0025 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)N)NC(=O)C" - } - amount { - moles { - value: 0.00214 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.00214 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000214 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000107 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "in microwave tube was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (500 mg, 2.14 mmol), N-(5-amino-2-methylphenyl)acetamide (351 mg, 2.14 mmol), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (124 mg, 0.21 mmol) in DMA (2.5 mL).Pd2(dba)3 (98 mg, 0.11 mmol) and cesium carbonate (1394 mg, 4.28 mmol) were added.degassed, filled with N2.capped. then microwave 150C for 30 min.The reaction was divided by 5, run 100mg scale five time.combined all of crude mixture, filtered and washed with MeOH.the organic solvent was removed. The black residue was tried to purifed by ISCO.(40g cloumn, Hex to EtOAc:Hex =1:1 to EtOAc), colleceted product fraction. concentrated to give offwhite solid. LCMS showed about 10% impurity.The solid was washed with hot EtOAc(5 mL), filtered.The solild was washed withnbsp;to give about 175mg white solid.LCMS and NMR are OK, see attachment.low yield was due to hot EtOAc wash, lost some prod." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)NC(=O)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 22.63 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/10/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "901" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000257 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.0015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)N)NC(=O)C" - } - amount { - moles { - value: 0.000171 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.000171 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1CCC(CC1)P(C2CCCCC2)C3=CC=CC=C3C4=CC=CC=C4" - } - amount { - moles { - value: 1.71e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 8.56e-06 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 25 mL round-bottomed flask (t=g) was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (40 mg, 0.17 mmol), Pd2(dba)3 (7.84 mg, 8.56 mol), and [Reactants] in DMA (1.5 mL) ([VOLUME]) to give a black suspension.[Reactants] and N-(5-amino-2-methylphenyl)acetamide (28.1 mg, 0.17 mmol) were added.stirred at 110C for 2 days. TLC showed major is SM, small amount of product was formeddid not workupLCMS showed 349 mass ??" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)NC(=O)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/19/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "902" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[K+]" - } - amount { - moles { - value: 0.00298 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C[C@@H]1CNCCN1C(=O)OC(C)(C)C" - } - amount { - moles { - value: 0.00213 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CS(=O)(=O)C1=CC=C(C=C1)Br" - } - amount { - moles { - value: 0.00213 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" - } - amount { - moles { - value: 0.00011 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C.[Pd]" - } - amount { - moles { - value: 0.000106 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "13-May-09 10:32:28 +01001-bromo-4-(methylsulfonyl)benzene (515 mg, 2.13 mmol), (R)-tert-butyl 2-methylpiperazine-1-carboxylate (426 mg, 2.13 mmol) and BIS(TRI-T-BUTYLPHOSPHINE)PALLADIUM(0) (54.3 mg, 0.11 mmol) and potassium 2-methylpropan-2-olate (352 mg, 2.98 mmol) were suspended in dioxane (10 mL) and heated to 90C for 3 hours. LC-MS shows starting material. Reaction abandoned. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C[C@@H]1CN(CCN1C(=O)OC(C)(C)C)C2=CC=C(C=C2)S(=O)(=O)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/13/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "906" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00323 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.035 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00323 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C=C1Br)Cl)C#N" - } - amount { - moles { - value: 0.00323 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000314 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000162 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 250 mL round-bottomed dried flask , diacetoxypalladium (0.036 g, 0.16 mmol) was treated with 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.195 g, 0.31 mmol) under nitrogen in toluene (35 mL). The reaction was heated to 80 C and was stirred for 10 min. To the flask was then added tert-butyl piperazine-1-carboxylate (0.602 g, 3.23 mmol), cesium carbonate (0.527 g, 1.62 mmol),nbsp;potassium carbonate (0.447 g, 3.23 mmol) and 1,4,7,10,13,16-hexaoxacyclooctadecane (0.085 g, 0.32 mmol). The reaction was then treated with 4-bromo-2-chlorobenzonitrile (0.7 g, 3.23 mmol) and was allowed to stir at 80C for 5 h. The mixture was then filtered over celite and celite was washed with heptanes. The mixture was condensed under reduced pressure and the crude material was purified on preparative HPLC MS using the short high pH shallow gradient method (Mobile phase: 50-70% B; A: H2O with 10 mM NH4CO3 and 0.375% NH4OH vv, B: CH3CN, 10 min run) on XBridg18 OBD, 30x50 mm, 5 mm, Waters reverse phase column, to afford tert-butyl 4-(3-chloro-4-cyanophenyl)piperazine-1-carboxylate (0.490 g, 47.1 %) as a white solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC(=C(C=C2)C#N)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 47.09 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/14/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "907" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 5.54e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.00542 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C/C=C(/C1=CC=C(C=C1)C)\\N(C2=CC=C(C=C2)OC)C(=O)NC" - } - amount { - moles { - value: 0.000554 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=NC(=CC=C1)Br" - } - amount { - moles { - value: 0.00111 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 5.54e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.77e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(Z)-1-(4-methoxyphenyl)-3-methyl-1-(1-p-tolylprop-1-enyl)urea (0.17200 g, 0.55 mmol),2-bromo-6-methylpyridine (0.126 ml, 1.11 mmol),SODIUM TERT-BUTOXIDE (0.160 g, 1.66 mmol),XANTPHOS (0.032 g, 0.06 mmol) and Pd2(dba)3 (0.025 g, 0.03 mmol) were dissolved intoluene (5.42 ml) and sparged under nitrogen for 15minutes . The resulting mixture was then heated to 110 C for 29032010 48 hours or unitil conversion was complete by TLC. NH4Cl (10 mL) was added 31-Mar-10 09:49:52 +0100 and the mixture was extracted twice (EtOAc 20 mL). The organic phases were combined, washed with brine (20 mL), dried (MgSO4) and the solvent removed under reduced pressure. The crude product was then purified by flash column chromatography to give (Z)-1-(4-methoxyphenyl)-3-methyl-3-(6-methylpyridin-2-yl)-1-(1-p-tolylprop-1-enyl)urea (0.189 g, 85 %)633-444 = 189 mg" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C/C=C(/C1=CC=C(C=C1)C)\\N(C2=CC=C(C=C2)OC)C(=O)N(C)C3=CC=CC(=N3)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 84.95 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/25/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "909" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00144 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)NC1=CC(=C(C=C1C2CC2)F)N" - } - amount { - moles { - value: 0.00048 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1C(CO1)NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.000528 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C(C)(C)C)C(C)(C)C)C(C)C" - } - amount { - moles { - value: 9.6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 4.8e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 140.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "dioxane (4 mL) was adde to the mixture of N-(5-amino-2-cyclopropyl-4-fluorophenyl)acetamide (100 mg, 0.48 mmol), 5-chloro-7-(oxetan-3-ylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (132 mg, 0.53 mmol),cesium carbonate (469 mg, 1.44 mmol), Pd2(dba)3 (44.0 mg, 0.05 mmol),nbsp;di-tert-butyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (40.8 mg, 0.10 mmol) in 5 ml microwave vial. N2 flow was bubbled through for 3 mins. Then the reaction solution was sealed with cap, degassed and refilled with argon 3 times. The resulting solution was heated at 140C for 40 mins in microwave. LCMS showed desired product as major peak. After the crude solution was concentrated, the crude residue was purified by chromatography (100% EtOAc to 3% MeOH in EtOAc). N-(5-(3-cyano-7-(oxetan-3-ylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)-2-cyclopropyl-4-fluorophenyl)acetamide (48.4 mg, 23.91 %) was obtained. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)NC1=CC(=C(C=C1C2CC2)F)NC3=NC4=C(C=NN4C(=C3)NC5COC5)C#N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 23.91 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/22/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "910" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000601 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)NC1=CC(=C(C=C1C2CC2)F)N" - } - amount { - moles { - value: 0.00026 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1C(CO1)NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.0002 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C(C)(C)C)C(C)(C)C)C(C)C" - } - amount { - moles { - value: 4.01e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 130.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "The mixture of N-(5-amino-2-cyclopropyl-4-fluorophenyl)acetamide (54.2 mg, 0.26 mmol), 5-chloro-7-(oxetan-3-ylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (50.0 mg, 0.20 mmol), cesium carbonate (196 mg, 0.60 mmol), Pd2(dba)3 (18.34 mg, 0.02 mmol) and di-tert-butyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (17.01 mg, 0.04 mmol) sealed with microwave vial was degassed and refilled with argon 3 times. Then the degassed dioxane (4 mL) was added. The resulting solution was heated at 130C for 30 mins in microwave.nbsp;After removed all the solvents, the crude residue was purified by chromatography (100% EtOAc to 3% MeOH in EtOAc). N-(5-(3-cyano-7-(oxetan-3-ylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)-2-cyclopropyl-4-fluorophenyl)acetamide (10.00 mg, 11.85 %) was obtained. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)NC1=CC(=C(C=C1C2CC2)F)NC3=NC4=C(C=NN4C(=C3)NC5COC5)C#N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 11.85 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/19/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "911" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0016 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.001 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)NC1=CC(=C(C=C1C2CC2)F)N" - } - amount { - moles { - value: 0.000801 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1C(CO1)NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.000801 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C(C)(C)C)C(C)(C)C)C(C)C" - } - amount { - moles { - value: 8.01e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 4.01e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 145.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a microwave tube, was Cs2CO3 (0.522 g, 1.60 mmol), N-(5-amino-2-cyclopropyl-4-fluorophenyl)acetamide (0.167 g, 0.80 mmol), Pd2dba3 (0.037 g, 0.04 mmol),5-chloro-7-(oxetan-3-ylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (0.200 g, 0.80 mmol),di-tert-butyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.034 g, 0.08 mmol). anhydrous DMA (1.0 mL) was added. The resulting mixture was bubbled through N2. Then the tube was capped. under microwave 145C for 25min.LCMS showed product and byproduct mass, did not showed SMThe mixture was filtered through celite. The resulting black solution was concentrated to dryness by rotavapor. The crude product was purified by ISCO (40g, Hex to EtOAc:HEx=1;2 to 1;1 to EtOAcO) to give product (offwhite solid). HPLC showed some impurity. This offwhite solid was washed with warm EtOAc (1mL) to giveN-(5-(3-cyano-7-(oxetan-3-ylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)-2-cyclopropyl-4-fluorophenyl)acetamide (0.012 g, 3.55 %)nbsp;LCMS and NMR were OK, see attachment. