Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12](=O)[CH2:11][C@H:10]([NH2:14])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].S(=O)(=O)(O)O>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CC(=O)N(Cc2ccccc2)C1=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N[C@H]1CCN(Cc2ccccc2)C1
Temperature: 65 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
Into a 200 ml four-necked flask with a stirrer, a dropping funnel, a Dimroth condenser, and a thermometer, 9.5 g (46.5mmol) of the (S)-1-benzyl-3-aminopyrrolidine-2,5-dione, 50 ml of tetrahydrofuran, and 8.8 g (0.23 mol) of sodium borohydride were introduced, and a solution in which 11.5g (0.12 mol) of 98% sulfuric acid were diluted with 20 ml of tetrahydrofuran was added dropwise over approximately 30 minutes while stirring under an ice-bath, and then stirring was performed for 2 hours. The reaction mixture was heated to 65° C. and was stirred for 2 hours. After the reaction was complete, vacuum concentration was performed. 70 g of water was added for dissolution, and 25 g of concentrated hydrochloric acid were added thereto, followed by stirring at 65° C. for 4 hours. The reaction mixture was cooled to room temperature and was neutralized by adding 32 g of 46% sodium hydroxide while stirring. Extraction was performed three times using 100 ml of toluene, and all the toluene layers were simultaneously subjected to vacuum concentration. The concentrate was subjected to vacuum distillation, and thus 7.3 g of (S)-1-benzyl-3-aminopyrrolidine were obtained as the distillate collected at 130 to 133° C./1.3 kPa. As a result of analysis, the chemical purity was 99% and the optical purity was 91% e.e. 7.0 g of the (S)-1-benzyl-3-aminopyrrolidine, 25 ml of methanol, and 0.7 g of 5% Pd/C were introduced into a 100 ml autoclave, and hydrogen was adjusted to have a pressure of 1 MPa. The temperature was increased to 70° C. and stirring was performed for 8 hours. After the reaction was complete, the temperature was decreased to room temperature and the pressure was released. The content was filtered and the mother liquor was concentrated and distilled, and thus 3.2 g of (S)-3-aminopyrrolidine were obtained as the distillate collected at 80 to 83° C./40 kPa. As a result of analysis, the chemical purity was 99% and the optical purity was 90% e.e.
Reaction SMILES: [I-:1].[Na+].C(#N)C.[CH2:6]([Si:16]([CH3:22])([CH3:21])[CH2:17][CH2:18][CH2:19]Cl)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].O>C1(C)C=CC=CC=1>[CH2:6]([Si:16]([CH3:22])([CH3:21])[CH2:17][CH2:18][CH2:19][I:1])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCC[Si](C)(C)CCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CCCCCCCCCC[Si](C)(C)CCCI

Procedure:
A mixture of 25.0 g (166 mmoles) of sodium iodide, 120 ml. of acetonitrile (dried over molecular sieves) and 26.4 g (95.4 mmoles) of n-decyl-dimethyl (3-chloropropyl)-silane is stirred at near the reflux temperature of the mixture (at about 80°) for 40 hrs. After cooling, the mixture is mixed with water and toluene, and the organic phase recovered, washed thrice with water, then dried and concentrated (to about 40 ml) of an oil which on distillation using a Kugelrohr apparatus yields as the main fraction, refined title product of this step at 83° to 139°, at 0.140-0.095 mm Hg. for use in the next step.
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]=1[CH3:13])[C:3](=[O:6])[CH:4]=[CH2:5].C(N(C(C)C)CC)(C)C.Br[C:28]1[CH:37]=[N:36][C:35]2[NH:34][CH2:33][C:32](C)(C)[O:31][C:30]=2[CH:29]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:31]1[CH2:32][CH2:33][NH:34][C:35]2[N:36]=[CH:37][C:28](/[CH:5]=[CH:4]/[C:3]([N:2]([CH3:1])[CH2:7][C:8]3[O:9][C:10]4[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=4[C:12]=3[CH3:13])=[O:6])=[CH:29][C:30]1=2
Reactant: CC1(C)CNc2ncc(Br)cc2O1
Reactant: C=CC(=O)N(C)Cc1oc2ccccc2c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCC#N
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)OCCN3)oc2ccccc12
Yield: 51.8 %

