Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][N:22]1[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH:23]1[CH:29]([CH3:31])[CH3:30])C1C=CC=CC=1>C(O)C.[Pd]>[CH3:31][CH:29]([CH:23]1[N:22]([CH2:21][C@H:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)[CH2:27][CH2:26][NH:25][C:24]1=[O:28])[CH3:30]
Reactant: CC(C)C1C(=O)NCCN1C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)C1C(=O)NCCN1C[C@H]1CNCCN1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-(((2R)-1,4-dibenzyl-2-piperazinyl)methyl)-3-(1-methylethyl)-2-piperazinone (0.414 g, 0.984 mmol) in ethanol (4.92 mL) was placed under an atmosphere of N2 and charged with 10% palladium on carbon (10% wt. (dry basis) on activated carbon, wet, Degussa type (0.314 g, 0.295 mmol, Sigma-Aldrich, St. Louis, Mo.)). The mixture was purged with hydrogen gas and stirred at room temperature under a hydrogen atmosphere (1 atm) for 72 h. The solids were then removed by filtering through a pad of Celite® (diatomaceous earth), rinsing with EtOH, the filtrate was concentrated, and the product was carried forward without further purification (238 mg).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[F:19][C:20]1[N:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]2=[N:22][C:21]=1[C:29](O)=[O:30]>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:29]([C:21]3[N:22]=[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]4[C:20]=3[F:19])=[O:30])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1nc2ccccn2c1F
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1nc2ccccn2c1F

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.767 mmol) and 3-fluoroimidazo[1,2-a]pyridine-2-carboxylic acid (180 mg, 0.997 mmol). The product was triturated with acetonitrile. Yield 217 mg (67%). 1H-NMR (400 MHz; d6-DMSO): δ 1.15 (d, 3H), 4.31-4.44 (m, 2H), 4.47-4.55 (m, 1H), 6.95 (d, 1H), 7.06 (t, 1H), 7.37 (m, 1H), 7.55-7.58 (m, 1H), 7.85 (d, 1H), 7.97 (d, 1H), 8.08 (t, 1H), 8.31 (1H, d), 8.55 (d, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[CH2:9][CH2:8][C:7]1=[O:18].[CH3:19][C@H:20]1[CH2:25][NH:24][CH2:23][CH2:22][NH:21]1>>[CH3:19][C@@H:20]1[NH:21][CH2:22][CH2:23][N:24]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:7](=[O:18])[CH2:8][CH2:9][C:10](=[O:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=3)[CH2:25]1
Reactant: O=C1CCC(=O)N(CCCCCl)c2ccccc21
Reactant: C[C@H]1CNCCN1
Product: C[C@H]1CN(CCCCN2C(=O)CCC(=O)c3ccccc32)CCN1
Yield: 22.5 %

Procedure:
Analogously to the method for Example 12b, reaction of 1-(4-chlorobutyl)-3,4-dihydro-1H-1-benzazepine-2,5-dione (0.56 mmol, 0.15 g) with (S)-(+)-2-methylpiperazine (0.54 mmol, 0.05 g) afforded 40.0 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24](Br)[CH:25]=2)[NH:20][CH:19]=1)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([Sn](CCCC)(CCCC)C=C)[CH2:29]CC.C(OCC)(=O)C>CN(C=O)C>[CH:28]([C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[C:16]([C@H:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:17])=[CH2:29]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(c1c[nH]c2ccc(Br)cc12)[C@H]1CCCN1C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=Cc1ccc2[nH]cc(C(=O)[C@H]3CCCN3C(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
A solution (R)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylcarbonyl )-5-bromo-1H-indole (Example 5a, 252 mg, 0.59 mmol), tributyl(vinyl)tin (0.20 mL, 0.68 mmol) and tetrakistriphenyphosphine palladium (0) (84 mg, 0.073 mmol) in anhydrous DMF (3 mL) was stirred at 95-100° C. for 1 day. After cooling to room temperature, the product was taken into ethyl acetate, filtered through celite, washed with water (2×) and brine (1×), dried over sodium sulfate and the solvent was removed in vacuo. Flash chromatography on silica gel (60-100% ethyl acetate in hexanes) yielded (R)-5-vinyl-3-[(N-carbobenzyloxypyrrolidin-2-yl)carbonyl]-1H-indole (115 mg, 52%). A solution of LAH (0.77 mL, 1M in THF, 0.77 mmol) was added slowly to a cooled (0° C.) solution of (R)-5-vinyl-3-[(N-carbobenzyloxypyrrolidin-2-yl) carbonyl]-1H-indole (115 mg, 0.31 mmol) in THF (5 mL). Once the addition was completed, the reaction mixture was stirred at reflux for 2 h prior to quenching with sodium sulfate decahydrate. The product was taken into ethyl acetate, filtered to remove the solid residue, and the solvent was removed in vacuo. Flash chromatography on silica gel (5% 2M methanolic ammonia in dichloromethane) yielded (R)-5-vinyl-3-[(N-methylpyrrolidin-2-yl) methyl]-1H-indole (52 mg, 71%). HRMS-FAB+ for C16H20N2 : calculated MH+ :241.17047; found MH+ :241.17036.
