Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][C:12]([C:25]#[N:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-:28].[Na+].[Na+]>S(=O)(=O)(O)O>[C:13]1([C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:11][CH2:10][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:9])[C:25]([NH2:26])=[O:28])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN(CCC(C#N)(c1ccccc1)c1ccccc1)Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CN(CCC(C(N)=O)(c1ccccc1)c1ccccc1)Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 3-(N-benzyl-N-methylamino)-1-cyano-1,1-diphenylpropane (11.1 g--see Preparation 5) in 90% sulphuric acid (66 ml) was heated at 100° for 1 hour. The mixture was allowed to cool to room temperature and poured into ice/water (300 ml). The aqueous mixture was basified with saturated aqueous sodium carbonate and extracted with dichloromethane (3×100 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give the title compound, yield 10.6 g. A sample recrystallised from ethanol had a melting point of 145°-148°.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]2[CH2:25][O:24]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH3:26][NH2:27].O1CCCC1.Cl>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([OH:24])[CH2:25][NH:27][CH3:26])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2)=[O:5]
Reactant: CN
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(C[C@H]2CO2)ccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC[C@@H](O)Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
2-Chloro-5-[(2S)-2-oxiranylmethyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 13b) (110 mg), methylamine (40% aqueous solution, 2 mL) and tetrahydrofuran (10 mL) were heated together at 50° C. under nitrogen for 20 hours, cooled and concentrated to give an oil. This was purified by Waters' MCX resin and then by column chromatography eluting with 9:1:0.1 dichloromethane/methanol/ammonia. The oil obtained was dissolved in dichloromethane (5 mL) and 1M ethereal hydrogen chloride (4 mL) was added. The resulting white solid was filtered off to give the titled compound (121 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[S:16]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[C:5]([Cl:24])=[CH:4][N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:28][CH2:27]1>C(Cl)Cl.CO>[Cl:24][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[S:16]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])=[N:7][C:2]([NH:37][C:36]2[CH:35]=[CH:34][C:33]([CH2:32][N:29]3[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]3)=[CH:39][CH:38]=2)=[N:3][CH:4]=1
Reactant: O=S(=O)(c1cc(F)ccc1Nc1nc(Cl)ncc1Cl)N1CCCC1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(Nc3ncc(Cl)c(Nc4ccc(F)cc4S(=O)(=O)N4CCCC4)n3)cc2)CC1
Yield: 78 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2,5-dichloro-N-(4-fluoro-2-(pyrrolidin-1-ylsulfonyl)phenyl)pyrimidin-4-amine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 78% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 9.30 (s, 1H), 8.49 (dd, 1H, J=9.2, 4.8 Hz), 7.60 (dd, 1H, J=8.0, 2.9 Hz), 7.41 (d, 2H, J=8.2 Hz), 7.23 (d, 2H, J=8.2 Hz), 7.19 (m, 1H), 3.48 (s, 2H), 3.23 (m, 4H), 2.50 (bs, 8H), 2.31 (s, 3H), 1.78 (m, 4H); MS (ESI): 560.3 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:37]=[CH:36][C:7]([CH2:8][S:9][C@@H:10]2[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[O:16])[C@H:12]([C:28]([N:30]3[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31]3)=[O:29])[CH2:11]2)=[CH:6][CH:5]=1.[N+:38]([C:41]1[CH:54]=[CH:53][C:44]([CH2:45][O:46][C:47](NC(=N)C)=[O:48])=[CH:43][CH:42]=1)([O-:40])=[O:39].[C:55](#[N:57])[CH3:56]>>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][S:9][C@@H:10]2[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)=[O:16])[C@H:12]([C:28]([N:30]3[CH2:34][CH2:33][C@H:32]([NH:35][C:55](=[NH:57])[CH2:56][C:47]([O:46][CH2:45][C:44]4[CH:43]=[CH:42][C:41]([N+:38]([O-:40])=[O:39])=[CH:54][CH:53]=4)=[O:48])[CH2:31]3)=[O:29])[CH2:11]2)=[CH:36][CH:37]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](N)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: CC(=N)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC#N
Agent: Cl
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](NC(=N)CC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 53 °C
Reaction time: 2 h

Procedure:
A suspension of 1.00 g of (2S,4S)-4-(4-methoxybenzylthio)-2-[(3S)-3-aminopyrrolidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine hydrochloride [prepared as described in step (ii) above] and 0.47 g of N-(4-nitrobenzyloxycarbonyl)acetamidine in 20 ml of dry acetonitrile was stirred at 53° C. for 2 hours. The reaction mixture was then freed from impurities by filtration, and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, using a 45:45:5 by volume mixture of methylene chloride, ethyl acetate and methanol as the eluent, to give 0.89 g of the title compound, as a powder.