Procedure:
A solution of N-methyl-N-(3-methylbenzofuran-2-ylmethyl)acrylamide (0.190 g, 0.637 mmol) in propionitrile (3 mL) and DMF (0.6 mL) was deoxygenated with Ar for 20 min. The solution was treated with diisopropylethylamine (0.34 mL, 1.97 mmol) and 7-bromo-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (0.188 g, 0.828 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (0.014 g, 0.078 mmol) and P(o-tol)3 (0.038 g, 0.15 mmol) were then added and the solution was deoxygenated again with Ar for 20 min. The mixture was heated to reflux for 2 h, then allowed to cool. The mixture was diluted with H2O (200 mL) and the resulting solution was washed with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×30 mL), dried (Na2SO4) and concentrated to a dark green oil. Column chromatography (silica gel, CH2Cl2/MeOH, 100 to 98:2) gave the title compound (0.12 g, 52%) as a light yellow solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 7.83 (br s, 1H), 7.62-7.60 (m, 1H), 7.56-7.51 (m, 2H), 7.48-7.41 (m, 1H), 7.38-7.69 (m, 4H), 5.01-4.95 (m, 2H), 4.03 (s, 2H), 3.48 (s, 2H), 3.06-2.90 (m, 3H), 2.18 (s, 3H); MS (ESI) m/e 364 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>ClCCl.N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][S:14]([CH3:13])(=[O:16])=[O:15])=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1sc(NS(C)(=O)=O)nc1C
Yield: 86.6 %

Procedure:
A stirred solution of ethyl-2-amino-4-methyl-thiazole-5-carboxylate (558 mg, 3 mmol) in dichloromethane (15 mL) and pyridine (5 mL) was treated with methanesulfonyl chloride (687 mg, 6 mmol) at rt overnight. The solution was diluted with dichloromethane (50 mL) and washed with 2N aq. HCl solution (15 mL, 3×), dried (MgSO4), filtered and concentrated. The crude residue was diluted with ether (25 mL) and the solid was filtered, washed with 1:1 ether:hexane mixture (10 mL, 3×), and dried in vacuo to obtain the title compound (687 mg, 87%) as an off-white solid.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=[O:11])[C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.CCCCCC.[CH2:24]([N:28]([CH2:32][CH2:33][CH2:34][CH3:35])[C:29](Cl)=[O:30])[CH2:25][CH2:26][CH3:27]>O1CCCC1>[CH2:24]([N:28]([CH2:32][CH2:33][CH2:34][CH3:35])[C:29]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=[O:11])[C:4]=2[CH:3]=[CH:2]1)=[O:30])[CH2:25][CH2:26][CH3:27]
Reactant: O=C(O)c1cccc2[nH]ccc12
Reactant: CCCCN(CCCC)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(=O)n1ccc2c(C(=O)O)cccc21
Reaction time: 0.5 h

Procedure:
To 1H-Indole-4-carboxylic acid (611, 251 mg, 1.56 mmol) in tetrahydrofuran (3 mL), was added 2.5M n-butyllithium in hexane (1.28 mL, 3.19 mmol) at −78° C. After 30 minutes, dibutyl carbamyl chloride (657 mg, 3.43 mmol) was added and stirred for two hours. The reaction solution was quenched with 1M HCl (aq.) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtrated and concentrated. The desired compound was isolated with silica gel column chromatography using 10% ethyl acetate in hexane to give a white solid (612, 88 mg, 18%). MS (ESI) [M−H+]−=315.1.
Reaction SMILES: B1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:11]=2)OC(C)(C)C(C)(C)O1.I[C:21]1[C:29]2[C:24](=[N:25][CH:26]=[N:27][C:28]=2[NH2:30])[N:23]([CH:31]([CH3:33])[CH3:32])[N:22]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:30][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[N:23]([CH:31]([CH3:33])[CH3:32])[N:22]=[C:21]([C:10]3[CH:11]=[C:12]([S:16]([NH2:19])(=[O:17])=[O:18])[CH:13]=[CH:14][CH:15]=3)[C:29]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: CC1(C)OB(c2cccc(S(N)(=O)=O)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)n1nc(-c2cccc(S(N)(=O)=O)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 28 %