Reaction SMILES: Br.COC([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([N:17]3[CH2:21][CH2:20][C@H:19]([N:22]4[CH2:26][CH2:25][CH2:24][C@@H:23]4[CH3:27])[CH2:18]3)[CH:15]=[CH:16][C:9]=2[CH2:8][CH2:7]1)=O>C(O)(=O)C>[CH3:27][C@H:23]1[CH2:24][CH2:25][CH2:26][N:22]1[C@H:19]1[CH2:20][CH2:21][N:17]([C:14]2[CH:15]=[CH:16][C:9]3[CH2:8][CH2:7][NH:6][CH2:12][CH2:11][C:10]=3[CH:13]=2)[CH2:18]1
Reactant: COC(=O)N1CCc2ccc(N3CC[C@H](N4CCC[C@@H]4C)C3)cc2CC1
Agent: Br
Solvent: CC(=O)O
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNCC3)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.5 %

Procedure:
Hydrobromic acid in acetic acid (28.4 mL of 33% by weight) was added to 7-((2S,3′S)-2-Methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid methyl ester (700 mg, 1.96 mmol) and the mixture was stirred at ambient temperature for 24 h. The volatiles were removed in vacuo, and the residue was basified with saturated sodium bicarbonate solution and extracted into ethyl acetate (3×). The combined organic layers were washed with brine, dried over Magnesium sulfate, filtered and concentrated to leave 584 mg of an oil. This material was purified by column chromatography on silica gel (24 g SiO2, Analogix column) eluting @ 30 mL/min as follows: dichloromethane (containing 2% triethylamine for 5 min. then stepped to 85/15 dichloromethane (containing 2% triethylamine)/methanol in a linear gradient over 10 min to obtain 473 mg of the title compound as an oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH:12]([C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]3[C:29]4[CH:30]=[CH:31][C:32]([CH3:34])=[CH:33][C:28]=4[N:27]=[C:26]3[C:35]([OH:38])([CH3:37])[CH3:36])[CH2:21][CH2:20]1)=[O:18])[CH2:11]2)(C)(C)C.Cl>O1CCOCC1>[NH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH:12]([C:17]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]3[C:29]4[CH:30]=[CH:31][C:32]([CH3:34])=[CH:33][C:28]=4[N:27]=[C:26]3[C:35]([OH:38])([CH3:36])[CH3:37])[CH2:23][CH2:24]1)=[O:18])[CH2:11]2
Reactant: Cc1ccc2c(c1)nc(C(C)(C)O)n2C1CCN(C(=O)C2Cc3ccc(NC(=O)OC(C)(C)C)cc3C2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)nc(C(C)(C)O)n2C1CCN(C(=O)C2Cc3ccc(N)cc3C2)CC1
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a solution of (2-{4-[2-(1-hydroxy-1-methyl-ethyl)-5-methyl-benzoimidazol-1-yl]-piperidine-1-carbonyl}-indan-5-yl)-carbamic acid tert-butyl ester (266 mg, 0.49 mmol) in dioxane (2 mL) was added 4 M HCl (2 ml). After the addition was complete, the reaction mixture was stirred for 1 hour. The solvent mixture was quenched with saturated NaHCO3 and extracted with ethyl acetate, the extracts was dried over Na2SO4 and concentrated to afford (5-amino-indan-2-yl)-{4-[2-(1-hydroxy-1-methyl-ethyl)-5-methyl-benzoimidazol-1-yl]-piperidin-1-yl}-methanone (200 mg 95%) as a white solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH:24]([CH2:30][CH2:31][CH2:32][CH2:33]I)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[CH2:9]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(CCCCI)CCN1CCN(Cc2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCN2CCN(Cc3ccccc3)CC2)CCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of