Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:8]2[C:9]([C:12]3[CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[S:15][CH:16]=3)=[N:10][NH:11][C:7]=2[CH:6]=[CH:5][N:4]=1.CC1C=CC(S(O[CH:31]([CH2:35][CH3:36])[CH2:32][O:33][CH3:34])(=O)=O)=CC=1>O.C(#N)C>[CH3:34][O:33][CH2:32][C@@H:31]([N:11]1[C:7]2[CH:6]=[CH:5][NH:4][C:3](=[O:2])[C:8]=2[C:9]([C:12]2[CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[S:15][CH:16]=2)=[N:10]1)[CH2:35][CH3:36]
Reactant: COc1nccc2[nH]nc(-c3csc(C(N)=O)c3)c12
Reactant: CCC(COC)OS(=O)(=O)c1ccc(C)cc1
Solvent: CC#N
Solvent: O
Product: CC[C@@H](COC)n1nc(-c2csc(C(N)=O)c2)c2c(=O)[nH]ccc21

Procedure:
The racemic form of the title compound was obtained using 4-(4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide obtained in Step A of Example 148 and 1-methoxybutan-2-yl 4-methylbenzenesulfonate, in the same manner as in Step B of Example 148 and Step C of Example 148. The obtained racemic form was resolved by HPLC (column: L-column2 ODS (trade name) 20 mmID×150 mmL, 5 μm, manufactured by Daicel Chemical Industries, mobile phase: water/acetonitrile (containing 10 mM ammonium carbonate)) to give the title compound having a shorter retention time.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:7]([CH2:20][C:21]([O:23]C(C)C)=[O:22])[C:6]=2[C:5]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:7]([CH2:20][C:21]([OH:23])=[O:22])[C:6]=2[C:5]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(Cl)cc3Cl)n(CC(=O)OC(C)C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(Cl)cc3Cl)n(CC(=O)O)c12
Reaction time: 4 h
Yield: 69.4 %

Procedure:
To a solution of isopropyl {4-chloro-2-[(2,4-dichlorophenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl}acetate (521 mg, 1.08 mmol) in methanol (4 mL) was added 8N aqueous sodium hydroxide (1 mL) at 0° C., and the mixture was stirred at the same temperature for 4 hours. Methanol was evaporated in vacuo; and the aqueous residue was adjusted to pH 4. Ethyl acetate was added to the mixture, followed by stirring at 0° C. for 1 hour. The resulting solid was collected by filtration and washed with water to give the title compound (330 mg, 0.749 mmol, 69%) as a colorless solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:51])[C:6]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:19][CH2:18][CH2:17][C@H:16]([N:20]([CH2:27][C:28]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=3)[C:21]3[N:22]=[N:23][N:24]([CH3:26])[N:25]=3)[C:15]3[CH:42]=[C:43]([CH3:50])[C:44]([C:46]([F:49])([F:48])[F:47])=[CH:45][C:14]2=3)[CH:9]=[N:8][CH:7]=1.[ClH:52]>CO>[ClH:52].[F:41][C:38]([F:39])([F:40])[C:30]1[CH:29]=[C:28]([CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=1)[CH2:27][N:20]([C:21]1[N:22]=[N:23][N:24]([CH3:26])[N:25]=1)[C@H:16]1[CH2:17][CH2:18][CH2:19][N:13]([CH2:12][C:10]2[CH:9]=[N:8][CH:7]=[C:6]([CH:11]=2)[C:5]([OH:51])=[O:4])[C:14]2[CH:45]=[C:44]([C:46]([F:47])([F:48])[F:49])[C:43]([CH3:50])=[CH:42][C:15]1=2
Reactant: COC(=O)c1cncc(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2c(cc1C(F)(F)F)N(Cc1cncc(C(=O)O)c1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 60 °C
Yield: 78 %