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)NC1=CC(=C(C=C1C2CC2)F)NC3=NC4=C(C=NN4C(=C3)NC5COC5)C#N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 3.55 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/30/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "912" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.174 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.193 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CSC(=N1)N" - } - amount { - moles { - value: 0.0579 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=NC(=C1)Br)C(=O)O" - } - amount { - moles { - value: 0.0579 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 0.00579 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.00145 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "iThe aim of this reaction is to synthesize material to check some ideas for route development and see if \'normal\' Buchwald conditions is applicable here. IPC.s were taken and the reaction was monitored either by LCMS or HNMR (a crude sample dissolved in DMSO).i1911-201514:00A dried 250 mL rb-flask under nitrogen atmosphere was charged with 4-methylthiazol-2-amine (C0033995, BT250061) (6.61 g, 57.92 mmol), 6-bromopicolinic acid (C0013377, BT249846) (11.7 g, 57.92 mmol), TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM(0)nbsp;(C0007769, BT234652) (1.326 g, 1.45 mmol), dicyclohexyl(2\',4\',6\'-triisopropyl-[1,1\'-biphenyl]-2-yl)phosphane (C0018897, BT153355) (2.76 g, 5.79 mmol), SODIUM T-BUTOXIDEnbsp;(C0006296, BT235115) (16.70 g, 173.76 mmol), Toluene (193 ml) was added and the suspension was heated and stirred at reflux (110 C).Start heating 14:30 -IPC was taken after 18 h bIPC1 LCMSb, seems difficult to identify if any of the desired product was formed.Man aqueous wash between citric acidwater and ethyl acetate, tedious separation, analysed the two phases IPC2 LCMS but still impossible to identify any product neither in the organic phase IPC3 LCMS.bNo evidence of product formation.bThe phases were discarded and the reaction judged as failed" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CSC(=N1)NC2=CC=CC(=N2)C(=O)O" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/19/2015" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "915" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00568 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.03 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00474 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=NC(=C1)Cl)C(F)(F)F" - } - amount { - moles { - value: 0.00474 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000474 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000237 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 105.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 20 mL microwave vial was charged with 2-chloro-6-(trifluoromethyl)pyridine (860 mg, 4.74 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (295 mg, 0.47 mmol), Sodium tert-butoxide (546 mg, 5.68 mmol), tert-butyl piperazine-1-carboxylate (882 mg, 4.74 mmol) and a mixture of toluene (25 mL) and DMF (5 mL). The reaction mixture was degassed for 10 minutes with nitrogen, and then Tris(dibenzylideneacetone)dipalladium(0) (217 mg, 0.24 mmol) was added. The reaction mixture was stirred at 105C in an oil bath 12h.nbsp;The solution was diluted with EtOAc and washed with saturated NaHCO3 solution, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was loaded on a 80g silica gel column and purified on a Teledyne Isco instrument, eluting with 0% to 100% ethyl acetate in heptane to provide tert-butyl 4-(6-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (811 mg, 51.7 %) as a solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC=CC(=N2)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 51.68 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/08/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "916" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000568 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.000474 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=NC(=C1)Cl)C(F)(F)F" - } - amount { - moles { - value: 0.000474 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 4.74e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.37e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 105.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 2.0-5.0 mL microwave vial was charged with 2-chloro-6-(trifluoromethyl)pyridine (86 mg, 0.47 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (29.5 mg, 0.05 mmol), Sodium tert-butoxide (54.6 mg, 0.57 mmol), tert-butyl piperazine-1-carboxylate (88 mg, 0.47 mmol) and a mixture of toluene (2.5 mL) and DMF (.5 mL). The reaction mixture was degassed for 10 minutes with nitrogen, and then Tris(dibenzylideneacetone)dipalladium(0) (21.69 mg, 0.02 mmol) was added. The reaction mixture was stirred at 105C in an oil bath 12h.nbsp;The solution was diluted with EtOAc and washed with saturated NaHCO3 solution, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was loaded on a 24g silica gel column and purified on a Teledyne Isco instrument, eluting with 0% to 100% ethyl acetate in heptane to provide tert-butyl 4-(6-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate (72.8 mg, 46.4 %) as a solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC=CC(=N2)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 46.38 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/07/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "917" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00135 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CC2CNCC2C1" - } - amount { - moles { - value: 0.000966 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=CC(=C1)Br)Cl" - } - amount { - moles { - value: 0.00106 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 4.83e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 4.83e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (205 mg, 0.97 mmol), 5-Bromo-2-chloroanisole (235 mg, 1.06 mmol), Sodium tert-butoxide (130 mg, 1.35 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (30.1 mg, 0.05 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (44.2 mg, 0.05 mmol) in toluene (10 mL) under a nitrogen atmosphere was stirred at 90 C for 12h.nbsp;The solution was washed with saturated NaHCO3 solution, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.nbsp;The crude material was loaded on a 24g silica gel column and purified on a Teledyne Isco instrument, eluting with 20% to 40% ethyl acetate in heptane to provide tert-butyl 5-(4-chloro-3-methoxyphenyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (220 mg, 64.6 %) as a solid.nbsp;Used directly for the next step.MS mz 353.3 [M+H]+ (ESI)nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CC2CN(CC2C1)C3=CC(=C(C=C3)Cl)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 64.57 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/05/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "918" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.3 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000372 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.00065 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCNCC1" - } - amount { - moles { - value: 0.000186 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=CC(=C1)Cl)I" - } - amount { - moles { - value: 0.000186 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 1.86e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.86e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "1-methylpiperazine (0.021 mL, 0.19 mmol) was added to 4-chloro-1-iodo-2-methoxybenzene (50 mg, 0.19 mmol) and sodium 2-methylpropan-2-olate (35.8 mg, 0.37 mmol) in toluene (0.650 mL) and the solution degassed. rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (11.60 mg, 0.02 mmol) and Palladium II acetate (4.18 mg, 0.02 mmol) were added to the resulting mixture and the vial stirred at 80 C for 17 hours. LCMS revelead product peak, but not great. Product not isolated. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CCN(CC1)C2=C(C=C(C=C2)Cl)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/05/2016" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "919" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0021 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CSC(=N1)N" - } - amount { - moles { - value: 0.00175 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCC(=O)N1C2=NC(=CC=C2)Br" - } - amount { - moles { - value: 0.00175 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00014 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" - } - amount { - moles { - value: 7.01e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 115.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "biSeptember 24 2015ib4-methylthiazol-2-amine (200 mg, 1.75 mmol), 4-(6-bromopyridin-2-yl)morpholin-3-one (450 mg, 1.75 mmol), 4-(6-bromopyridin-2-yl)morpholin-3-one (450 mg, 1.75 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (81 mg, 0.14 mmol) and cesium carbonate (685 mg, 2.10 mmol) in toluene (15 mL) and DMF (1)were microwaved at 115 C under N2 for one hour.i(Note: Initially, DMF was not added as co-solvent, the microwave instrument was repeatly failed to reach the temperature, and shut down ar 100 C.nbsp;It was due to the low thremal absorbance of toluene.nbsp;Therefore, DMF was added to improve this situation.)iLCMS showed no precursors and 87% of the desired mass MH+291 @ 0.87 min on a 2-min basic run.nbsp;The reaction was cooled to RT.biSeptember 25 2015ibThe reaction mixture was diluted with EtOAc, washed with water, filtered, and evaporated to give a brown solid as the crude product.nbsp;The oduct was added to a silica gel column, and was eluted with 20-100%EtOAc in Heptane.nbsp;Collected fractions.nbsp;Based on TLC and LCMS, most product fractions contained a non-MS-ionization unknown, were combined, and evpoarated to give an orange-yellow solid. The orange-yellow solid was reloaded to a silica gel column and was eluted with 20-100%EtOAc in Heptanenbsp;.nbsp;Collected fractions .biSeptember 28 2015ibBased on TLC and LCMS, the product fractions were combined, and evpoarated to give a pale-yellow solid.nbsp;Based on LCMS, it was 93% pure; based on NMR, it was 94~95% pure." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CSC(=N1)NC2=NC(=CC=C2)N3CCOCC3=O" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 80.02 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/23/2015" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "920" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000683 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CSC(=N1)N" - } - amount { - moles { - value: 0.000569 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1COCC(=O)N1C2=NC(=CC=C2)Br" - } - amount { - moles { - value: 0.000569 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 4.55e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd]" - } - amount { - moles { - value: 2.28e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 120.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "biSeptember 16 2015ib4-methylthiazol-2-amine (65 mg, 0.57 mmol), 4-(6-bromopyridin-2-yl)morpholin-3-one (146 mg, 0.57 mmol), 4-(6-bromopyridin-2-yl)morpholin-3-one (146 mg, 0.57 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (26.4 mg, 0.05 mmol) and cesium carbonate (223 mg, 0.68 mmol) in toluene (5 mL) were microwaved at 120 C under N2 for one hour.LCMS showed no precursors and 68% of the desired mass MH+291 @ 0.87 min on a 2-min basic run.The reaction mixture was diluted with EtOAc, washed with water, filtered, and evaporated to give a brown solid as the crude product.nbsp;biSeptembernbsp;17 2015ibThe crude product was added to a Biotage column, and was eluted with 0-10% ammoniated MeOH in DCM.nbsp;Collected fractions.Based on TLC and LCMS, the product fractions were combined, and evpoarated to give an orange-brown solid (150 mg).nbsp;Based on LCMS, it was only 89% pure.The orange-brown solid was loade a Grace column, and eluted with 20-100%EtOAc in Heptane.nbsp;Collected fractions. (Note: the solubility of the orange-brown solid was not good, and about 12 mL CH2Cl2 was used to dissolved everything)Based on TLC and LCMS, the product fractions were combined, and evpoarated to give an off-white solid (110 mg).nbsp;Based on LCMS, it was 100% pure; based on M;R, it was gt; 95% pure." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CSC(=N1)NC2=NC(=CC=C2)N3CCOCC3=O" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 66.55 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/15/2015" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "921" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0134 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.02 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N" - } - amount { - moles { - value: 0.0336 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=NN=C1Cl)Cl" - } - amount { - moles { - value: 0.00671 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00201 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "biApril 15 2016ib3,5-dichloropyridazine (1 g, 6.71 mmol),nbsp;tert-butyl carbamate (3.93 g, 33.56 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (0.583 g, 1.01 mmol), PdOAc2 (0.452 g, 2.01 mmol) and CS2CO3 (4.37 g, 13.43 mmol) in 1,4-dioxane (20 mL) was degassed through recharged with nitrogen, and was heated at 80 C overnight.biApril 18 2016ibLCMS showed 23% of the precursor @ 0.55 min (no mass ionization) left on a 2-min basic run.nbsp;GCMS showed no precursor and 94% of an unknown @ 6.90 min (whihcnbsp;might be the desired product but not ionizable) on a 10-min run.The reaction was cooled to RT.nbsp;The crude mixture was concentrated to givr a dark-brown gum. The dark-brown gum was dissolved in EtOAc, washed with water, and evaporated to give a brown solid.nbsp;The brown solid was passed through a 10 g SiO2 flash column eluting with EtOAc, collected all of the eluent, and then evaporated to give a brown solid as the crude.;The crude would be used in EN08121-59 without purification, assuming 100% yield." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)NC1=NN=CC(=C1)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/18/2016" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "922" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.0043 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.004 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C(CN)N" - } - amount { - moles { - value: 0.0215 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C(=C1)Cl)Br" - } - amount { - moles { - value: 0.0043 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=C(C=C1)P(C2=CC=C(C=C2)C)C3=CC=C(C=C3)C" - } - amount { - moles { - value: 0.000861 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00043 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 140.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Ref: R2239To a mixture of 1-bromo-2-chlorobenzene (0.824 g, 4.30 mmol), tri-p-tolylphosphine (0.262 g, 0.86 mmol), sodium 2-methylpropan-2-olate (0.414 g, 4.30 mmol), diacetoxypalladium (0.097 g, 0.43 mmol) in toluene (4 mL) was added ethane-1,2-diamine (1.293 g, 21.52 mmol). The mixture was heated with microwave at 140 C for 1 h. No product was formed." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CC=C(C(=C1)NCCN)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/09/2014" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "924" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[K+]" - } - amount { - moles { - value: 0.00295 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCCN1" - } - amount { - moles { - value: 0.00211 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC2=C(C=C1Br)OC(O2)(F)F" - } - amount { - moles { - value: 0.00211 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" - } - amount { - moles { - value: 0.00011 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C.[Pd]" - } - amount { - moles { - value: 0.000105 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "13-May-09 10:32:07 +01005-bromo-2,2-difluorobenzo[d][1,3]dioxole (0.500 g, 2.11 mmol), piperazine (0.182 g, 2.11 mmol) and BIS(TRI-T-BUTYLPHOSPHINE)PALLADIUM(0) (0.054 g, 0.11 mmol) and potassium 2-methylpropan-2-olate (0.349 g, 2.95 mmol) were suspended in dioxane (10vol) (10 mL) and heated to 90C for 1 hour. LC-MS shows no starting material 52% product and 41% dimer. The reaction mixture was combined with EN02263-54 filtered and the crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)piperazine (0.259 g, 50.7 %) as a yellow oil. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CN(CCN1)C2=CC3=C(C=C2)OC(O3)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 50.68 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/01/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "925" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000121 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0118 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C/C=C(/C1=CC=C(C=C1)Cl)\\N(C2=CC=C(C=C2)OC)C(=O)NC" - } - amount { - moles { - value: 0.00121 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=NC(=CC=C1)Br" - } - amount { - moles { - value: 0.00242 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000121 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 6.05e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(Z)-1-(1-(4-chlorophenyl)prop-1-enyl)-1-(4-methoxyphenyl)-3-methylurea (0.400 g, 1.21 mmol),2-bromo-6-methoxypyridine (0.292 ml, 2.42 mmol),SODIUM TERT-BUTOXIDE (0.349 g, 3.63 mmol),XANTPHOS (0.070 g, 0.12 mmol) and Pd2(dba)3 (0.055 g, 0.06 mmol) were dissolved intoluene (11.80 ml) and sparged under nitrogen for 1 hour. The resulting mixture was then heated to 110 C for 48 hours or unitil conversion was complete by TLC. NH4Cl (10 mL) was added and the mixture was extracted twice (EtOAc 20 mL). The organic phases were combined, washed with brine (20 mL), dried (MgSO4) and the solvent removed under reduced pressure. The crude product was then purified by flash column chromatography to give (Z)-1-(1-(4-chlorophenyl)prop-1-enyl)-1-(4-methoxyphenyl)-3-(6-methoxypyridin-2-yl)-3-methylurea (0.381 g, 72.0 %)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C/C=C(/C1=CC=C(C=C1)Cl)\\N(C2=CC=C(C=C2)OC)C(=O)N(C)C3=NC(=CC=C3)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 71.95 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/22/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "928" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00191 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C1=CC(=CC2=C1OC(=CC2=O)N3CCOCC3)C(=O)N(C)C)N" - } - amount { - moles { - value: 0.000869 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=C(C=C1F)Br)C#N" - } - amount { - moles { - value: 0.00191 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000217 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 6.51e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a mixture of 8-(1-aminoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (300 mg, 0.87 mmol), cesium carbonate (1104 mg, 3.39 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (126 mg, 0.22 mmol) and 3-bromo-5-fluorobenzonitrile (382 mg, 1.91 mmol) in degassed 1,4-dioxane (2ml), was addednbsp;TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (59.7 mg, 0.07 mmol). The suspension was heated in a sealed container up to 85-95Cnbsp;for 16hours. The reaction mixture was filtered through a short pad of dicalite, concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 0 to 5% methanol in dichloromethane. The solvent was evaporated to dryness to afford the product which still containing some impurities (see UPLC 03441-77-003). The product mixture was then re-purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml minute) and decrealy polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-(3-cyano-5-fluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (330 mg, 82 %)nbsp;as a clear white solid.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C1=CC(=CC2=C1OC(=CC2=O)N3CCOCC3)C(=O)N(C)C)NC4=CC(=CC(=C4)C#N)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 81.8 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "12/09/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "930" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00676 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(N=C1)N" - } - amount { - moles { - value: 0.00338 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.00338 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000405 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00027 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium(II) acetate (0.061 g, 0.27 mmol) was added to 2,4-dichloropyridine (0.500 g, 3.38 mmol), 2-Aminopyrimidine (0.321 g, 3.38 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (0.235 g, 0.41 mmol) and Cesium carbonate (2.202 g, 6.76 mmol) in dioxane (15 mL) at 20C under nitrogen. The resulting suspension was stirred at 100 C for 90 minutes. Complete reaction by LCMS, cooled to room temperature. The reaction mixture was then filtered, washed with DCM and filtrate concentrated iin vacuoi to give a yellow gum. This was then dissolved in DCM (200 mL), washed with water (200 mL) and brine (200 mL). The organic layer was passed through phase separating cartridge and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford N-(4-chloropyridin-2-yl)pyrimidin-2-amine (0.361 g, 51.7 %) as an off-white solid. n" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CN=C(N=C1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 51.71 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/30/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "931" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0676 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.015 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(N=C1)N" - } - amount { - moles { - value: 0.0338 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1Cl)Cl" - } - amount { - moles { - value: 0.0338 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.00405 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.0027 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Palladium(II) acetate (0.607 g, 2.70 mmol) was added to 2,4-dichloropyridine (5.00 g, 33.79 mmol), 2-Aminopyrimidine (3.21 g, 33.79 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (2.346 g, 4.05 mmol) and Cesium carbonate (22.02 g, 67.57 mmol) in dioxane (15 mL) at 20C under nitrogen. The resulting suspension was stirred at 100 C for 90 minutes. Complete reaction by LCMS, cooled to room temperature. The reaction mixture was then filtered, washed with DCM and filtrate concentrated iin vacuoi to give a yellow gum. This was then dissolved in DCM (200 mL), washed with water (200 mL) and brine (200 mL). The organic layer was passed through phase separating cartridge and concentrated under reduced pressure. The crude material was suspended in DCM, solid filtered off and dried to give EN01580-46-2 N-(4-chloropyridin-2-yl)pyrimidin-2-amine (2.975 g, 42.6 %). The filtrate was purified by silica gel chromatography, elution gradient 0 to 50% EtOAc in isohexane. Pure fractions were evaporated ts to afford EN01580-46-1, N-(4-chloropyridin-2-yl)pyrimidin-2-amine (0.889 g, 12.73 %) as a white solid. nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1=CN=C(N=C1)NC2=NC=CC(=C2)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 55.35 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/03/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "932" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000965 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.0018 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)N)NC(=O)C" - } - amount { - moles { - value: 0.000585 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(N=C1)NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.000292 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 2.92e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.46e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a microwave vial containing N-(5-amino-2-methylphenyl)acetamide (0.096 g, 0.58 mmol), 5-chloro-7-(1-methyl-1H-imidazol-4-ylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (0.08 g, 0.29 mmol), sodium tert-butoxide (0.093 g, 0.96 mmol) and 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (0.014 g, 0.03 mmol) was added DMA (1.8 ml). Vial was flushed with argon and to it was added Pd2(dba)3 (0.013 g, 0.01 mmol) and the reaction was heated in a MW reactor at 100 C for 50 min . Reaction was filtered through celite and the filterate diluted with EtOAC (5 ml) and the organic solution was washed with minimum amt ofnbsp;brine( 1X 5 ml) and organic layer dried over Na2SO4 filtered and concentrated to give crude liquid. this was purified by flash column using 5-8% MeOH: DCM (1% NH4OH) as gradient to give N-(5-(3-cyano-7-(1-methyl-1H-imidazol-4-ylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)-2-methylphenyl)acetamide (0.015 g, 12.78 %) as desired product. nmr amp; MASS AGREE WITH THE STRUCTURE." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)NC2=NC3=C(C=NN3C(=C2)NC4=CN(C=N4)C)C#N)NC(=O)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 12.78 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/20/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "933" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00121 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.0022 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)N)NC(=O)C" - } - amount { - moles { - value: 0.000731 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C=C(N=C1)NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.000365 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 3.65e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.83e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a microwave vial containingN-(5-amino-2-methylphenyl)acetamide (0.120 g, 0.73 mmol),nbsp;5-chloro-7-(1-methyl-1H-imidazol-4-ylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (0.1 g, 0.37 mmol) ,sodium 2-methylpropan-2-olate (0.116 g, 1.21 mmol) and 2-Dicyclohexylphosphino-2\',4\',6\'-tri-iso-propyl-1,1\'-biphenyl (0.017 g, 0.04 mmol)was added DMA (2.2 ml). Vial was flushed with argon and to it was added Pd2(dba)3 (0.017 g, 0.02 mmol) and the reaction was heated in a MW reactor at 100 C for 60 min.Reaction was filtered, and filterate concentrated under reduced pressure to give dark red gum. This was suspended in 10% MeOH : DCM (10 ml) filtered and filterate concentrated to give crude solid. This was purified by flash column using 5-8% MeoH :DCM (1% NH4OH) to give 75 mg of pale yellow solid (EN02331-12-1). LCMS short purity indicated 90% pure. This sample was further purifiednbsp;by trituratingnbsp;the solid in 20% EtOAC: ether (10ml). The solid was filtered, dried to give pale yellow solid (EN 023312) as desired pdt. Mass spec and NMR are in agreement with the structure. (Note : The Etoac:Ether solution(filterate in the above step)nbsp;obtained after trituration was concentrated to give solid (23 mg) this was stored for future use." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)NC2=NC3=C(C=NN3C(=C2)NC4=CN(C=N4)C)C#N)NC(=O)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 29.32 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/03/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "934" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00103 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)NC1=C(C=CC(=C1)N)N(C)CCO" - } - amount { - moles { - value: 0.000514 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.000514 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 5.14e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.57e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 40mL vialnbsp;(t=g) was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (120mg, 0.51 mmol), N-(5-amino-2-((2-hydroxyethyl)(methyl)amino)phenyl)acetamide (115 mg, 0.51 mmol), and cesium carbonate (335 mg, 1.03 mmol) in DMA (3.0 mL) (),Pd2(dba)3 (23.51 mg, 0.03 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (29.7 mg, 0.05 mmol) were added.to give a brown suspension. The vial was filled with N2,150C microwave for 30 min. LCMS showed SM and product. under microwave 150C for another 2h. 15% SM remained.nbsp;MeOH (2 mL) was added to the reaction mixture.nbsp;filtered. The mother liquid solvent was removed by ratovapor to yield stick oil. The crude product was loaded on ISCO (Hex to Hex:EtOAc To EtOAc to EtOAc:MeOH=10:1) to give sticky oil.The product was not pure. added 1 mL of EtOAc, the solid was promoted to form by scratching the flask wall. The resulting suspension was heated to reflux. When it was warm, the mixture was filtered to give offwhite solid. This solid was washed with EtOAc ( 2 mL) and dried at 80C under reduced press oven to givenbsp;N-(5-(3-cyano-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)-2-((2-hydroxyethyl)(methyl)amino)phenyl)acetamide (110 mg, 50.9 %)NMR and LCMS showed desired product, see attachment" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)NC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)N(C)CCO" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 50.94 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/09/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "935" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000377 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CC(C1)N2CCN(CC2)C(=O)C3CC4(C3)CCNCC4" - } - amount { - moles { - value: 0.000343 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CN=C1)Br" - } - amount { - moles { - value: 0.00036 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 6.86e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 3.43e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "cesium carbonate (123 mg, 0.38 mmol) was added to a solution of (4-cyclobutylpiperazin-1-yl)(7-azaspiro[3.5]nonan-2-yl)methanone (100 mg, 0.34 mmol), PdOAc2 (7.70 mg, 0.03 mmol), BINAP (42.7 mg, 0.07 mmol) and 3-bromopyridine (56.9 mg, 0.36 mmol) in toluene (2 mL). The reaction mixture was heated to 110C for 18hrs. The room temperature cooled down mixture was filtered over celite. The solvent was concentrated. The product was purified by preparative HPLC using a low pH shallow gradient method (Mobile phase: 20-40% B; A: H2O with 0.05% TFA , B: CH3CN,nbsp;25 min. run) on Luna 15 m, C8 (2), 21.2x250 mm Phenomenex reverse phase column to provide (4-cyclobutylpiperazin-1-yl)(7-(pyridin-3-yl)-7-azaspiro[3.5]nonan-2-yl)methanone (10.00 mg, 7.91 %) as white solid.1H NMR (400 MHz, CHLOROFORM-idi) d ppm 1.58 (s, 3 H) 1.63 (dd, iJi=6.25, 4.69 Hz, 2 H) 1.66 - 1.79 (m, 3 H) 1.80 - 1.94 (m, 2 H) 1.97 - 2.10 (m, 3 H) 2.12 - 2.21 (m, 2 H) 2.27 (q, iJi=5.60 Hz, 3 H) 2.71in, iJi=7.91 Hz, 1 H) 3.21 (quin, iJi=8.79 Hz, 1 H) 3.32 - 3.39 (m, 2 H) 3.41 (dd, iJi=6.64, 4.69 Hz, 2 H) 3.54 (dd, iJi=6.25, 4.69 Hz, 2 H) 3.63 (t, iJi=4.88 Hz, 2 H) 6.53 - 6.60 (m, 1 H) 6.65 (d, iJi=8.59 Hz, 1 H) 7.40 - 7.48 (m, 1 H) 8.16 (td, iJi=2.34, 1.17 Hz, 1 H)HRMS imzi calcd for C22H32N4O 369.26489 [M+H]+, found 369.26533.MS imzi 369.2 [M+H]+ (ES+)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CC(C1)N2CCN(CC2)C(=O)C3CC4(C3)CCN(CC4)C5=CN=CC=C5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 7.91 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/16/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "936" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000645 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)[C@@H]1CNCCN1C(=O)OC(C)(C)C" - } - amount { - moles { - value: 0.000553 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)Br)OC" - } - amount { - moles { - value: 0.000461 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C1=CC=CC=C1C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 2.76e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.3e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "21-Apr-09 08:58:54 +0100 4-bromo-1,2-dimethoxybenzene (0.068 mL, 0.46 mmol), (R)-tert-butyl 2-isopropylpiperazine-1-carboxylate (126 mg, 0.55 mmol) and 2-Dicyclohexylphosphino-2\'-(N,N-dimethylamino)biphenyl (11.21 mg, 0.03 mmol) and Sodium tert-butoxide (63.9 mg, 0.64 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (21.09 mg, 0.02 mmol) were suspended in toluene (5 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 20 minutes in the microwave reactor and cooled to RT.nbsp;LC-MS shows 36% product and 57% SM reaction will be combined with EN02263-47" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)[C@@H]1CN(CCN1C(=O)OC(C)(C)C)C2=CC(=C(C=C2)OC)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/22/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "938" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00129 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)[C@@H]1CNCCN1C(=O)OC(C)(C)C" - } - amount { - moles { - value: 0.00111 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)Br)OC" - } - amount { - moles { - value: 0.000921 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C1=CC=CC=C1C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4" - } - amount { - moles { - value: 2.76e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.3e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "21-Apr-09 08:58:54 +0100 4-bromo-1,2-dimethoxybenzene (0.135 mL, 0.92 mmol), (R)-tert-butyl 2-isopropylpiperazine-1-carboxylate (252 mg, 1.11 mmol) and 2-Dicyclohexylphosphino-2\'-(N,N-dimethylamino)biphenyl (10.88 mg, 0.03 mmol) and Sodium tert-butoxide (128 mg, 1.29 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (21.09 mg, 0.02 mmol) were suspended in toluene (5 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 30 minutes in the microwave reactor and cooled to RT. LC-MS show sproduct at 60% and SM 33% reaction mixture to be combined with EN02263-45 and worked up." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)[C@@H]1CN(CCN1C(=O)OC(C)(C)C)C2=CC(=C(C=C2)OC)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/21/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "939" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[K+]" - } - amount { - moles { - value: 0.000645 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1CCOC1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)[C@@H]1CNCCN1C(=O)OC(C)(C)C" - } - amount { - moles { - value: 0.000553 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC1=C(C=C(C=C1)Br)OC" - } - amount { - moles { - value: 0.000461 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C" - } - amount { - moles { - value: 5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C.[Pd]" - } - amount { - moles { - value: 4.61e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "22-Apr-09 09:56:23 +01004-bromo-1,2-dimethoxybenzene (0.068 mL, 0.46 mmol), (R)-tert-butyl 2-isopropylpiperazine-1-carboxylate (126 mg, 0.55 mmol) and BIS(TRI-T-BUTYLPHOSPHINE)PALLADIUM(0) (23.54 mg, 0.05 mmol) and potassium 2-methylpropan-2-olate (76 mg, 0.64 mmol) were suspended in THF (5 mL) and sealed into a microwave tube. The reaction was heated to 150 C for 10 minutes in the microwave reactor and cooled to RT. LC-MS shows no starting material. The reaction mixture was filtered and the crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-butyl 4-(3,4-dimethoxyphenyl)-2-isopropylpiperazine-1-carboxylate (152 mg, 91 %) as a yellow gum. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)[C@@H]1CN(CCN1C(=O)OC(C)(C)C)C2=CC(=C(C=C2)OC)OC" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 90.52 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/22/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "941" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "[O-]P(=O)([O-])[O-].[K+].[K+].[K+]" - } - amount { - moles { - value: 0.00515 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N" - } - amount { - moles { - value: 0.00447 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=CC(=N1)Cl)F" - } - amount { - moles { - value: 0.00343 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000172 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 8.59e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of 6-chloro-3-fluoro-2-methylpyridine (500 mg, 3.43 mmol), tert-Butyl carbamate (523 mg, 4.47 mmol), Potassium phosphate (1094 mg, 5.15 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (99 mg, 0.17 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (79 mg, 0.09 mmol) were combined in a sealed vial which was purged with nitrogen.nbsp;Degassed toluene (5 mL) and water (5.00 mL) were added and the mixture was stirred under a nitrogen atmosphere at 90 C for 6h. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3 solution, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with mixtures of 5-50%EtOAc in heptane.nbsp;Many spots isolated, but none of them seemed to be the desired product.nbsp;Not continued. nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=CC(=N1)NC(=O)OC(C)(C)C)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/29/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "942" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000192 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.012 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CN1CCNCC1" - } - amount { - moles { - value: 0.01 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=CC(=CC(=C1)Br)[N+](=O)[O-]" - } - amount { - moles { - value: 0.00769 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000192 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000192 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To the stirred suspension ofmethyl 3-bromo-5-nitrobenzoate (2 g, 7.69 mmol) , cesium carbonate (12.53 g, 38.46 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.111 g, 0.19 mmol) in Dioxane (12 mL) (degassed with N2) was added pd (dba)3 (0.176 g, 0.19 mmol) and cesium carbonate (12.53 g, 38.46 mmol) ANDnbsp;rxn was heated at 110 C for 1 hr in microwaved. LCMS showed the m+1= 280. The crude raection mixture was filtered over celite. The filtrate was concentarted. The crude solid was diluted by 20 mL ethyl acetate, washed with 3x10 mL water, brine, collected the organic layers, concentrated. The crude solid was added to a silica gel column and was eluted with 0-10% methanol in DCM. Collected desired fractions.Obtained=1.4 gm.1H NMR (300 MHz, DICHLOROMETHANE-idi2) d ppm 2.32 (s, 3 H) 2.43 - 2.64 (m, 4 H) 3.13 - 3.40 (m, 4 H) 3.93 (s, 3 H) 7.85 (d, iJi=1.70 Hz, 2H) 8.18 (t, iJi=1.60 Hz, 1 H)Registered as AZ1345." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CN1CCN(CC1)C2=CC(=CC(=C2)C(=O)OC)[N+](=O)[O-]" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 65.18 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/05/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "943" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00289 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCCN1" - } - amount { - moles { - value: 0.0188 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)Br)[N+](=O)[O-]" - } - amount { - moles { - value: 0.00231 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000231 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000289 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "palladium(II) acetate (0.065 g, 0.29 mmol), BINAP (0.144 g, 0.23 mmol) and CS2CO3 (0.943 g, 2.89 mmol) were added to a mixture of 4-bromo-1-methyl-2-nitrobenzene (0.5 g, 2.31 mmol) and piperazine (1.623 g, 18.84 mmol) . The suspension were heated to 110 C for 24 hours, LCMS showed product mass [M+1]: 222.1 at retension time RT=1.21 min (polar short purity method). Workup reaction by additional of water (10mL), extracted with EtOAc (3x20 mL), washed with brine, dried with Na2SO4, evaporated off solvent to give a residue, which was purified by isco chromatographer, eluting with 0-10% MeOH in DCM to give 1-(4-methyl-3-nitrophenyl)piperazine (0.201 g, 39.3 %) as a yellow solid. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)N2CCNCC2)[N+](=O)[O-]" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 39.25 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/22/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "944" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0174 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.01 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCCN1" - } - amount { - moles { - value: 0.113 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)Br)[N+](=O)[O-]" - } - amount { - moles { - value: 0.0139 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00139 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.00174 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "palladium(II) acetate (0.390 g, 1.74 mmol), BINAP (0.865 g, 1.39 mmol) and CS2CO3 (5.66 g, 17.36 mmol) were added to a mixture of 4-bromo-1-methyl-2-nitrobenzene (3 g, 13.89 mmol) and piperazine (9.74 g, 113.04 mmol) innbsp;microwave. The suspension were heated to 110 C for 24 hours, LCMS showed product mass [M+1]: 222.0 at retension time RT=1.38 min (polar short purity method). Workup reaction by additional of water (10mL), extracted with EtOAc (3x20 mL), washed with brine, dried with Na2SO4, evaporated off solvent to give a residue, which was purified by isco chromatographer, eluting with 0-10% MeOH in DCM to give 1-(4-methyl-3-nitrophenyl)piperazine (1.670 g, 54.4 %) as a yellow solid. LCMS confirmed the target compound." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)N2CCNCC2)[N+](=O)[O-]" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 54.35 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/29/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "945" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000646 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC(=C(C=C1NC(=O)C)N)F" - } - amount { - moles { - value: 0.000323 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CC(C1)NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.000323 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.23e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.61e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "nbsp;5-chloro-7-(cyclobutylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (80 mg, 0.32 mmol), N-(5-amino-4-fluoro-2-methylphenyl)acetamide (58.8 mg, 0.32 mmol), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (18.69 mg, 0.03 mmol) in DMA (5 mL) were added to a microwave tube. Pd2(dba)3 (14.79 mg, 0.02 mmol) and cesium carbonate (210 mg, 0.65 mmol) were added.The solution was degassed, filled with N2, capped, then microwaved at 150C for 30 min.The organic solvent was removed. TLC showed two closely associated peaks, so product was purified via Gilson. Appropriate fractions were collected, concentrated by rotovap, and dried in the oven overnight. LCMS, HPLC, and NMR revealed desired product. See attachments. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CC(=C(C=C1NC(=O)C)NC2=NC3=C(C=NN3C(=C2)NC4CCC4)C#N)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 5.51 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/13/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "946" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00657 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.025 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00548 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(N=CC(=N1)Cl)C(F)(F)F" - } - amount { - moles { - value: 0.00548 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000548 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000274 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 105.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 20 mL microwave vial was charged with 2-chloro-5-(trifluoromethyl)pyrazine (1 g, 5.48 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.341 g, 0.55 mmol), Sodium tert-butoxide (0.632 g, 6.57 mmol), tert-butyl piperazine-1-carboxylate (1.020 g, 5.48 mmol) and a mixture of toluene (25 mL) and DMF (5 mL). The reaction mixture was degassed for 10 minutes with nitrogen, and then Tris(dibenzylideneacetone)dipalladium(0) (0.251 g, 0.27 mmol) was added. The reaction mixture was stirred at 105C in an oil bath 12h.nbsp;The solution was diluted with EtOAc and washed with saturated NaHCO3 solution, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was loaded on a 80g silica gel column and purified on a Teledyne Isco instrument, eluting with 0% to 25% ethyl acetate in heptane to provide tert-butyl 4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1-carboxylate (0.390 g, 21.41 %) as a solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=NC=C(N=C2)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 21.41 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/27/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "947" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000644 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.000537 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C2C(=C1)C=CC(=N2)Cl" - } - amount { - moles { - value: 0.000644 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 5.37e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.68e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 2.0-5.0 mL microwave vial was charged with tert-Butyl 1-piperazinecarboxylate (100 mg, 0.54 mmol), 2-Chloroquinoline (0.086 mL, 0.64 mmol), Sodium tert-butoxide (61.9 mg, 0.64 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (33.4 mg, 0.05 mmol) and toluene (3 mL). The reaction mixture was degassed for 10 minutes with nitrogen, and then Tris(dibenzylideneacetone)dipalladium(0) (24.58 mg, 0.03 mmol) was added. The reaction mixture was stirred at 100C in an oil bath for 12h.nbsp;The solution was diluted with EtOAc and washed with saturated NaHCO3,nbsp;brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.nbsp;The crude material was loaded on a 40g silica gel column and purified on a Teledyne Isco instrument, eluting with 10% to 40% ethyl acetate in heptane.nbsp;Product not pure.nbsp;Product was repurifed using a 40g Gold column with same eluent to provide tert-butyl 4-(quinolin-2-yl)piperazine-1-carboxylate (78 mg, 46.4 %) as a solid.MS mz 314.3 [M+H]+I)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=NC3=CC=CC=C3C=C2" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 46.36 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/01/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "948" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000781 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C=O" - } - amount { - volume { - value: 0.001 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CN=C(C=C1NC(=O)C)N" - } - amount { - moles { - value: 0.00026 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.000364 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C(C)(C)C)C(C)(C)C)C(C)C" - } - amount { - moles { - value: 5.21e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Ref:i Angew. Chem. Int. Ed.i b2006b, i45i, 6523-65271. To a microwave tube was added N-(2-amino-5-methylpyridin-4-yl)acetamide (43 mg, 0.26 mmol), 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (85 mg, 0.36 mmol), Cs2CO3 (254 mg, 0.78 mmol), Pd2dba3 (23.84 mg, 0.03 mmol), and di-tert-butyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (22.11 mg, 0.05 mmol). The mixture was dissolved in DMF (1 mL) and sealed. The tube was de-gassed and inflated with N2.2. The reaction was heated at 90C in oil-bath for 4 hr. LCMS showed partial formation of product. Heated overnight at 90C.3. The reaction mixture was filtered through celite pad and the filtrate was loaded onto column and run chromotography to purify (10% MeOH in DCM), semi-pure product was obtained and the sample was mitted to analytical group for further purification. 4. 10 mg pure product was obtained. 1H NMR (400 MHz, DMSO-idi6) d ppm 0.73 (d, iJi=2.78 Hz.85 (d, iJi=5.05 Hz, 2 H) 2.15 (d, iJi=12.88 Hz, 7 H) 2.62 (br. s., 1 H) 7.36 (s, 1 H)7.98 (s, 1 H) 8.09 (s, 1 H) 8.35 (s, 1 H) 8.38 (s, 1 H) 9.38 (s, 1 H) 10.11 (s, 1 H)" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CN=C(C=C1NC(=O)C)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 10.6 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/12/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "949" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0556 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.1 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCCC1O" - } - amount { - moles { - value: 0.0554 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC(=C1)Br)C(F)(F)F" - } - amount { - moles { - value: 0.0444 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000889 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000889 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of 1-bromo-3-(trifluoromethyl)benzene (6.13 mL, 44.44 mmol), piperidin-4-ol (5.608 g, 55.44 mmol), diacetoxypalladium (0.200 g, 0.89 mmol), 2,2\'-bis(diphenylphosphino)-1,1\'-binaphthyl (0.553 g, 0.89 mmol) and cesium carbonate (18.10 g, 55.55 mmol) in dioxane (100 mL) was evacuated and backfilled with N2 three times and then it was heated at 100 C for 6h. The mixture was filtered through filter agent(supercell), washed with EtOAc. The combined filtrate was concentrated. The residue was purified by silica gel column(0-35% EtOAchexane) to give 1-(3-(trifluoromethyl)phenyl)piperidin-4-ol (4.70 g, 43.1 %) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) d 7.38 (t, iJi = 8.03 Hz, 1H), 7.20 (dd, iJi = 2.38, 8.41 Hz, 1H), 7.13 (s, 1H), 7.00 (d, iJi = 7.78 Hz, 1H), 4.64 - 4.72 (m, 1H), 3.53 - 3.72 (m, 3H), 2.93 (ddd, iJi = 3.01, 9.98, 12.86 Hz, 2H), 1.71 - 1.88 (m, 2H), 1.45 (dtd, iJi = 3.89, 9.44, 12.86 Hz, 2H). LCMS 246." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CN(CCC1O)C2=CC=CC(=C2)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 43.09 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/26/2011" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "951" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 4.22e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.003 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1COCCC1N" - } - amount { - moles { - value: 0.000422 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=NC(=C1)Br)Br" - } - amount { - moles { - value: 0.000422 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 4.22e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 4.22e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: nan - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "to 2,6-dibromopyridine (100 mg, 0.42 mmol), 4-Aminotetrahydropyran (42.7 mg, 0.42 mmol) in dioxane (3 mL) while bubbling N2 was added Xantphos (24.43 mg, 0.04 mmol), CS2CO3 (316 mg, 0.97 mmol) and palladium(II) acetate (9.48 mg, 0.04 mmol). This was heated in a microwave at 130 oC for 30 mins. A small peak corresponding to product was obseved. Discontinued" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1COCCC1NC2=NC(=CC=C2)Br" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/27/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "953" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0016 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.002 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)N)NC(=O)C" - } - amount { - moles { - value: 0.000801 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1C(CO1)NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.000801 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C(C)(C)C)C(C)(C)C)C(C)C" - } - amount { - moles { - value: 8.01e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 4.01e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 145.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a microwave tube, was Cs2CO3 (0.522 g, 1.60 mmol), N-(5-amino-2-methylphenyl)acetamide (0.132 g, 0.80 mmol), Pd2dba3 (0.037 g, 0.04 mmol),5-chloro-7-(oxetan-3-ylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (0.200 g, 0.80 mmol),di-tert-butyl(2\',4\',6\'-triisopropyl-[1,1\'-biphenyl]-2-yl)phosphine (0.034 g, 0.08 mmol). anhydrous DMA (2.0 mL) was added. The resulting mixture was bubbled through N2. Then the tube was capped. under microwave 145C for 30min.This reaction was repeated at 150mg again.The two batches were combined to workupThe mixture was concentrated to dryness. Water (20 mL) was added. it was extracted with 10% MeOH in EtOAc, The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness. It was purified by chromatography )Hex to 50% etAOc in Hex to EtOAc to 5% MeOH in EtOAc) to collect the pure product to give the product (86mg, 16.5% from total 350mg SM 5-chloro-7-(oxetan-3-ylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile) which was washed with EtOAc and dried under a high vacuum at 60C for 16h as an offwhite solid" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)NC2=NC3=C(C=NN3C(=C2)NC4COC4)C#N)NC(=O)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 16.54 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/10/2012" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "954" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00289 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.017 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC1=NC(=NC=C1Br)N" - } - amount { - moles { - value: 0.00255 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C=C1C(F)(F)F)I)F" - } - amount { - moles { - value: 0.00307 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000262 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000263 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a microwave vial was added a mixture of 5-bromo-4-methoxypyrimidin-2-amine (0.520 g, 2.55 mmol), diacetoxypalladium (0.059 g, 0.26 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (151.8 mg, 0.26 mmol), 1-fluoro-2-iodo-4-(trifluoromethyl)benzene (0.89 g, 3.07 mmol) and toluene (17 mL) under inert atmosphare.The reaction mixture was sealed and heated at 90 C under 16h.The LCMS indicated a complete conversion of the SM.The reaction mixture was partitioned between ethyl acetate and NH4Cl-solution.The organic layer was washed with NH4Cl-solution, brine dried over sodium sulphate, filtered and concentrated in vacuum to give a yellow gum.The oil dissolved in dichloromethane charged on silica 100g and purified by flash chromatography eluting with Ethyl acetate (0-80)% in heptane giving the product 5-bromo-N-(2-fluoro-5-(trifluoromethyl)phenyl)-4-methoxypyrimidin-2-amine (792 mg, 85 %) as a white solid.Collected at 260 nm1H NMR (500 MDMSO) d 3.93 (s, 3H), 7.49 (td, 2H), 8.29 - 8.35 (m, 1H), 8.40 (s, 1H), 9.60 (s, 1H).Expected Number of Hs: 8Assigned Hs: 8." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=NC(=NC=C1Br)NC2=C(C=CC(=C2)C(F)(F)F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 84.88 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/21/2014" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "955" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.4 [N-arylation with Ar-X] Iodo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00304 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.017 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "COC1=NC(=NC=C1Br)N" - } - amount { - moles { - value: 0.00279 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C=C1C(F)(F)F)I)F" - } - amount { - moles { - value: 0.00341 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000264 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000263 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 100.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a microwave vial was added a mixture of 5-bromo-4-methoxypyrimidin-2-amine (0.570 g, 2.79 mmol), diacetoxypalladium (0.059 g, 0.26 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (152.9 mg, 0.26 mmol), 1-fluoro-2-iodo-4-(trifluoromethyl)benzene (0.99 g, 3.41 mmol) and toluene (17 mL) under inert atmosphare.The reaction mixture was sealed and heated at 100 C under 16h.The LCMS indicated a complete conversion of the SM.The reaction mixture was partitioned between ethyl acetate and aqueous NH4Cl-solution.The organic layer was washed with NH4Cl-solution, brine dried over sodium sulphate, filtered and concentrated in vacuum to give a yellow gum.The oil dissolved in dichloromethane charged on silica 100g and purified by flash chromatography eluting with Ethyl acetate (0-80)% in heptane giving the product 5-bromo-N-(2-fluoro-5-(trifluoromethyl)phenyl)-4-methoxypyrimidin-2-amine (827 mg, 81 %) as a white solid.Collected at 260 nm1H N500 MHz, DMSO) d 3.94 (d, 3H), 7.45 - 7.53 (m, 2H), 8.33 (t, 1H), 8.40 (d, 1H), 9.60 (s, 1H).Expected Number of Hs: 8Assigned Hs: 8." - } - outcomes { - products { - identifiers { - type: SMILES - value: "COC1=NC(=NC=C1Br)NC2=C(C=CC(=C2)C(F)(F)F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 80.85 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "02/27/2014" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "956" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00036 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0045 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CC(C1)N2CCN(CC2)C(=O)C3CC34CCNCC4" - } - amount { - moles { - value: 0.00036 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=NC(=C1)Br" - } - amount { - moles { - value: 0.000397 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 1.8e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 1.8e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 160.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "(4-cyclobutylpiperazin-1-yl)(6-azaspiro[2.5]octan-1-yl)methanone (100 mg, 0.36 mmol), Sodium tert-butoxide (34.6 mg, 0.36 mmol) and 2-bromopyridine (62.7 mg, 0.40 mmol) were weighted in a microwave vial. A solution of Palladium(II) acetate (4.05 mg, 0.02 mmol) and dicyclohexyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (X-Phos) (8.59 mg, 0.02 mmol) in toluene (3.75 mL) and tert-butanol (0.75 mL)was added and the mixture heated at 160 C for 10 minutes, and then 20 minutes more. The mixture was evaporated to dryness, redissolved in a minimum of methanol, filtered and purified on preparative HPLC using the long high pH (acetonitrile in water ammonium carbonate buffer, 25 min.) 20 to 40% gradient method on XBridge Prep C18 OBD, 30x150 mm, 5 mm, Waters reverse phase column, giving (4-cyclobutylpiperazin-1-yl)(6-(pyridin-2-yl)-6-azaspiro[2.5]octan-1-yl)methanone (34.0 mg, 26.6 %) as a slightly yellow solid after lyophilization.1H NMR (400 MHz, DMSO-idi6) d ppm 0.75 (dd, iJi=7.81, 3.91 H H) 1.06 (t, iJi=4.49 Hz, 1 H) 1.31 - 1.67 (m, 6 H) 1.74 (d, iJi=10.16 Hz, 2 H) 1.85 - 2.00 (m, 3 H) 2.01 - 2.36 (m, 4 H) 2.65 (quin, iJi=7.52 Hz, 1 H) 3.35 - 3.69 (m, 8 H) 6.58 (dd, iJi=6.64, 5.08 Hz, 1 H) 6.82 (d, iJi=8.59 Hz, 1 H) 7.49 (td, iJi=7.81, 1.95 Hz, 1 H) 8.08 (dd, iJi=4.88, 1.37 Hz, 1 H)HRMS imiizi calcd for C21H31N4O [M + H]+ 355.24924, found 355.24965." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CC(C1)N2CCN(CC2)C(=O)C3CC34CCN(CC4)C5=CC=CC=N5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 26.61 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "05/07/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "957" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000238 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CC(C1)N2CCN(CC2)C(=O)C3CC34CCNCC4" - } - amount { - moles { - value: 0.000216 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=NC(=C1)Br" - } - amount { - moles { - value: 0.000238 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C3CCCCC3)C4CCCCC4)C(C)C" - } - amount { - moles { - value: 6.49e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 6.49e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 160.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Reagents were put in a sealed vial and heated in the microwave oven for 10 minutes at 160C. According to LC-MS analysis, the conversion is gt;90%. The crude mixture was transferred to a round-bottomed flask and volatiles were evaporated under vacuum. The residue was purified on preparative HPLC using the long high pH (acetonitrile in water ammonium carbonate buffer, 25 min.) 20 to 40% gradient method on XBridge Prep C18 OBD, 30x150 mm, 5 mm, Waters reverse phase column, giving (4-cyclobutylpiperazin-1-yl)(6-(pyridin-2-yl)-6-azaspiro[2.5]octan-1-yl)methanone (7.20 mg, 9.39 %). However, the compound was not pure enought for mission and there was not enough of it to attempt another purification." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CC(C1)N2CCN(CC2)C(=O)C3CC34CCN(CC4)C5=CC=CC=N5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 9.39 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/10/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "958" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000235 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=CC2=C1C=CN2)CO" - } - amount { - moles { - value: 0.000214 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.000214 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 2.14e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.07e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 40mL vialnbsp;(t=g) was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (50 mg, 0.21 mmol), [Reactants], and cesium carbonate (77 mg, 0.24 mmol) in DMA (0.5 mL) ([VOLUME]),Pd2(dba)3 (9.80 mg, 10.70 mol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (12.38 mg, 0.02 mmol) were added.to give a brown suspension. The vial was filled with N2,150C microwave for 30 min. LCMS showed completion.added MeOH (3 mL), filtered through celite. concentrated. The residue was purified by ISCO (Hexane to EtOAc:Hex=1;1 to EtOAc) to give about 34 mg offwhite solid" - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)N4C=CC5=C4C=C(C=C5)CO" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 47.5 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/26/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "960" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000445 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)NC1=C(C=CC(=C1)N)N2CCN(CC2)C" - } - amount { - moles { - value: 0.000342 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.000342 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.42e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.71e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 40mL vialnbsp;(t=g) was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (80 mg, 0.34 mmol), [Reactants], and cesium carbonate (145 mg, 0.45 mmol) in DMA (0.5 mL) ([VOLUME]),Pd2(dba)3 (15.68 mg, 0.02 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (19.81 mg, 0.03 mmol) were added.to give a brown suspension. The vial was filled with N2,150C microwave for 30 min. LCMS showed completion.concentrated. loaded on ISCO (Hex to Hex:EtOAc To EtOAc:MeOH=10:1 to EtOAc:MeOH:Et3N=10:1:0.1) to give yellow solid.This yellow solid was washed with EtOAc(1mL) to give 40mg pure compound.NMR, 1H,HPLC are OK, see attachment" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)NC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)N5CCN(CC5)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 32.78 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/14/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "963" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0016 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.016 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.0016 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "COC(=O)C1=C(C=C(C=C1)Br)Cl" - } - amount { - moles { - value: 0.0016 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00016 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 8.02e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a solution of palladium acetate (18.00 mg, 0.08 mmol) in dry toluene (16 mL) under nitrogen was added BINAP (100 mg, 0.16 mmol).nbsp;The reaction was heated to 80 C and stirred for 10 min.nbsp;To the reaction was then added tert-butyl piperazine-1-carboxylate (299 mg, 1.60 mmol), cesium carbonate (261 mg, 0.80 mmol), potassium carbonate (222 mg, 1.60 mmol), 18-crown-6 (42.4 mg, 0.16 mmol) and methyl 4-bromo-2-chlorobenzoate (400 mg, 1.60 mmol).nbsp;The reaction was stirred at 80C overnight, filtered through celite and washed with small amounts of DCM.nbsp;The filtrate was concentrated under reduced pressure and purified by flash chromatography on silica gel, eluting with mixtures of EtOAc and heptane, to afford tert-butyl 4-(3-chloro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (517 mg, 91 %) as a so" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC(=C(C=C2)C(=O)OC)Cl" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 90.88 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/09/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "964" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000961 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)NC1=C(C=CC(=C1)N)C2CC2" - } - amount { - moles { - value: 0.000352 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1C(CO1)NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.00032 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C(C)(C)C)C(C)(C)C)C(C)C" - } - amount { - moles { - value: 3.2e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 10 mL microwave reactor vial was charged with 5-chloro-7-(oxetan-3-ylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (80 mg, 0.32 mmol), N-(5-amino-2-cyclopropylphenyl)acetamide (67.1 mg, 0.35 mmol), Cs2CO3 (313 mg, 0.96 mmol), Pd2(dba)3 (14.67 mg, 0.02 mmol) and 2-Di-t-butylphosphino-2\',4\',6\'-tri-i-propyl-1,1\'-biphenyl (13.61 mg, 0.03 mmol). The suspended in DMA (.5 mL), added via syringe. The resulting brown suspension was stirred under nitrogen, then microwave vial capped and heated at 150 C under microwave irradiation for 20 min.LCMS indicated formation of product.The cooled reaction mixture was put through vacuum filtration and concentrated in rotovap. The crude material was purified by ISCO using MeOH and EtOAc (1:10). The solid was suspended in water, stirred for 12 h at rt, repurified with EtOAc, collected and dried to afford a light brown powder (9 mg, 6%) at 93% purity. LCMS, HPLC, and HNMR consistent with desired product- see attached.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)NC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4COC4)C#N)C5CC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 6.96 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "06/26/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "965" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000601 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CN(C)C=O" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)NC1=C(C=CC(=C1)N)C2CC2" - } - amount { - moles { - value: 0.0002 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1C(CO1)NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.00024 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C(C)(C)C)C(C)(C)C)C(C)C" - } - amount { - moles { - value: 4.01e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "Ref:i Angew. Chem. Int. Ed.i b2006b, i45i, 6523-65271. To a microwave tube was added N-(5-amino-2-cyclopropylphenyl)acetamide (0.038 g, 0.20 mmol), 5-chloro-7-(oxetan-3-ylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (0.060 g, 0.24 mmol), Cs2CO3 (0.196 g, 0.60 mmol), Pd2dba3 (0.018 g, 0.02 mmol), and di-tert-butyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.017 g, 0.04 mmol). The mixture was dissolved in DMF (0.5 mL) and sealed. The tube was de-gassed and inflated with N2.2. The reaction was heated at 90C in oil-bath overnight. LCMS showed SM and byproducts and small amount of product mass.did not workup" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)NC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4COC4)C#N)C5CC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/29/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "966" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0016 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.001 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)NC1=C(C=CC(=C1)N)C2CC2" - } - amount { - moles { - value: 0.000801 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1C(CO1)NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.000801 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC(C)C1=CC(=C(C(=C1)C(C)C)C2=CC=CC=C2P(C(C)(C)C)C(C)(C)C)C(C)C" - } - amount { - moles { - value: 8.01e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 4.01e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 145.