lithium diisopropylamide (2 M, 13.3 ml, 26.7 mmol) in tetrahydrofuran (113 ml) was added the solution of ethyl 2-[2-(4-benzyl-1-piperazinyl)ethyl]-6-iodohexanoate (6.3 g) in tetrahydrofuran (20 ml) at −78° C. After 30 min, the temperature was gradually raised to 0° C. during a period of 30 min. After 15 min at 0° C., the reaction was quenched by adding AcOH (0.230 ml). After the mixture was basified with aq. saturated NaHCO3, then the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over NASO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 200-350 mesh/500 g/hexane:ethyl acetate=2:1) to provide a yellow oil (4.2 g/92%).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[N+](C)([O-])=O>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:13]([C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]([F:9])([F:20])[F:21])=[O:14])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(=O)c2ccccc2C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
To commercially available nitromethane (10 ml) were added commercially available anisole (1.081 g), commercially available 2-(trifluoromethyl)benzoyl chloride (2.086 g) and commercially available ytterbium(III) trifluoromethanesulfonate (620 mg), and the admixture was stirred at 60° C. for 6 hours. The reaction mixture was partitioned between water and chloroform, abd the chloroform layer was then dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by chromatography on silica gel eluting with hexane/ethyl acetate to obtain 1.402 g of the title compound (yield: 50%).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][C:6](Cl)=[O:7])[CH3:4].C(=O)(O)[O-].[Na+].[NH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1>C(#N)C>[CH3:2][N:3]([CH2:5][C:6]([NH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)=[O:7])[CH3:4]
Reactant: CN(C)CC(=O)Cl
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)CC(=O)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
To a solution of N,N-dimethylaminoacetyl chloride hydrochloride (137, 10.1 g, 64.2 mmol) in acetonitrile (300 ml.) was added powdered sodium bicarbonate (11.9 g, 141 mmol) followed by 4-aminobenzoic acid (138, 9.68 g, 70.6 mmol). The mixture was vigorously stirred over 16 h at r.t. and acetonitrile was decanted. The remaining gum was triturated with methanol and filtration afforded the title compound 139 (10.9 g, 76% yield). 1H NMR: (400 MHz, DMSO-d6) δ(ppm): 10.21 (s, 1H), 7.84 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.6 Hz, 2H), 4.17 (bs, 2H), 2.27 (s, 6H). LRMS: (m/z): 223.3 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=2[CH3:20])[CH2:7][CH2:6]1.C1COCC1>CO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[CH3:20])[CH2:7][CH2:6]1
Reactant: COCCN1CCN(c2ccc([N+](=O)[O-])cc2C)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COCCN1CCN(c2ccc(N)cc2C)CC1

Procedure:
A solution of 0.85 g (3.04 mmol) 1-(2-methoxy-ethyl)-4-(2-methyl-4-nitro-phenyl)-piperazine in 20 ml MeOH:THF=1:1 is hydrogenated in the presence of 0.2 g 10% Pd/C (Engelhard 4505). The reaction mixture is filtered (2 glass fiber filters used) and the filtrate is concentrated in vacuo to afford the title compound as an oil.