Reaction SMILES: [C:1]([N:4]1[CH:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][O:6][C:5]1=[O:16])(=[O:3])[CH3:2].C(NC(C)C)(C)C.[Li].[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]=[CH:40][N+:41]([O-:43])=[O:42])=[CH:35][C:34]=1[O:44][CH:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH2:9]([CH:8]1[CH2:7][O:6][C:5](=[O:16])[N:4]1[C:1](=[O:3])[CH2:2][CH:39]([C:36]1[CH:37]=[CH:38][C:33]([O:32][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:34]([O:44][CH:45]2[CH2:49][CH2:48][CH2:47][CH2:46]2)[CH:35]=1)[CH2:40][N+:41]([O-:43])=[O:42])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)N1C(=O)OCC1Cc1ccccc1
Reactant: O=[N+]([O-])C=Cc1ccc(OCc2ccccc2)c(OC2CCCC2)c1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(CC(C[N+](=O)[O-])c1ccc(OCc2ccccc2)c(OC2CCCC2)c1)N1C(=O)OCC1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
A mixture of 3-acetyl-4-benzyl-oxazolidin-2-one (2.1 g, 9.4 mmol) in THF (40 mL) was stirred under N2 at −78° C. Lithium diisopropyl amine (5.2 mL, 10.3 mmol, 2.0 M in heptane/THF/ethylbenzene) was then added dropwise. The mixture was stired for 20 min. 1-Benzyloxy-2-cyclopentyloxy-4-(2-nitrovinyl)benzene (3.2 g, 9.4 mmol) dissolved in 20 mL THF was cannulated over and the mixture was stirred for 2 h at −78° C. After quenching the reaction sat. NH4Cl, the mixture was warmed to r.t., extracted with CH3Cl, washed with water and brine, dried and concentrated. Filtration of the solids with 1:1 hexane/EtOAc, afforded 4 g of white solids. Yield: 75%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:12](SC)=[N:13][N:14]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Cl[C:18]1C=CC=C(C(OO)=O)C=1.[S:28]([O-:32])([O-])(=[O:30])=S.[Na+].[Na+]>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][C:12]([S:28]([CH3:18])(=[O:32])=[O:30])=[N:13][N:14]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CSc1nnc(-c2ccc3c(c2)CCO3)o1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: CC#N
Product: CS(=O)(=O)c1nnc(-c2ccc3c(c2)CCO3)o1
Temperature: 25 °C
Reaction time: 48 h
Yield: 78 %

Procedure:
To a solution of 2-(2,3-dihydro-1-benzofuran-5-yl)-5-(methylthio)-1,3,4-oxadiazole (0.50 g, 2.13 mmol) in acetonitrile (10 mL) was added m-chloroperbenzoic acid (70%, 1.51 g, 6.40 mmol) at 0° C., and the obtained mixture was stirred at room temperature for 2 days. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give the title compound (0.44 g, yield 78%) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][C@H:8]([CH2:13][N:14]([C:27]1[CH:32]=[CH:31][C:30]([O:33][Si](C(C)(C)C)(C)C)=[CH:29][CH:28]=1)[C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1)=[O:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:41])[NH:7][C@H:8]([CH2:13][N:14]([C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=1)=[O:16])[C:27]1[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=1)[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1ccc(F)cn1)c1ccc(O[Si](C)(C)C(C)(C)C)cc1)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1ccc(F)cn1)c1ccc(O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a solution of [(1S,2S)-1-({[4-(t-butyl-dimethyl-silanyloxy)-phenyl]-[(1R,2R)-2-(5-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-amino}-methyl)-2-methyl-butyl]-carbamic acid tert-butyl ester (190 mg) in THF (3 mL) was added TBAF in THF (1M, 1 mL) the resulting solution was stirred at rt for 2 h. The reaction mixture was diluted with EtOAc (30 mL) and washed with H2O (2×15 mL) and brine (15 mL). The EtOAc layer was dried (Na2SO4) and concentrated to give the titled compound (102 mg). MS (MH+ 472).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)[CH2:7][C@@H:6]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:25]([C@H:6]1[CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)[CH:12]=2)[CH2:9][CH2:10][N:5]1[CH2:4][CH2:3][OH:2])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)CN1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(CCO)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 12 h