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a microwave tube, was Cs2CO3 (0.522 g, 1.60 mmol), N-(5-amino-2-cyclopropylphenyl)acetamide (0.152 g, 0.80 mmol), Pd2dba3 (0.037 g, 0.04 mmol),5-chloro-7-(oxetan-3-ylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (0.200 g, 0.80 mmol),di-tert-butyl(2\',4\',6\'-triisopropylbiphenyl-2-yl)phosphine (0.034 g, 0.08 mmol). anhydrous DMA (1.0 mL) was added. The resulting mixture was bubbled through N2. Then the tube was capped. under microwave 145C for 25min.LCMS showed product and byproduct mass, did not showed SMThe mixture was filtered through celite. The resulting black solution was concentrated to dryness by rotavapor. The crude product was purified by ISCO (40g, Hex to EtOAc:HEx=1;2 to 1;1 to EtOAcO) to give product (offwhite solid). HPLC showed some impurity. This offwhite solid was washed with warm EtOAc (1mL) to give N-(5-(3-cyano-7-(oxetan-3-ylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)-2-cyclopropylphenyl)acetamide (0.028 g, 8.66 %).LCMS and NMR were OKlt; see attachment. " - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)NC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4COC4)C#N)C5CC5" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 8.66 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "07/29/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "971" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00103 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)NC1=C(C=CC(=C1)N)N2CCC[C@H](C2)N(C)C" - } - amount { - moles { - value: 0.000514 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.000514 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 5.14e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 2.57e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 40mL vialnbsp;(t=g) was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (120mg, 0.51 mmol), (R)-N-(5-amino-2-(3-(dimethylamino)piperidin-1-yl)phenyl)acetamide (142 mg, 0.51 mmol), and cesium carbonate (335 mg, 1.03 mmol) in DMA (0.5 mL) (),Pd2(dba)3 (23.51 mg, 0.03 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (29.7 mg, 0.05 mmol) were added.to give a brown suspension. The vial was filled with N2,150C microwave for 30 min. LCMS showed completion. added MeOH (2 mL), filtered. The solvent was removed by ratovapor to yield stick oil. The crude product was loaded on ISCO (Hex to Hex:EtOAc To EtOAc to EtOAc:MeOH:Et3N=10:1:0.1) to give sticky oil.The product was not pure. It was purifed by Gilson to give (R)-N-(5-(3-cyano-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)-2-(3-(dimethylamino)piperidin-1-yl)phenyl)acetamide (22.00 mg, 7.29 %) as anbsp;light brown solid (TFA salt).the solid was dried under high vacuum under 60C for 2h.LCMS and NMR were OK, see the attachment" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)NC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)N5CCC[C@H](C5)N(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 7.29 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/31/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "972" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000253 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.00225 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C1=CC(=CC2=C1OC(=CC2=O)N3CCOCC3)C(=O)N(C)C)N" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=C(C(=C1F)F)Br)F" - } - amount { - moles { - value: 0.00223 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000253 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 7.6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a mixture of 8-(1-aminoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (350 mg, 1.01 mmol), cesium carbonate (1288 mg, 3.95 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (147 mg, 0.25 mmol) and 1-bromo-2,3,5-trifluorobenzene (470 mg, 2.23 mmol) in degassed 1,4-dioxane (2.2ml), was addednbsp;TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (69.6 mg, 0.08 mmol). The suspension was heated in a sealed container up to 85-95Cnbsp;for 24 hours. The reaction mixture was filtered through a short pad of dicalite, concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 0 to 5% methanol in dichloromethane. The solvent was evaporated to dryness to afford the N,N-dimethyl-2-morpholino-4-oxo-8-(1-(2,3,5-trifluorophenylamino)ethyl)-4H-chromene-6-carboxamide (400 mg, 83 %) as a yellow gum, which still containing some impurities. The product mixture was then re-purified by preparative HPLC using a Waters X-Bridge reverse-phaseumn (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford N,N-dimethyl-2-morpholino-4-oxo-8-(1-(2,3,5-trifluorophenylamino)ethyl)-4H-chromene-6-carboxamide (135 mg, 28 %)nbsp;as a clear yellow solid.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C1=CC(=CC2=C1OC(=CC2=O)N3CCOCC3)C(=O)N(C)C)NC4=C(C(=CC(=C4)F)F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 83.02 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "12/21/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "973" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000322 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)N)NC(=O)C" - } - amount { - moles { - value: 0.000292 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CN1C=CC(=N1)NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.000292 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 2.92e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.46e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "in microwave tube was 5-chloro-7-(1-methyl-1H-pyrazol-3-ylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (80 mg, 0.29 mmol), N-(5-amino-2-methylphenyl)acetamide (48.0 mg, 0.29 mmol), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (16.91 mg, 0.03 mmol) in DMA (0.5 mL).Pd2(dba)3 (13.38 mg, 0.01 mmol) and cesium carbonate (105 mg, 0.32 mmol) were added.degassed, filled with N2.capped. then microwave 150C for 30 min.added 2 mL of MeOH, filtered through celite. concentrated. The residue was purified by ISCO (Hex to Hex:EtOAc=1:4 to 1:1 to EtOAc), collected prod fractions. concentrated to give offwhite solid. This solid was washed with 0.5 mL of EtOAc to give pure prod" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=C(C=C(C=C1)NC2=NC3=C(C=NN3C(=C2)NC4=NN(C=C4)C)C#N)NC(=O)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 33.24 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "08/25/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "974" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000685 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC(=C(C=C1NC(=O)C)N)F" - } - amount { - moles { - value: 0.000342 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.000342 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3.42e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.71e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "in microwave tube was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (80 mg, 0.34 mmol), N-(5-amino-4-fluoro-2-methylphenyl)acetamide (62.4 mg, 0.34 mmol), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (19.81 mg, 0.03 mmol) in DMA (0.5 mL).Pd2(dba)3 (15.68 mg, 0.02 mmol) and cesium carbonate (223 mg, 0.68 mmol) were added.degassed, filled with N2.capped. then microwave 150C for 30 min.the organic solvent was removed. The black residue was tried to purifed by ISCO. impurity and prod came out together too quickly. concentrated to give offwhite solid. LCMS showed about 10% impurity.The solid was washed with hot EtOAc(1mL) to give about 21mg white solid.LCMS and NMR are OK, see attachment.low yield was due to hot EtOAc wash, lost some prod." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC1=CC(=C(C=C1NC(=O)C)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 16.17 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/24/2008" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "976" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00123 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.0123 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00123 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C=C1Br)F)C(F)(F)F" - } - amount { - moles { - value: 0.00123 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000123 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 6.17e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 80.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 50 mL round-bottomed flask, PALLADIUM ACETATE (0.014 g, 0.06 mmol) was treated with BINAP (0.077 g, 0.12 mmol) under nitrogen in degassed Toluene (12.35 ml). The reaction was heated to 80 C and was stirred for 10 min. To the flask was then added tert-butyl piperazine-1-carboxylate (0.230 g, 1.23 mmol), cesium carbonate (0.201 g, 0.62 mmol), potassium carbonate (0.171 g, 1.23 mmol), and 18-CROWN-6 (0.033 g, 0.12 mmol). The reaction was then treated with 4-bromo-2-fluoro-1-(trifluoromethyl)benzene (0.300 g, 1.23 mmol) and was allowed to stir at 80C 5 h.bLCMS High pH:bSM Amine Rt = 1.21 minProduct Rt = 2.14 min, Rf = 0.28The reaction mixture was filtered through celite and washed with small amounts of DCM. The filtrate was evaporated in vacuo to a residue that was taken up in a mixture of Heptane and EtOAc (4:1). The residue was purified by flash chromatography on silica gel, eluting with mixtures of EtOAc and heptane, to afford tert-butyl 4-(3-fluoro-4-(tmethyl)phenyl)piperazine-1-carboxylate (0.258 g, 59.9 %) as a solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=CC(=C(C=C2)C(F)(F)F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 59.92 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/23/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "977" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.000253 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 2.25 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C1=CC(=CC2=C1OC(=CC2=O)N3CCOCC3)C(=O)N(C)C)N" - } - amount { - moles { - value: 0.00101 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=C(C=C(C=C1Cl)Br)F" - } - amount { - moles { - value: 0.00223 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 0.000253 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 7.6e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "To a mixture of 8-(1-aminoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (350 mg, 1.01 mmol), cesium carbonate (1288 mg, 3.95 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (147 mg, 0.25 mmol) and 1-bromo-3-chloro-5-fluorobenzene (467 mg, 2.23 mmol) in degassed 1,4-dioxane (2ml), was addednbsp;TRIS(DIBENZYLIDENEACETONE)DIPALLADIUM (69.6 mg, 0.08 mmol). The suspension was heated in a sealed container up to 95Cnbsp;for 16hours. The reaction mixture was filtered through a short pad of dicalite, concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 0 to 8 % iPrOH in CH2Cl2. The solvent was evaporated to dryness tonbsp;afford the 8-(1-(3-chloro-5-fluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (375 mg, 78 %). The product triturated with diethyl ether - CH2Cl2 (9-1) and thenbsp;desired compound was filtered and driednbsp;to afford 320 mg of product P1nbsp;as a clear ow solid.However the final sample product contain some diethyle ether which was removed under vacuum ON before sample mission.nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C1=CC(=CC2=C1OC(=CC2=O)N3CCOCC3)C(=O)N(C)C)NC4=CC(=CC(=C4)Cl)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 78.08 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "12/21/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "978" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.0155 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1COCCO1" - } - amount { - volume { - value: 0.00516 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CCOC(=O)C1CCNCC1" - } - amount { - moles { - value: 0.00516 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)C1=CC=C(C=C1)Br" - } - amount { - moles { - value: 0.00516 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00103 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000516 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 110.