Reaction SMILES: [CH:1]([CH:4]1[C:8](=[O:9])[O:7][CH:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[N:5]1[C:46](=[O:51])[CH2:47][CH2:48][CH2:49][CH3:50])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CN(C)C(=O)C.[Pd]>[CH3:50][CH2:49][CH2:48][CH2:47][C:46]([N:5]([C@H:4]([C:8]([OH:9])=[O:7])[CH:1]([CH3:3])[CH3:2])[CH2:6][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[NH:23][N:24]=[N:25][N:26]=2)=[CH:14][CH:15]=1)=[O:51]
Reactant: CCCCC(=O)N1C(c2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)OC(=O)C1C(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C
Temperature: 90 °C
Yield: 70 %

Procedure:
1.0 g (1.5 mmoles) of 4-isopropyl-3-pentanoyl-2-[2′-(1-trityl-1H-tetrazol-5-yl)-biphenyl-4-yl]oxazolidin-5-one are reacted in 50 ml of N,N,-dimethyl-acetamide with 1.2 g of ammonium formate (19.0 mmoles) and 1.2 g of 5% Pd/C catalyst. The temperature is raised to 90° C. and ammonium formate is added in 1.2 g (19.0 mmoles) portions, at 2 hours interval, until disappearance of the starting substrate. The mixture is cooled and the catalyst is filtered off. tert-Butyl methyl ether and 20% sulfuric acid are added to about pH 2, then sodium chloride to saturation of the aqueous phase. The organic phase is separated and washed with water 3 times. The organic phase is alkalinised with a 10% sodium hydroxide solution. The aqueous phase containing the salified product is separated and washed with tert-butyl methyl ether. Ethyl acetate is added and acidified with a 5% hydrochloric acid solution. The organic phase is separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to a residue. Crystallization from isopropyl ether affords 0.44 g of valsartan (1.05 mmoles; yield: 70%), having purity higher than 99.5% and content in azide derivatives lower than 20 ppm.
Reaction SMILES: [C:1]12([NH:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([CH2:22]Cl)=[CH:14][N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CN(C)C=O.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]12([NH:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([CH2:22][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:14][N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C1COCCN1
Reactant: FC(F)(F)c1nc(NC23CC4CC(CC(C4)C2)C3)ncc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1nc(NC23CC4CC(CC(C4)C2)C3)ncc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of N-adamantan-1-yl-5-(chloromethyl)-4-(trifluoromethyl)pyrimidin-2-amine (170 mg) and N,N-dimethyl formamide (4 mL) were added morpholine (0.21 mL) and potassium carbonate (136 mg) under ice-cooling, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain N-adamantan-1-yl-5-(morpholin-4-ylmethyl)-4-(trifluoromethyl)pyrimidin-2-amine (160 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2([OH:31])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[N:20])[CH:17]=3)[N:12]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:11]2=[O:30])=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2].Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:34]>N1C=CC=CC=1.ClCCl>[C:33](=[O:34])([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[O:31][C:10]1([C:9]2[C:4]([O:3][CH2:1][CH3:2])=[N:5][CH:6]=[CH:7][CH:8]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[N:20])[CH:17]=2)[N:12]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:11]1=[O:30]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOc1ncccc1C1(O)C(=O)N(S(=O)(=O)c2ccccc2)c2ccc(C#N)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1ncccc1C1(OC(=O)Oc2ccccc2)C(=O)N(S(=O)(=O)c2ccccc2)c2ccc(C#N)cc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2.65 g (6.09 mmol) of optically active 3-(2-ethoxypyridin-3-yl)-3-hydroxy-2-oxo-1-(phenylsulfonyl)indoline-5-carbonitrile from example 4B.1 were dissolved in 4.9 ml of pyridine and 6.0 ml of dichloromethane while cooling at 0° C. in ice, the solution becoming brown in color. At this temperature, 1.24 g (7.91 mmol) of phenyl chloroformate were slowly added dropwise. The reaction mixture was stirred in an ice bath for 2 hours. After conversion was complete, the reaction mixture was further diluted with dichloromethane and poured into ice-water. The phases were separated, and the organic phase was washed again with saturated sodium chloride solution (1×) and water (1×). The solvent was evaporated in vacuo, and excess pyridine was removed by codistillation with toluene. 50 ml of diisopropyl ether were added to precipitate the product, and, after the solid had been filtered off with suction and washed with diisopropyl ether, a total of 2.16 g (3.89 mmol, 64%) of the optically active 5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl phenyl carbonate was isolated. Further purification of the mother liquor by normal-phase chromatography with dichloromethane as mobile phase resulted in 800 mg of the optically active 5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-ylphenyl carbonate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH:10]([F:12])[F:11])[C:3]=1[C@H:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([C:24]3[CH:25]=[N:26][N:27]([CH:30]4[CH2:33][C:32](=[O:34])[CH2:31]4)[C:28]=3[CH3:29])[CH:22]=2)[NH:17][CH:16]=1)[CH3:14].[BH4-].[Na+].CCO.[NH4+].[Cl-]>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH:10]([F:12])[F:11])[C:3]=1[C@H:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([C:24]3[CH:25]=[N:26][N:27]([C@@H:30]4[CH2:31][C@H:32]([OH:34])[CH2:33]4)[C:28]=3[CH3:29])[CH:22]=2)[NH:17][CH:16]=1)[CH3:14]
Reactant: Cc1c(-c2cnc3[nH]cc([C@H](C)c4c(OC(F)F)ccc(F)c4Cl)c3c2)cnn1C1CC(=O)C1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1c(-c2cnc3[nH]cc([C@H](C)c4c(OC(F)F)ccc(F)c4Cl)c3c2)cnn1[C@H]1C[C@@H](O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-[4-(3-{(1S)-1-[2-chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methyl-1H-pyrazol-1-yl]cyclobutanone (10.0 mg, 0.0204 mmol), sodium borohydride (3.87 mg, 0.102 mmol) and EtOH (1 mL, 20 mmol) was stirred at rt for 30 min. Sat. NH4Cl was added, and the organic solvent was removed in vacuo. The material was extracted with DCM and water. The organic layer was concentrated in vacuo, redissolved in MeOH (0.7 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.84 (d, J=7.1 Hz, 3H), 2.17 (s, 3H), 2.48-2.58 (m, 2H), 2.78-2.87 (m, 2H), 4.07-4.17 (m, 1H), 4.34-4.45 (m, 1H), 5.10 (q, J=7.2 Hz, 1H), 6.42 (br. s., 1H), 7.07-7.15 (m, 1H), 7.15-7.21 (m, 1H), 7.36 (s, 1H), 7.39 (d, J=1.0 Hz, 1H), 7.50 (s, 1H), 8.14 (br. s., 1H). MS (ES+): m/z=491.15/493.15 (100/50) [MH+]. HPLC: tR=1.41 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=2[S:5][C:6]=1/[C:7](=[N:9]/[S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])/[CH3:8].O.[BH4-].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O.CCCCCC>[Br:1][C:2]1[C:3]2[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=2[S:5][C:6]=1[CH:7]([NH:9][S:10]([C:12]([CH3:14])([CH3:15])[CH3:13])=[O:11])[CH3:8]
Reactant: C/C(=N\S(=O)C(C)(C)C)c1sc2ccccc2c1Br
