Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1C2(CCC(C(O)=O)CC2)OCC1.[O:14]1[C:18]2([CH2:23][CH2:22][CH2:21][CH:20]([C:24]([O:26]CC)=[O:25])[CH2:19]2)[O:17][CH2:16][CH2:15]1.O1C2(CCC(C(OCC)=O)CC2)OCC1>>[O:14]1[C:18]2([CH2:23][CH2:22][CH2:21][CH:20]([C:24]([OH:26])=[O:25])[CH2:19]2)[O:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)C1CCCC2(C1)OCCO2
Agent: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: O=C(O)C1CCC2(CC1)OCCO2
Product: O=C(O)C1CCCC2(C1)OCCO2

Procedure:
1,4-Dioxaspiro[4.5]decane-7-carboxylic acid was synthesized in a manner similar to the synthesis of 1,4-dioxaspiro[4.5]decane-8-carboxylic acid, but with ethyl 1,4-dioxaspiro[4.5]decane-7-carboxylate substituted for ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N:7]1[N:14]2[C:10]([CH2:11][S:12][CH2:13]2)=[CH:9][C:8]=1[CH2:15][OH:16].[Cl-].[NH4+]>O.C(N(CC)CC)C.ClCCl.CS(C)=O>[N:7]1[N:14]2[C:10]([CH2:11][S:12][CH2:13]2)=[CH:9][C:8]=1[CH:15]=[O:16]
Reactant: OCc1cc2n(n1)CSC2
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1cc2n(n1)CSC2
Temperature: -45 °C
Reaction time: 0.25 h

Procedure:
The dry dichloromethane (8 mL) solution of dimethylsulfoxide (2.2 mL) was added dropwise to the dry dichloromethane (110 mL) solution of oxalyl chloride (2.0 mL) at −78° C. The reaction mixture was stirred for 15 min at the same temperature. The dry dichloromethane (40 mL) solution of (4H-5-thia-1,6a-diazapentalen-2-yl)methanol (1.7 g) was added dropwise to the reaction mixture at −78° C., and stirring was continued for an additional 15 min. The reaction mixture was allowed to warm to −45° C. and stirred for 1 h. Triethylamine (11.3 mL) was added dropwise and the reaction mixture was allowed to warm to 0° C. After 20 min, saturated ammonium chloride solution (50 mL) and water (100 mL) were added and separated. The aqueous layer was extracted with AcOEt (3×150 mL). The combined organic layers were washed with water (200 mL) and brine (200 mL), dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with hexane—AcOEt (1:1). The titled compound was obtained as a yellow solid (1.7 g, quant.).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[N:6]1([NH:12][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CS(=O)(=O)Cl
Reactant: NN1CCCCC1
Product: CS(=O)(=O)NN1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
TEA (2.43 mL, 17.46 mmol) and methanesulfonylchloride (2.0 g, 17.46 mmol). were added to a solution of piperidin-1-ylamine Compound 1i1 (1.75 g, 17.46 mmol) at 0° C., under a N2 atmosphere. The mixture was stirred for 3 hrs, while warming to r.t. The reaction was quenched with water (20 mL) and the organic layer was diluted with CH2Cl2 (100 mL), washed with water and brine, separated and dried with anhydrous sodium sulfate, then filtered and concentrated in vacuo to yield N-piperidin-1-yl-methanesulfonamide Compound 1i2 as an oil.
Reaction SMILES: [OH-].[Na+].[C:3]([N:6]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[N:21]=3)=[O:18])=[CH:16][C:11]=2[CH2:10][N:9]([CH3:27])[C:8](=[O:28])[CH:7]1[CH2:29][C:30]([O:32]C)=[O:31])(=[O:5])[CH3:4].CO>O>[C:3]([N:6]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[N:21]=3)=[O:18])=[CH:16][C:11]=2[CH2:10][N:9]([CH3:27])[C:8](=[O:28])[CH:7]1[CH2:29][C:30]([OH:32])=[O:31])(=[O:5])[CH3:4]
Reactant: COC(=O)CC1C(=O)N(C)Cc2cc(C(=O)Nc3cccc(N)n3)ccc2N1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)N1c2ccc(C(=O)Nc3cccc(N)n3)cc2CN(C)C(=O)C1CC(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.8 %