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "1. To a microwave tube was added tert-butyl 4-bromobenzoate (1.328 g, 5.16 mmol), ethyl piperidine-4-carboxylate (1.000 g, 5.16 mmol), Cs2CO3 (5.05 g, 15.49 mmol), Pd2dba3 (0.473 g, 0.52 mmol), and BINAP (0.643 g, 1.03 mmol). The mixture was dissolved in [Solvents] and sealed. The tube was de-gassed and inflated with N2.2. The reaction was heated at 110C in oil-bath overnight. LCMS showed reaction complete. The reaction mixture was filter through celite pad and the solution was loaded to column for a ISCO purification (30% EtOAc in Hex). The purification is difficult with multiple by-products. Several ISCO purification was carried out and fractions were combined with other batches. Yield was poor." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CCOC(=O)C1CCN(CC1)C2=CC=C(C=C2)C(=O)OC(C)(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 0.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "09/10/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "979" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.000956 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "C1CNCCN1" - } - amount { - moles { - value: 0.0041 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)C(C2=CC=CC=C2)(C3=CC=CC=C3)N4C=NC5=C4C=CC=C5Br" - } - amount { - moles { - value: 0.000683 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 4.1e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C(Cl)(Cl)Cl.[Pd].[Pd]" - } - amount { - moles { - value: 1.37e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 90.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 2.0-5.0 mL microwave vial was charged with 4-bromo-1-trityl-1H-benzo[d]imidazole (300 mg, 0.68 mmol), Sodium tert-butoxide (92 mg, 0.96 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (25.5 mg, 0.04 mmol), Piperazine (0.321 mL, 4.10 mmol) and toluene (5 mL). The reaction mixture was degassed for 10 minutes with nitrogen, and then Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (14.14 mg, 0.01 mmol) was added. The reaction mixture was stirred at 90C under microwave irradiation for 1h.nbsp;The solution was diluted with EtOAc and washed with water, saturated NaHCO3 solution, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced vacuum.nbsp;The crude material was loaded on a 24g silica gel column and purified on a Teledyne Isco instrument, eluting with 10 : 1 DCM : MeOH containing 0.2% ammonium hydroxide (vv) to provide 4-(piperazin-1-yl)-1-trityl-1H-benzo[d]imidazole (130 mg, 42.8 %) as a solid.nbsp;The product was analyzed by analytical HPLC MS usthe high pH gradient method (mobile phase: 5-95% B; A: H2O with 10 mM NH5CO3 and 0.375% NH4OH vv, B: MeOH, 2.25 min run) on X-Bridge C18, 2.1 x 30 mm, 5 mm particle size. MS imzi 445.6 [M+H]+ (ESI), Rt 2.61 min;nbsp;1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.64 (br. s., 1 H), 3.11 - 3.22 (m, 4 H), 3.48 - 3.59 (m, 4 H), 6.08 (d, J=8.20 Hz, 1 H), 6.54 (d, J=7.42 Hz, 1 H), 6.79 (t, J=8.01 Hz, 1 H), 7.13 - 7.23 (m, 6 H), 7.30 (d, J=3.91 Hz, 9 H), 7.79 (s, 1 H)." - } - outcomes { - products { - identifiers { - type: SMILES - value: "C1CN(CCN1)C2=CC=CC3=C2N=CN3C(C4=CC=CC=C4)(C5=CC=CC=C5)C6=CC=CC=C6" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 42.82 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "11/03/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "982" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.1 [N-arylation with Ar-X] Bromo Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.00502 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.03 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00418 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC(=C(C=C1C(F)(F)F)Br)F" - } - amount { - moles { - value: 0.00418 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000418 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000209 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 105.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 250 mL round flask was charged with 2-bromo-1-fluoro-4-(trifluoromethyl)benzene (1.016 g, 4.18 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.260 g, 0.42 mmol), Sodium tert-butoxide (0.482 g, 5.02 mmol), tert-butyl piperazine-1-carboxylate (0.779 g, 4.18 mmol) and a mixture of toluene (25 mL) and DMF (5 mL). The reaction mixture was degassed for 10 minutes with nitrogen, and then Tris(dibenzylideneacetone)dipalladium(0) (0.191 g, 0.21 mmol) was added. The reaction mixture was stirred at 105C in an oil bath 12h.nbsp;The solution was diluted with EtOAc and washed with saturated NaHCO3 solution, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The aqueous phase was evaporated and the residue was extracted with EtOAc (3X20mL), concentrated.nbsp;The combined crude material was loaded on a 80g silica gel column and purified on a Teledyne Isco instrument, eluting with 0% to 25% ethyl acetate in heptane to provide tert-butyl 4-(2-fluoro-5-(trifluoromethyl)pl)piperazine-1-carboxylate (0.622 g, 42.7 %) as an oil." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=C(C=CC(=C2)C(F)(F)F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 42.75 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "12/09/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "983" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)[O-].[Na+]" - } - amount { - moles { - value: 0.017 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC1=CC=CC=C1" - } - amount { - volume { - value: 0.03 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.0142 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CN=C(C=C1C(F)(F)F)Cl" - } - amount { - moles { - value: 0.0142 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.00142 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 0.000708 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 105.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A 250 mL round flask was charged with 2-chloro-4-(trifluoromethyl)pyridine (2.57 g, 14.16 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.881 g, 1.42 mmol), Sodium tert-butoxide (1.633 g, 16.99 mmol), tert-butyl piperazine-1-carboxylate (2.64 g, 14.16 mmol) and a mixture of toluene (25 mL) and DMF (5 mL). The reaction mixture was degassed for 10 minutes with nitrogen, and then Tris(dibenzylideneacetone)dipalladium(0) (0.648 g, 0.71 mmol) was added. The reaction mixture was stirred at 105C in an oil bath 12h.nbsp;The solution was diluted with EtOAc and washed with saturated NaHCO3 solution, brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The aqueous phase was evaporated and the residue was extracted with EtOAc (3X20mL), concentrated.nbsp;The combined crude material was loaded on a 80g silica gel column and purified on a Teledyne Isco instrument, eluting with 0% to 25% ethyl acetate in heptane to provide tert-butyl 4-(4-(trifluoromethyl)pyridin-2-yl)pipine-1-carboxylate (2.164 g, 46.1 %) as a solid." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=NC=CC(=C2)C(F)(F)F" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 46.13 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "10/13/2010" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "986" - } - identifiers { - type: NAME - details: "reaction type" - value: "0.0 [Unassigned] Unrecognized" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 0.00809 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "C1CCOC1" - } - amount { - volume { - value: 0.03 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCNCC1" - } - amount { - moles { - value: 0.00693 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1=CC2=C(C=CC(=C2N=C1)OS(=O)(=O)C(F)(F)F)Cl" - } - amount { - moles { - value: 0.00578 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)P(C2=CC=CC=C2)C3=C(C4=CC=CC=C4C=C3)C5=C(C=CC6=CC=CC=C65)P(C7=CC=CC=C7)C8=CC=CC=C8" - } - amount { - moles { - value: 0.000289 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "CC(=O)O.CC(=O)O.[Pd]" - } - amount { - moles { - value: 0.000289 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 75.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "A mixture of 5-chloroquinolin-8-yl trifluoromethanesulfonate (1.8 g, 5.78 mmol), Cesium carbonate (2.63 g, 8.09 mmol), rac-2,2\'-Bis(diphenylphosphino)-1,1\'-binaphthyl (0.180 g, 0.29 mmol), tert-Butyl 1-piperazinecarboxylate (1.291 g, 6.93 mmol) and Palladium(II) acetate (0.065 g, 0.29 mmol) in THF (30 mL) under a nitrogen atmosphere was stirred at 75 C for 6h.nbsp;The solution was cooled to rt and diluted with ether.nbsp;The mixtture was filtered through celite and the solvent was evaporated under reduced pressure.nbsp;The residue was purified by flash chromatography on silica gel, eluting with a gradient of 25-50% EtOAc in heptane, to afford tert-butyl 4-(5-chloroquinolin-8-yl)piperazine-1-carboxylate (0.489 g, 24.34 %) as an oil.1H NMR (400 MHz, CHLOROFORM-idi) d ppm 1.51 (s, 9 H), 3.28 - 3.37 (m, 4 H), 3.72 - 3.82 (m, 4 H), 7.06 (d, iJi=7.81 Hz, 1 H), 7.48 - 7.57 (m, 2 H), 8.57 (dd, iJi=8.59, 1.95 Hz, 1 H), 8.94 (dd, iJi=4.10, 1.76 Hz, 1 H); MS mz 348.31 ]+ (ESI).nbsp;" - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(C)(C)OC(=O)N1CCN(CC1)C2=C3C(=C(C=C2)Cl)C=CC=N3" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 24.34 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "03/26/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} -reactions { - identifiers { - type: CUSTOM - details: "reaction index" - value: "987" - } - identifiers { - type: NAME - details: "reaction type" - value: "1.3.2 [N-arylation with Ar-X] Chloro Buchwald-Hartwig amination" - } - inputs { - key: "Base" - value { - components { - identifiers { - type: SMILES - value: "C(=O)([O-])[O-].[Cs+].[Cs+]" - } - amount { - moles { - value: 3e-05 - units: MOLE - } - } - reaction_role: REAGENT - is_limiting: false - } - } - } - inputs { - key: "Solvent" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)N(C)C" - } - amount { - volume { - value: 0.0005 - units: LITER - } - } - reaction_role: SOLVENT - is_limiting: false - } - } - } - inputs { - key: "amine" - value { - components { - identifiers { - type: SMILES - value: "CC(=O)NC1=C(C=CC(=C1)N)N(C)CCCN(C)C" - } - amount { - moles { - value: 0.0003 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "aryl halide" - value { - components { - identifiers { - type: SMILES - value: "C1CC1NC2=CC(=NC3=C(C=NN23)C#N)Cl" - } - amount { - moles { - value: 0.0003 - units: MOLE - } - } - reaction_role: REACTANT - is_limiting: false - } - } - } - inputs { - key: "metal and ligand" - value { - components { - identifiers { - type: SMILES - value: "CC1(C2=C(C(=CC=C2)P(C3=CC=CC=C3)C4=CC=CC=C4)OC5=C1C=CC=C5P(C6=CC=CC=C6)C7=CC=CC=C7)C" - } - amount { - moles { - value: 3e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - components { - identifiers { - type: SMILES - value: "C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.C1=CC=C(C=C1)/C=C/C(=O)/C=C/C2=CC=CC=C2.[Pd].[Pd]" - } - amount { - moles { - value: 1.5e-05 - units: MOLE - } - } - reaction_role: CATALYST - is_limiting: false - } - } - } - conditions { - temperature { - setpoint { - value: 150.0 - precision: 10.0 - units: CELSIUS - } - } - } - notes { - procedure_details: "In a 40mL vialnbsp;(t=g) was 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (70mg, 0.30 mmol), N-(5-amino-2-((3-(dimethylamino)propyl)(methyl)amino)phenyl)acetamide (79 mg, 0.30 mmol), and cesium carbonate (195 mg, 0.60 mmol) in DMA (0.5 mL) (),Pd2(dba)3 (13.72 mg, 0.01 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (17.33 mg, 0.03 mmol) were added.to give a brown suspension. The vial was filled with N2,150C microwave for 30 min. LCMS comletion.nbsp;MeOH (2 mL) was added to the reaction mixture.nbsp;filtered. The mother liquid solvent was removed by ratovapor to yield sticky oil. The crude product was loaded on ISCO (Hex to Hex:EtOAc To EtOAc to EtOAc:MeOH=10:1) to give sticky oil.The product was not pure. It was purified by Gilson to givenbsp;N-(5-(3-cyano-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)-2-((3-(dimethylamino)propyl)(methyl)amino)phenyl)acetamide (50.0 mg, 29.0 %) as TFA saltNMR and LCMS showed desired product, see attachment." - } - outcomes { - products { - identifiers { - type: SMILES - value: "CC(=O)NC1=C(C=CC(=C1)NC2=NC3=C(C=NN3C(=C2)NC4CC4)C#N)N(C)CCCN(C)C" - } - is_desired_product: true - measurements { - type: YIELD - percentage { - value: 29.0 - } - } - reaction_role: PRODUCT - } - } - provenance { - experimenter { - organization: "AstraZeneca" - } - experiment_start { - value: "04/14/2009" - } - publication_url: "https://chemrxiv.org/engage/chemrxiv/article-details/60c9e3f37792a23bfdb2d471" - record_created { - time { - value: "10/19/2021, 12:16:25 PM" - } - person { - name: "Bozhao Nan" - organization: "Notre Dame" - email: "bnan@nd.edu" - } - } - } -} diff --git a/data/00/ord_dataset-00005539a1e04c809a9a78647bea649c.pb.gz b/data/00/ord_dataset-00005539a1e04c809a9a78647bea649c.pb.gz new file mode 100644 index 00000000..3afe8700 --- /dev/null +++ b/data/00/ord_dataset-00005539a1e04c809a9a78647bea649c.pb.gz @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:4fb9060dfef2ac61099e5a9b66ddc464ffff72f71dd0f69a4985a1ba54a40e1a +size 261316 From f533f01f352d76688175392bd6621c3f812fe9a0 Mon Sep 17 00:00:00 2001 From: github-actions Date: Fri, 22 Oct 2021 22:52:35 +0000 Subject: [PATCH 3/3] Update badges --- badges/reactions.svg | 2 +- 1 file changed, 1 insertion(+), 1 deletion(-) diff --git a/badges/reactions.svg b/badges/reactions.svg index 3cd5fcaf..fa332fba 100644 --- a/badges/reactions.svg +++ b/badges/reactions.svg @@ -1 +1 @@ -Reactions: 2268231Reactions2268231 \ No newline at end of file +Reactions: 2268981Reactions2268981 \ No newline at end of file