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(NS(=O)C(C)(C)C)c1sc2ccccc2c1Br
Reaction time: 0.5 h

Procedure:
To a solution of (E)-N-(1-(3-bromobenzo[b]thiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (1.35 g, 3.77 mmol) dissolved in THF (30 mL) and water (0.612 mL) cooled by a water-ice bath was added sodium borohydride (0.265 mL, 7.54 mmol) all in one portion. The reaction was stirred at low temperature for 30 min, and judged complete. To the reaction solution was added satd. aq. NaHCO3 and the resulting mixture stirred vigorously until gas evolution ceased. The aqueous layer was extracted with EtOAc, washed with brine, stirred over MgSO4, filtered and concentrated under reduced pressure to give a red oil. The product was isolated by column chromatography on a silica gel column using 30 to 70% gradient of EtOAc in hexane as eluent to give N-(1-(3-bromobenzo[b]thiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 1.24 (s, 10H), 1.63 (d, J=6.5 Hz, 3H), 3.85 (d, J=2.9 Hz, 1H), 5.16 (dd, J=6.7, 3.5 Hz, 1H), 7.35 (t, J=7.7 Hz, 1H), 7.41 (t, J=7.7 Hz, 1H), 7.76 (t, J=7.0 Hz, 2H). N-(1-(3-(3,5-Difluorophenyl)benzo[b]thiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:20][CH2:19][N:18]2[CH2:21][CH2:22][CH2:23][N:12]([CH2:13][CH2:14][N:15]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[CH2:16][CH2:17]2)[CH2:11][CH2:10]1)([O:3]C(C)(C)C)=[O:2]>C(C(O)=O)(F)(F)F.C(Cl)Cl>[C:25]([CH2:24][N:15]1[CH2:14][CH2:13][N:12]2[CH2:23][CH2:22][CH2:21][N:18]([CH2:19][CH2:20][N:9]([CH2:8][C:1]([OH:3])=[O:2])[CH2:10][CH2:11]2)[CH2:17][CH2:16]1)([OH:27])=[O:26]
Reactant: CC(C)(C)OC(=O)CN1CCN2CCCN(CC1)CCN(CC(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN1CCN2CCCN(CC1)CCN(CC(=O)O)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 166.2 %

Procedure:
Compound 5 (1.25 g, 2.84 mmol) was dissolved in a 1:1 (vol:vol) mixture of CF3CO2H (TFA) and CH2Cl2 (45 mL). The mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure to give an oily residue which was triturated with Et2O to provide white solid 6 (1.55 g, 98% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[N:10][C:5]2=[C:4]([CH3:12])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:27]3[C:26]([CH3:28])=[N:25][N:24]([C:29]4[C:30]([O:35][CH3:36])=[N:31][CH:32]=[CH:33][CH:34]=4)[C:23]=3[C:22](=[O:37])[NH:21]2)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:27]3[C:26]([CH3:28])=[N:25][N:24]([C:29]4[C:30]([O:35][CH3:36])=[N:31][CH:32]=[CH:33][CH:34]=4)[C:23]=3[C:22](=[O:37])[N:21]2[C:2]2[N:7]=[C:6]3[N:8]([CH3:11])[N:9]=[N:10][C:5]3=[C:4]([CH3:12])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: COc1ncccc1-n1nc(C)c2c1C(=O)NC2c1ccc(Cl)cc1
Reactant: Cc1cc(Cl)nc2c1nnn2C
Product: COc1ncccc1-n1nc(C)c2c1C(=O)N(c1cc(C)c3nnn(C)c3n1)C2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 102 using 5-chloro-3,7-dimethyl-3H-[1,2,3]triazolo[4,5-b]pyridine (Step 109.4) and 4-(4-chlorophenyl)-1-(2-methoxypyridin-3-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 71.4). The crude material was first purified by silica gel chromatography (40% EtOAc/Hexane) followed by preparative achiral SFC (column 4-Ethyl-pyridine, gradient 6-11% in 6 min_total 11 min). tR: 1.25 min (LC-MS 2); ESI-MS: 501 [M+H]+ (LC-MS 2); Rf=0.19 (40% EtOAc/hexane); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.04 (s, 3H) 2.66 (s, 3H) 3.92 (s, 3H) 4.10 (s, 3H) 6.74 (s, 1H) 7.14-7.26 (m, 1H) 7.36 (m, J=8.6 Hz, 2H) 7.49 (m, J=8.6 Hz, 2H) 7.96-8.05 (m, 1H) 8.14 (d, J=0.8 Hz, 1H) 8.28-8.38 (m, 1H).