Procedure:
Add 2 N sodium hydroxide solution (2 mL) to a solution of (S)-5-{5-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-nicotinic acid methyl ester (0.090 g, 0.128 mmol) in methanol (5 mL) and heat at 60° C. for 4 h. After the reaction cools to room temperature, acidify to pH 4 with 2 N hydrochloric acid solution and extract the aqueous mixture with ethyl acetate (3×10 mL). Wash the organic layer with water and brine (10 mL each). Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure to provide the title compound as a white solid (0.076 g, 78%). 1H NMR (CDCl3, 300 MHz) δ 1.23-2.34 (m, 1H), 1.57-1.64 (m, 2H), 2.03-2.13 (m, 2H), 2.32 (s, 3H), 2.67-2.73 (m, 1H), 3.04-3.14 (m, 1H), 4.14 (s, 3H), 4.32-4.56 (m, 2H), 4.89-5.10 (m, 2H), 5.67-5.70 (m, 1H), 6.89 (s, 1H), 7.23-7.30 (m, 1H), 7.60-7.70 (m, 3H), 8.45 (s, 1H), 8.89 (s, 1H), 9.22 (s, 1H); ESI MS m/z 688 [C30H26F9N7O2+H]+.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Cl[S:16]([C:19]1[CH:28]=[CH:27][C:26]2[NH:25][C:24](=[O:29])[C:23]3[NH:30][CH:31]=[C:32]([C:33]([OH:35])=[O:34])[C:22]=3[C:21]=2[CH:20]=1)(=[O:18])=[O:17]>ClCCl.CN(C)C=O>[CH:8]1([NH:14][S:16]([C:19]2[CH:28]=[CH:27][C:26]3[NH:25][C:24](=[O:29])[C:23]4[NH:30][CH:31]=[C:32]([C:33]([OH:35])=[O:34])[C:22]=4[C:21]=3[CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NC1CCCCC1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)NC4CCCCC4)cc3c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 44.2 %

Procedure:
314 μL (2.25 mmol) of triethylamine and 189 μL (1.65 mmol) of cyclohexylamine are added to 490 mg (1.5 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid suspended in 4 mL of anhydrous dichloromethane and 1 mL of anhydrous dimethylformamide. The reaction mixture is stirred for 2 days at room temperature. The solvents are evaporated, and the residue is taken up in water. The solid is filtered, rinsed with water then diisopropyl ether and dried under vacuum to give 258 mg (44%) of 8-cyclohexylsulfamoyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid in the form of a cream-coloured solid.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([O:32]C2CCCCO2)[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=1)[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].Cl.C(=O)(O)[O-].[Na+]>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:3]=1[CH2:4][N:5]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)=[CH:16][CH:15]=1)[C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7]
Reactant: O=C(C1CCCCC1)N(Cc1ccc(OC2CCCCO2)cc1Cl)c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(C1CCCCC1)N(Cc1ccc(O)cc1Cl)c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 175.5 %

Procedure:
A solution of cyclohexanecarboxylic acid [2-chloro-4-(tetrahydro-pyran-2-yloxy)-benzyl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amide (2.0 g) in 3:1 ethanol:1N HCl (40 mL) was stirred at room temperature for 1.5 hr. Saturated aqueous sodium bicarbonate solution was added and the aqueous solution was washed with methylene chloride. The organic solution was dried (magnesium sulfate), filtered and concentrated in vacuo. The crude product was purified by Biotage® chromatography (methylene chloride to 4% methanol/methylene chloride). The resulting white solid (1.53 g) was suspended in methanol (20 mL) and 4M HCl in dioxane was added. The mixture was stirred at room temperature for 1 hr. and was concentrated in vacuo to yield the title compound as a tan solid (1.60 g). MS 317.2 (MH+−40)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].N1C=CC=CC=1.[N:31]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:36]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:37])[CH:17]=1)[C:10]([CH3:23])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: O=C(Cl)N1CCCC1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N)c1)N2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)N3CCCC3)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (648 mg, 2 mmol) in dichloromethane (5 mL) and pyridine (1 mL, 12 mmol) was added a solution of pyrrolidine-1-carbonyl chloride (0.243 mL, 2.2 mmol) in dichloromethane (2 mL) dropwise at 0° C. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was extracted with dichloromethane (2×50 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3,3-dimethyl-2-{3-[(pyrrolidine-1-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (842 mg, 100%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C25H31N3O3 (M+H)+: 422.54, observed: 422.2.