Procedure:
1 N NaOH (1.0 mL, 1.0 mmol) was added to a cold solution of methyl (±)-1-acetyl-7-[[(6-amino-2-pyridinyl)amino]carbonyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (0.23 g, 0.54 mmol), MeOH (2 mL) and H2O (1 mL). The solution was stirred at room temperature for 18 h then was concentrated. Chromatography (ODS, 10% CH3CN/H2O-0.1% TFA) gave the title compound (0.215 g, 90%): 1H NMR (400 MHz, DMSO-d6) δ1.7-1.9 (s, 3H), 2.0-2.6 (m, 2H), 3.0-3.1 (s, 3H), 4.1-4.2 (d, 1H), 4.7-4.8 (d, 1H), 5.7-5.9 (m, 1H), 6.4-6.5 (d, 1H), 7.0-7.1 (d, 1H), 7.5-7.6 (d, 1H), 7.6-7.8 (t, 1H), 8.0-8.1 (d, 1H), 8.2-8.3 (s, 1H); MS (ES) m/e 412.2 (M+H)+. Anal. Calcd for C20H21N5O5.2.75 CF3CO2H: C, 42.25; H, 3.30; N, 9.66. Found: C, 42.01; H, 3.25; N, 9.85.
Reaction SMILES: C(OC([NH:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:32][CH2:31][CH2:30][N:29]([C:33]4[CH:38]=[CH:37][C:36]([C:39]5[CH:44]=[C:43]([O:45][CH3:46])[C:42]([NH:47]C(OCC6C=CC=CC=6)=O)=[C:41]([O:58][CH3:59])[CH:40]=5)=[CH:35][N:34]=4)[CH2:28][CH2:27]3)=[N:24][CH:25]=2)=[CH:14][C:13]=1[O:60][CH3:61])=O)C1C=CC=CC=1.[ClH:62].C(OCC)(=O)C.C(O)C>C(O)(=O)C.[Pd].C(Cl)(Cl)Cl>[ClH:62].[ClH:62].[ClH:62].[ClH:62].[NH2:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:32][CH2:31][CH2:30][N:29]([C:33]4[CH:38]=[CH:37][C:36]([C:39]5[CH:44]=[C:43]([O:45][CH3:46])[C:42]([NH2:47])=[C:41]([O:58][CH3:59])[CH:40]=5)=[CH:35][N:34]=4)[CH2:28][CH2:27]3)=[N:24][CH:25]=2)=[CH:14][C:13]=1[O:60][CH3:61]
Reactant: COc1cc(-c2ccc(N3CCCN(c4ccc(-c5cc(OC)c(NC(=O)OCc6ccccc6)c(OC)c5)cn4)CC3)nc2)cc(OC)c1NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(-c2ccc(N3CCCN(c4ccc(-c5cc(OC)c(N)c(OC)c5)cn4)CC3)nc2)cc(OC)c1N
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
To a solution of 1,4-bis[5-(4-benzyloxycarbonylamino-3,5-dimethoxyphenyl)-2-pyridyl]hexahydro-1,4-diazepine (120.0 mg, 0.140 mmol) in acetic acid (2.0 mL) was added 10% palladium on charcoal (24.0 mg), and the resulting mixture was stirred at 50° C. for 1.5 hours under hydrogen. Insoluble materials were removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. A solution of the residue in chloroform was washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a solution of the residue in chloroform (5.0 mL) a 4.0 M solution of hydrogen chloride in ethyl acetate (0.14 mL, 0.56 mmol), and the resulting mixture was concentrated under reduced pressure. Ethanol (5.0 mL) was added to the residue, and the resulting mixture was concentrated under reduced pressure. Diethyl ether was added to the residue, and the resulting precipitate was collected by filtration to yield the title compound as a pale brown amorphous powder (84.0 mg, yield: 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][NH2:5].[CH:11]1[C:20]2[C:15](=[C:16]([CH:21]([CH3:25])[C:22](O)=[O:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][NH:5][C:22](=[O:23])[CH:21]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][N:12]=[CH:11]2)[CH3:25]
Reactant: CC(C(=O)O)c1cccc2cnccc12
Reactant: NCc1cc(Cl)ccc1Cl
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1cc(Cl)ccc1Cl)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 2,5-dichlorobenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 359 (M+H)+; MS (ESI−) m/z 357 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.54 (d, J 7.1, 3H), 4.20 (m, 2H), 4.53 (q, J 7.1, 1H), 7.06 (s, 1H), 7.32 (d, J 8.4, 1H), 7.44 (d, J 8.4, 1H), 7.51 (s, 1H), 7.78 (t, J 7.8, 1H), 7.90 (d, J 6.5, 1H), 8.16 (d, J 8.1, 1H), 8.26 (d, J 6.4, 1H), 8.60 (d, J 6.2, 1H), 8.65 (t, J 5.8, 1H), 9.49 (s, 1H).
Reaction SMILES: C([O:3][C@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]3[CH:29]=[C:28](/[CH:30]=[CH:31]/[C:32]4[S:33][CH:34]=[C:35]([CH:37]([CH3:39])[CH3:38])[N:36]=4)[CH:27]=[CH:26][N:13]3[C:14](=[O:25])[C:15]=2/[CH:16]=[CH:17]/[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:5]1)=O.C(O[C@@H]1CCCN(C2N=C3C=C(/C=C/C4SC=C(C(C)C)N=4)C=CN3C(=O)C=2/C=C/C(OC(C)(C)C)=O)C1)=O.OC1CCCN(C2N=C3C=C(/C=C/C4SC=C(C(C)C)N=4)C=CN3C(=O)C=2/C=C/C(OC(C)(C)C)=O)C1>>[OH:3][C@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]3[CH:29]=[C:28](/[CH:30]=[CH:31]/[C:32]4[S:33][CH:34]=[C:35]([CH:37]([CH3:39])[CH3:38])[N:36]=4)[CH:27]=[CH:26][N:13]3[C:14](=[O:25])[C:15]=2/[CH:16]=[CH:17]/[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:5]1
Reactant: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCC[C@H](OC=O)C4)nc3c2)n1
Agent: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCCC(O)C4)nc3c2)n1
Agent: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCC[C@@H](OC=O)C4)nc3c2)n1
Product: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCC[C@H](O)C4)nc3c2)n1
Yield: 100.2 %