Yield: 73.1 %

Procedure:
A solution of [(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1yl]-acetic acid methyl ester (Example 57) (110 mg, 0.25 mmol) in THF (2 mL) at room temperature was treated with a 1 N THF solution of lithium aluminum hydride (750 μL, 0.75 mmol) and allowed to stir for 12 h. The reaction mixture was quenched with an aqueous 15% NaOH solution (250 μL) followed by water (250 μL) and THF (2 mL) the reaction mixture was then treated with MgSO4, filtered, and evaporated. The residue was then dissolved in EtOAc (3 mL), retreated with MgSO4, filtered, and evaporated to afford product as an oil (75 mg, 73%). 1H NMR (CDCl3) 1.58-1.62 (m, 2 H), 1.67-1.88 (m, 6 H), 2.74-3.22 (m, 12 H), 3.65-3.76 (m, 2 H), 3.78 (s, 3 H), 4.64-4.67 (m, 1 H), 6.34 (dd, J=8.6, 2.9, 1 H), 6.40 (d, J=2.6, 1 H), 6.75 (d, J=8.6, 1 H), 7.20-7.33 (m, 5 H). 13C NMR 24.2 (CH2), 33.0 (CH2), 33.0 (CH2), 48.4 (CH2), 49.7 (CH2), 53.9 (CH2), 55.5 (CH2), 56.9 (CH3), 58.1 (CH2), 61.6 (CH), 80.5 (CH), 106.5 (CH), 108.1 (CH), 113.4 (CH), 126.5 (CH) 128.8 (CH), 129.5 (CH), 139.6, 144.7, 146.5, 148.5. LC/MS 4.81 min, [M+1]+ 411.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].[F:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[CH2:23][NH2:24].C(N(CC)CC)C>ClCCl>[F:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[CH2:23][NH:24][S:2]([NH:5][C:6](=[O:7])[O:12][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:4])=[O:3]
Reactant: NCc1ccc([N+](=O)[O-])cc1F
Reactant: CC(C)(C)O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34 %

Procedure:
Chlorosulfonyl isocyanate (0.1 mL) and t-butanol (0.12 mL) was mixed in dichloromethane. After 10 minutes, a solution of (2-fluoro-4-nitrophenyl)methanamine (200 mg, 1.176 mmol) in dichloromethane was added at 50° C. After stirring for 30 min the mixture was cooled to room temperature and triethylamine (0.11 mL) was added. After 3 h stirring at room temperature, the mixture was extracted with ethyl acetate and washed with brine. Drying over magnesium sulfate, evaporation of the ethyl acetate and purification by column chromatography gave tert-butyl N-(2-fluoro-4-nitrobenzyl)sulfamoylcarbamate (139 mg, 34%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:13]2[N:18]=[C:17]([CH3:19])[N:16]=[C:15]([NH2:20])[N:14]=2)[C:9](F)=[N:10][CH:11]=1)=[CH2:5])C.[Cl:21][C:22]1[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][C:23]=1[O:29][CH3:30].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.CN(C=O)C>[NH2:20][C:15]1[N:16]=[C:17]([CH3:19])[N:18]=[C:13]([C:8]2[CH:7]=[C:6]([C:4](=[O:3])[CH3:5])[CH:11]=[N:10][C:9]=2[NH:28][C:25]2[CH:26]=[N:27][C:22]([Cl:21])=[C:23]([O:29][CH3:30])[CH:24]=2)[N:14]=1
Reactant: C=C(OCC)c1cnc(F)c(-c2nc(C)nc(N)n2)c1
Reactant: COc1cc(N)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)=O)cc2-c2nc(C)nc(N)n2)cnc1Cl
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
To a mixture of 4-(5-(1-ethoxyvinyl)-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (100 mg, 0.363 mmol) and 6-chloro-5-methoxypyridin-3-amine (Small Molecules, Inc) (86 mg, 0.545 mmol) in 1 mL of THF and 0.3 mL of DMF at 0° C. was added sodium bis(trimethylsilyl)amide (1.09 mL of 1.0 M solution in THF, 1.09 mmol) dropwise and the dark red solution was stirred at this temperature for 30 min. It was quenched with 4 mL of 0.5N HCl and stirred at RT for 10 min. The mixture was treated with 1 N NaOH to pH of about 8. It was extracted twice with EtOAc (30 mL). The combined organic phases were washed with brine and dried over Na2SO4. It was concentrated to half of its volume, the precipitated tan solid was filtered through a fritted funnel, rinsed with 2 mL of ether, collected and dried to give 1-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(6-chloro-5-methoxypyridin-3-ylamino)pyridin-3-yl)ethanone (90 mg, 64% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.63 (s, 1H), 9.29 (s, 1H), 9.03 (s, 1H), 8.47 (s, 1H), 8.30 (s, 1H), 8.06 (br., 1H), 7.90 (br., 1H), 3.96 (s, 3H), 2.60 (s, 3H), 2.47 (s, 3H). m/z (ESI, positive ion) 386.