Procedure:
A solution of Benzenesulfonamide-3-boronic acid pinacol ester (31 mg, 0.11 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 mL). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA41 (9.2 mg, 28% yield). ESI-MS (M+H)+ m/z calcd 333.1, found 333.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[N:25]=[C:24]([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[NH:23][N:22]=3)[C:9]=2[CH3:31])=[CH:4][CH:3]=1.I[CH3:33].[OH-].[K+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[N:25]=[C:24]([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[N:23]([CH3:33])[N:22]=3)[C:9]=2[CH3:31])=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cc1c(-c2n[nH]c(C3CCCC3)n2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(-c2nc(C3CCCC3)n(C)n2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.7 %

Procedure:
A solution of 3-(5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-5-cyclopentyl-1H-1,2,4-triazole (400 mg, 0.82 mmol), iodomethane (0.19 ml, 2.5 mmol) and potassium hydroxide (138 mg, 2.5 mmol) dissolved in methanol (3 ml) was placed in a round bottom flask, stirred at room temperature for 1 day. After evaporation of the volatile solvent, the crude residue was purified by column chromatography to obtain the title compound (330 mg, 80%) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[NH:11][CH3:12])[C:6]#N.[CH:15](O)=O.[OH2:18]>[Ni]>[CH3:12][N:11]([CH3:15])[C:10]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([CH:6]=[O:18])=[CH:8][C:9]=1[O:13][CH3:14]
Reactant: CNc1c(OC)cc(C#N)cc1OC
Reactant: O=CO
Reactant: O
Agent: [Ni]
Product: COc1cc(C=O)cc(OC)c1N(C)C

Procedure:
A mixture of 91 g of the 3,5-dimethoxy-4-methylaminobenzonitrile obtained in Example 2, 726 g of formic acid and 29 g of p-formaldehyde are heated to reflux for 1 hour. The mixture is then cooled to 20°-30° C. and treated with 181 ml of water and 91 g of Raney-nickel alloy. The reaction mixture is heated to reflux for 1.5 hours, whereby the reaction starts vigorously at 80° C. The reaction mixture is cooled to 25°-30° C. and filtered in such a manner that the metal is always covered with solvent. The filter cake is washed with formic acid and the solution is evaporated under reduced pressure and thereafter treated with 360 ml of toluene and 360 ml of water. The pH is adjusted to 5.5 to 6 by adding 30% aqueous sodium hydroxide solution. After adding 7 g of active charcoal, the reaction mixture is filtered. The filter cake is washed with toluene and the organic phase is concentrated under reduced pressure. 80 g of 4-dimethylamino-3,5-dimethoxybenzaldehyde are obtained as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:30])[O:11][CH2:12][C@@H:13]2[CH2:17][C@@H:16]([NH2:18])[CH2:15][N:14]2[C:19](=[O:29])[NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[CH:5][CH:4]=1)[CH3:2].[NH:31](C(OC(C)(C)C)=O)[CH2:32][C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:30])[O:11][CH2:12][C@@H:13]2[CH2:17][C@@H:16]([NH:18][C:33](=[O:34])[CH2:32][NH2:31])[CH2:15][N:14]2[C:19](=[O:29])[NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCc1ccc(NC(=O)OC[C@@H]2C[C@@H](N)CN2C(=O)NCc2ccccc2Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCc1ccc(NC(=O)OC[C@@H]2C[C@@H](NC(=O)CN)CN2C(=O)NCc2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a solution of ((2S,4R)-4-amino-1-(2-chlorobenzylcarbamoyl)pyrrolidin-2-yl)methyl 4-ethylphenylcarbamate (60 mg, 0.14 mmol) in DMF were added Boc-Gly-OH (37 mg, 0.21 mmol) and HBTU (80 mg, 0.21 mmol). The reaction mixture was stirred at rt overnight and purified on RP-HPLC using a mixture of acetonitrile and H2O. The fraction containing the product was combined and concentrated. The residue was dissolved in MeOH and 4N HCl in dioxane. The reaction mixture was stirred at rt for 1 h and concentrated to give ((2S,4R)-4-(2-aminoacetamido)-1-(2-chlorobenzylcarbamoyl)pyrrolidin-2-yl)methyl 4-ethylphenylcarbamate (37 mg, 51%). LRMS (M+H+) m/z 488.1.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]1([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[N:12]1([C:6]2[CH:11]=[CH:10][C:9]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:8][CH:7]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: c1ccc(-n2ccnc2)cc1
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1ccc(-n2ccnc2)cc1