Procedure:
The tert-butyl (E)-3-{2-[(3S)-3-formyloxyhexahydro-1-pyridinyl]-8-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (164 mg, 0.298 mmol) obtained in (A) was treated in the same manner as in Example 102, (H) to obtain the title compound (156 mg, 100%).
Reaction SMILES: [CH:1]([C@H:14]1[CH2:19][C@H:18]([OH:20])[CH2:17][CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>>[CH:1]([C@H:14]1[CH2:19][C@@H:18]([O:20][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:17][CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O[C@@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Product: CS(=O)(=O)O[C@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Yield: 97.9 %

Procedure:
Cis-2-diphenylmethyl-4-hydroxy-pyran 3b (0.3 g, 1.12 mmol) was reacted with methanesulfonyl chloride (0.26 g, 2.24 mmol) (Procedure A) to give compound 4b (0.38 g, 98%) as an oil.
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[C:13](=[O:15])[CH3:14].ClC1C=C([N+]([O-])=O)C=CC=1C(Cl)=O.COC(=O)CC(OC)=O>C(O)C.[Fe].C(Cl)Cl.O>[NH2:10][C:8]1[CH:7]=[CH:6][C:5]([C:13](=[O:15])[CH3:14])=[C:4]([Cl:3])[CH:9]=1
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CC(=O)c1ccc(N)cc1Cl
Reaction time: 0.03 h

Procedure:
Iron (2.7 g), ammonium chloride (2.6 g) and water (8.1 ml) were added to a solution of 1-(2-chloro-4-nitro-phenyl)-ethanone ([CAS Reg. No. 67818-41-1], 960 mg) in ethanol (68 ml), which was made from 2-chloro-4-nitro-benzoyl chloride and malonic acid dimethyl ester according to a procedure from Dai et al.; J. Med. Chem. 2005, 48, 6066. The mixture was heated 1 h under reflux. DCM (35 ml) was added, stirred for 2 min and filtered over Celite. The residue was washed with DCM (50 ml). Water (100 ml) was added to the combined organic layers, and then extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound (837 mg) as light yellow oil, which was used in the next step without further purification. MS (m/e)=170.1 [M+H+].
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([Cl:12])[CH:4]=1.[CH3:13][S-:14].[Na+].C(OCC)(=O)C>C(O)C.[Cl-].[Na+].O>[Cl:12][C:5]1[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=[C:3]([CH2:2][S:14][CH3:13])[CH:4]=1
Reactant: C[S-]
Reactant: O=[N+]([O-])c1cc(Cl)cc(CBr)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CSCc1cc(Cl)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of 1-(bromomethyl)-3-chloro-5-nitrobenzene (10.0 g) in ethanol (200 mL) was treated at −20° C. with portions of sodium methanthiolat (3.32 g) and stirred for 3 hours at room temperature. The reaction mixture was treated with brine (100 mL) extrakted with ethyl acetate (300 mL), washed with water (2×100 mL) and, dried with sodium sulfate and evaporated to dryness. One obtained the title compound (8.6 g) which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+].Br[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[C:12]([CH2:24][N:25]([CH:33]1[CH2:35][CH2:34]1)[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:13][N:14]2[CH2:19][CH2:20][CH2:21][O:22][CH3:23]>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.C1(C)C=CC=CC=1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:33]1([N:25]([CH2:24][C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:14]([CH2:19][CH2:20][CH2:21][O:22][CH3:23])[CH:13]=2)[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:31])[CH3:29])[CH2:35][CH2:34]1
Reactant: C1COCCN1
Reactant: COCCCn1cc(CN(C(=O)OC(C)(C)C)C2CC2)c2c(Br)cccc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Product: COCCCn1cc(CN(C(=O)OC(C)(C)C)C2CC2)c2c(N3CCOCC3)cccc21
Temperature: 90 °C
Reaction time: 23 h