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([C:19]#[N:20])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1.[CH3:28][NH2:29]>O1CCCC1>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:10]([C:11]([NH:29][CH3:28])=[O:13])=[CH:14][C:15]([C:19]#[N:20])=[CH:16][C:17]=2[CH3:18])=[O:12])[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: Cc1cc(C#N)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc(C#N)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the cyanobenzoxazinone product of Step F) (100 mg, 0.22 mmol) in tetrahydrofuran (5 mL) was added dropwise methylamine (2.0 M solution in THF, 0.5 mL, 1.0 mmol) and the reaction mixture was stirred for 5 minutes, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford the title compound, a compound of the present invention, as a white solid (41 mg), which decomposed in the melting apparatus above 180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[S:11])[CH:5]=[CH:6][C:7]=1[CH3:8].Cl.C([O:15][C:16](=O)[CH2:17][NH:18][CH3:19])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:16](=[O:15])[CH2:17][N:18]([CH3:19])[C:10]2=[S:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)CNC
Reactant: Cc1ccc(N=C=S)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(N2C(=O)CN(C)C2=S)cc1Cl
Yield: 57.1 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 18.3 g of 3-chloro-4-methylphenyl-isothiocyanate, 15.3 g of sarcosine ethyl ester hydrochloride, 25 g of triethyl amine, and 300 mL of chloroform. Crystallization from ethyl acetate afforded the title compound (14.5 g) as an off-white solid, m.p. 178°-180° C. Anal. Calcd. for C11H11Cl N2O S: C, 51.87; H, 4.35; N,11.00. Found: C, 1.89; H, 4.20; N, 10.95. Mass spectrum (+FAB, [M+H]+) m/z 255/257.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:16](OC(=O)C)(=[O:18])[CH3:17].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:16]([NH:1][C:2]1[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:18])[CH3:17]
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(C(F)(F)F)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of methyl 2-amino-4-(trifluoromethyl)benzoate (8.00 g, 0.036 mol), acetic anhydride (11.18 g, 0.109 mol), pyridine (8.62 g, 0.109 mol) and chloroform (20 ml) was stirred at room temperature for 48 h. The reaction mixture was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The extracts were washed with 1N hydrochloric acid and water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 50% ethyl acetate/n-hexane to give 8.10 g (0.031 mol 86%) of the title compound as a white powder.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:20][N:19]=2)[C:3]1=[O:31].C([SiH2][O:37][C:38](C)(C)[C:39]1[C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][CH:42]=[CH:41][C:40]=1[N:54]1[CH:63]=[CH:62][C:61]2[C:56](=[CH:57][CH:58]=[C:59]([CH:64]3[CH2:66][CH2:65]3)[CH:60]=2)[C:55]1=[O:67])(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].O.ClCCl>O1CCOCC1>[CH:64]1([C:59]2[CH:60]=[C:61]3[C:56](=[CH:57][CH:58]=2)[C:55](=[O:67])[N:54]([C:40]2[CH:41]=[CH:42][CH:43]=[C:44]([C:6]4[CH:5]=[C:4]([NH:17][C:18]5[CH:23]=[CH:22][C:21]([CH2:24][N:25]6[CH2:26][CH2:27][O:28][CH2:29][CH2:30]6)=[CH:20][N:19]=5)[C:3](=[O:31])[N:2]([CH3:1])[CH:7]=4)[C:39]=2[CH2:38][OH:37])[CH:63]=[CH:62]3)[CH2:66][CH2:65]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(CN3CCOCC3)cn2)c1=O