Procedure:
To chlorosulfonic acid cooled to 0° C. in an ice bath is added portionwise 1-phenyl-1H-imidazole. Monitor the progress of the reaction by thin-layer chromatography. When the reaction is complete, quench the mixture on ice. Saturated aqueous NaHCO3 is added until the solution is no longer acidic. Extract the mixture with CH2Cl2. Dry the organic layer over anhydrous Na2SO4 and remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:20]2[CH:28]=[C:27]([Cl:29])[N:26]=[CH:25][C:21]=2[N:22]=[CH:23][N:24]=1>>[ClH:18].[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:19]3[C:20]4[CH:28]=[C:27]([Cl:29])[N:26]=[CH:25][C:21]=4[N:22]=[CH:23][N:24]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2c(cnn2Cc2ccccc2)c1
Reactant: Clc1cc2c(Cl)ncnc2cn1
Product: Cl
Product: Clc1cc2c(Nc3ccc4c(cnn4Cc4ccccc4)c3)ncnc2cn1

Procedure:
Prepared according to Procedure A from 1-benzyl-1H-indazol-5-ylamine and 4,6-dichloropyrido[3,4-d]pyrimidine; δH [2H6]-DMSO 9.08 (1H,s), 8.92 (1H,s), 8.82 (1H,s), 8.23 (1H,d), 8.19 (1H,s), 7.80 (1H,d), 7.70 (1H,dd), 7.38–7.22 (5H,m), 5.69 (2H,s); m/z (M+1)+ 387.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:18](I)[CH3:19].[CH3:21][C:22](C)=O>>[CH2:21]([O:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:18][CH3:19])=[O:5])[CH3:22]
Reactant: Cc1ccc(C(=O)O)c(O)c1
Reactant: CC(C)=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1ccc(C)cc1OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 85 %

Procedure:
To a mixture of 2-hydroxy-4-methylbenzoic acid (5.0 g, 32.9 mmol), K2CO3 (18.9 g, 136.6 mmol) and acetone (50 mL) was added ethyl iodide (41.0 g, 263.2 mmol). The mixture was stirred at room temperature for 3 days. After filtration, the organic layer was concentrated to afford ethyl 2-ethoxy-4-methylbenzoate as colorless oil (5.7 g, 85%), which was used directly for next step.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH3:7][C@H:8]([OH:13])[CH2:9][CH2:10][CH2:11][CH3:12].F[C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:17]([NH2:30])[N:16]=1>COCCOC>[CH3:7][C@H:8]([O:13][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:17]([NH2:30])[N:16]=1)[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: Nc1nc(F)nc2c1ncn2C1CCCCO1
Reactant: CCCC[C@H](C)O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCC[C@H](C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C
Yield: 41.2 %

Procedure:
Sodium t-butoxide (4.86 g, 50.6 mmol) was added portionwise to a stirred mixture of (S)-2-hexanol (12 g, 117 mmol) and 1,2-dimethoxyethane (12 ml). The resultant mixture was heated to 50° C. under an atmosphere of nitrogen and then 2-fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (3 g, 12.65 mmol) was added. The resultant mixture was maintained at 50° C. for 20 hours when LCMS indicated complete reaction. The mixture was cooled to room temperature and partitioned between ethyl acetate (100 ml) and water (100 ml). The organic phase was washed with water (100 ml) then saturated brine (50 ml), dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was dissolved in dichloromethane and purified on an aminopropyl (NH2) cartridge (100 g) eluting with a 0-100% ethyl acetate in cyclohexane gradient over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white foam (1.665 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10]C(C(OC)=O)=[CH:4][C:3]=1[CH3:12].[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:14]([C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:4][C:3]=1[CH3:12]
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1Br
Reaction time: 0.17 h

Procedure:
To a mixture of methyl 4-bromo-3-methylbenzoate (4.85 g) and tert-butyl acetate (3 mL) was added 1M potassium tert-butoxide in THF (0.3 mL). The mixture was stirred under vacuum for 10 minutes and treated with another equivalent of tert-butyl acetate and 1 mol % of (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) dichloromethane. This procedure was repeated three times. The mixture was diluted with ethyl acetate (40 mL) and washed with 5% aqueous HCl, water and brine. After drying over Na2SO4, the mixture was concentrated.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10](=[CH:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH3:29])[CH3:28])[C:9]1=[O:35])=O)(C)(C)C.[F:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=1[CH:44]=[N:45][C:46]([O:48][Si](C)(C)C)=[CH2:47]>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:35])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH3:29])[CH3:28])[CH2:47][C:46](=[O:48])[NH:45][CH:44]3[C:38]3[CH:39]=[C:40]([F:43])[CH:41]=[CH:42][C:37]=3[F:36])[C:11]2=[CH:12][CH:13]=1
Reactant: C=C(N=Cc1cc(F)ccc1F)O[Si](C)(C)C
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C=C1C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C
Yield: 0.1 %