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ccc2cc(C3CC3)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cccc(-n3ccc4cc(C5CC5)ccc4c3=O)c2CO)cc(Nc2ccc(CN3CCOCC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl-3-(5-morpholin-4-ylmethyl-pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridin-2-one (96 mg, 0.25 mmol), 2-[2-(tert-butyl-dimethyl-silanyloxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-6-cyclopropyl-2H-isoquinolin-1-one (124 mg, 0.233 mmol), 2 mL dioxane, and a 0.86 mg/μL solution of cesium carbonate in water (450 μL, 1.2 mmol) were charged into a 4 mL reaction vial fitted with a stir bar and septum. Sparged mixture with nitrogen for 5 min. Added [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride 1:1 complex with dichloromethane (10 mg, 0.012 mmol). The reaction was sparged with nitrogen for 5 min. Sealed the vial and stirred at 90° 16 hr. Cooled to room temperature and filtered the reaction mixture through a 300 mg C18 cartridge. Washed the cartridge with 4 mL EtOAc, 4 mL water, and 4 mL EtOAc. Separated filtrate phases and washed the organic phase with 5 mL of water and 5 mL of brine. Dried the solution over Na2SO4 and concentrated in vacuo. Purified by C18 reverse phase flash chromatography (gradient elution, 10 to 95% acetonitrile+0.1% TFA/water+0.1% TFA). Added 1 mL of saturated NaHCO3 to the pooled product fractions and concentrated in vacuo. Extracted the remaining aqueous mixture with 2×10 mL CH2Cl2, dried over Na2SO4, and concentrated in vacuo to obtain 6-Cyclopropyl-2-{2-hydroxymethyl-3-[1-methyl-5-(5-morpholin-4-ylmethyl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-2H-isoquinolin-1-one as an off-white solid. (73 mg, 0.12 mmol). MS (ESI) 590 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]3)[CH2:9][NH:8][C:5]2=[CH:6][CH:7]=1.[CH3:19][N:20]([CH2:22][C:23]1[N:24]=[C:25]([NH2:28])[S:26][CH:27]=1)[CH3:21].[C:29](N1C=CN=C1)(N1C=CN=C1)=[O:30].CN(C1C=CC=CN=1)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:29](=[O:30])[NH:28][C:25]3[S:26][CH:27]=[C:23]([CH2:22][N:20]([CH3:21])[CH3:19])[N:24]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)N1CCC2(CNc3ccc(Cl)cc32)C1
Reactant: CN(C)Cc1csc(N)n1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: COC(=O)N1CCC2(C1)CN(C(=O)Nc1nc(CN(C)C)cs1)c1ccc(Cl)cc12
Temperature: 45 °C
Reaction time: 12 h
Yield: 35.1 %

Procedure:
The methyl 5-chlorospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (20 mg, 0.076 mmol) obtained in Step 1 of Example 89 was dissolved in tetrahydrofuran (1.0 mL). Thereafter, the 4-((dimethylamino)methyl)thiazole-2-amine (12 mg, 0.076 mmol) synthesized by a method described in the known methods (International Publication WO2008/086047 etc.) or a method similar thereto, carbonyldiimidazole (24 mg, 0.152 mmol), and dimethylaminopyridine (1.0 mg, 0.008 mmol) were added to the above obtained solution, and the thus obtained mixture was then stirred at 45° C. for 12 hours. Thereafter, the reaction solution was concentrated in vacuo, and the obtained residue was then purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain the captioned compound (12 mg, 34%) in the form of a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH2:8])=[O:7].[CH3:9][C:10]([CH:13]=O)([CH3:12])[CH3:11].[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:15]1([CH:13]([NH:8][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[C:10]([CH3:11])([CH3:12])[CH3:9])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: NC(=O)c1cccs1
Reactant: CC(C)(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)C(NC(=O)c1cccs1)n1nnc2ccccc21

Procedure:
A suspension of thiophene-2-carboxamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid was processed as in Example 1C to provide the title compound.