Procedure:
Under argon protection, E/Z 6-Chloro-3-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 229c (8 g, 15.4 mmol) and 1-(2,5-difluoro-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (30.8 mmol) were dissolved in toluene. The solution was heated at 80° C. for 5 h. Then the solution was concentrated and the residue was purified by chromatography (CH2Cl2:CH3OH=50:1) to obtain 1.7 g crude product. The crude product (50 mg) was purified again by Prep-HPLC to obtain give title compound as a white solid (12 mg).
Reaction SMILES: CC(C)([O-])C.[K+].[N:7]1([S:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[C:18]23[O:29][CH2:28][CH2:27][CH2:26][O:25]2)(=[O:14])=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]1.Br[CH2:31][CH2:32][CH:33]([Br:35])[CH3:34].O>CS(C)=O>[N:7]1([S:12]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH:32]([CH3:31])[CH:33]([Br:35])[CH3:34])[C:19](=[O:24])[C:18]23[O:29][CH2:28][CH2:27][CH2:26][O:25]2)(=[O:13])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCCC3)cc2C12OCCCO2
Reactant: CC(Br)CCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(Br)C(C)N1C(=O)C2(OCCCO2)c2cc(S(=O)(=O)N3CCCC3)ccc21
Reaction time: 0.17 h

Procedure:
To a solution of potassium t-butoxide (0.12 g, 1 mmol, 1 eq) in anhydrous DMSO (5 mL) at room temperature under dry N2 atmosphere was added 5′-{[pyrrolidin-1-yl]sulfonyl}spiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one (previously described in step 2, Example 12) (0.33 g, 1 mmol). After stirring for 10 minutes, 1,3-dibromobutane (0.22 g, 1 mmol, 1 eq) was added dropwise to the reaction over a 5 minute period. The reaction mixture was stirred at room temperature for one hour. The mixture was poured into H2O (20 ml) and exhaustively extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel using 30% EtOAc/hexane to give the title compound as an off white solid (0.23 g, 50% yield). NMR (400 MHz, DMSO-d6): consistent. MS: (API-ES+) m/z 474 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[S:19])[NH:9]2)[CH:7]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]3([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:17])([CH3:18])[O:12][CH2:11][C:10](=[S:19])[NH:9]3)[CH:7]=2)=[O:30])=[N:27][CH:28]=1
Reactant: CC1(C)OCC(=S)N[C@](C)(c2cc(N)ccc2F)C1(F)F
Reactant: O=C(O)c1ccc(Cl)cn1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)C1(F)F

Procedure:
The compound was prepared in an analogous manner as described for intermediate B14A from (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepane-3-thione (intermediate A17B) (150 mg, 0.47 mmol) and commercially available 5-chloro-pyridine-2-carboxylic acid [CAS No. 86873-60-1] (111 mg, 0.71 mmol). The compound was obtained as a yellow foam (330 mg, 99%, 65% purity). MS (ISP): m/z=460.4 [(M+H)+] and 462.1 [(M+2+H)+].
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5](Br)=[C:6]([CH3:8])[N:7]=1.[SH:10][C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:2][C:3]1[S:4][C:5]([S:10][C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1nc(N)sc1Br
Reactant: Sc1ncccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(N)sc1Sc1ncccn1
Temperature: 90 °C
Yield: 57.8 %

Procedure:
A mixture of 2-amino-5-bromo-4-methylthiazole hydrochloride (1.15 g), 2-mercaptopyrimidine (0.6 g) and potassium carbonate (1.7 g) in N,N-dimethylformamide (20 ml) was heated at 90° C. for 3.5 hours with stirring. The reaction mixture was poured into ice water. The mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1), washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh,; Merck: 100 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-4-methyl-5-(2-pyrimidinylthio)thiazole (0.65 g, yield: 58.0%). mp: 165°-170° C. (dec.) IR (Nujol): 3300, 3175, 1630, 1555, 1490, 1320 cm-1