Procedure:
Morpholine (73.5 μL), cetyltrimethylammoniumbromide (14.6 mg), bis(tri-tert-butylphosphine)palladium(0) (41 mg) and 50% aqueous solution of sodium hydroxide (96 μL) were added to a solution of tert-butyl {[4-bromo-1-(3-methoxypropyl)-1H-indol-3-yl]methy}cyclopropylcarbamate (205 mg) in toluene (3 ml) and the mixture was stirred under argon atmosphere at 90° C. for 23 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The obtained solution was washed with water and saturated brine successively, dried over magnesium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=20/1 to 3/2) to give tert-butyl cyclopropyl{[1-(3-methoxypropyl)-4-morpholin-4-yl-1H-indol-3-yl]methy}carbamate (280 mg) as a yellow oil.
Reaction SMILES: [CH2:1]([CH:4]1[N:8]([CH2:9][CH3:10])[S:7](=[O:12])(=[O:11])[NH:6][C:5]1=[O:13])[CH2:2][CH3:3].[C:14]1([S:20][CH2:21]Cl)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CN(C=O)C>[C:14]1([S:20][CH2:21][N:6]2[C:5](=[O:13])[CH:4]([CH2:1][CH2:2][CH3:3])[N:8]([CH2:9][CH3:10])[S:7]2(=[O:12])=[O:11])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCSc1ccccc1
Reactant: CCCC1C(=O)NS(=O)(=O)N1CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCCC1C(=O)N(CSc2ccccc2)S(=O)(=O)N1CC
Yield: 73.5 %

Procedure:
A mixture of 4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (3.7 g, 16.6 mmol), phenylthiomethyl chloride (2.9 g, 18.28 mmol) and tetrabutylammonium bromide (0.53 g, 3.1 mmol) suspended in toluene/DMF (90 ml/10 ml) was refluxed for 8 hours, cooled, and concentrated in vacuo. The residue was diluted with water, extracted with ether/ethyl acetate (500 ml, 1:1), and the organic layer was washed with water and brine. The organic layer was dried, concentrated in vacuo, and the residue was purified by flash chromatography to afford 4.01 g of 2-phenylthiomethyl-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula VI: R1 =H; R2 =propyl; R3 =ethyl) as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:22][OH:23])([S:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>ClCCl>[ClH:24].[OH:23][CH2:22][C:11]1([S:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1cccc(SC2(CO)CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: ClCCl
Product: Cc1cccc(SC2(CO)CCNCC2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of N-tert-butoxycarbonyl-4-hydroxymethyl-4-(3-tolylsulfanyl)piperidine (0.27 g) in dichloromethane (25 mL) at 0° C. was saturated with hydrogen chloride gas. The resultant solution was sealed with a rubber septum and stirred at 0° C. for one h. The product solution was concentrated under vacuum to provide the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:17])=[C:9]([C:11]#[C:12][Si](C)(C)C)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:17])=[C:9]([C:11]#[CH:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(C)(C)C)cc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(C(C)(C)C)ccc1C

Procedure:
Following general procedure F and using (5-tert-butyl-2-methyl-phenylethynyl)-trimethyl-silane (Intermediate 109, 0.16 g, 0.66 mmol), methanol (5 mL) and potassium carbonate (0.05 g, 0.36 mmol), the title compound was obtained (0.08 g, 67%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:8][C:9]3[C:14]([C:15](=[O:17])[CH:16]=2)=[CH:13][C:12]([C:18]([O:20][CH3:21])=[O:19])=[CH:11][C:10]=3[C@H:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)[CH2:3][CH2:2]1.Br[C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(O[Pd]OC(=O)C)(=O)C>[F:34][C:32]1[CH:33]=[C:28]([N:23]2[CH2:24][CH2:25][CH2:26][C@@H:22]2[C:10]2[CH:11]=[C:12]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=[C:14]3[C:9]=2[O:8][C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:16][C:15]3=[O:17])[CH:29]=[C:30]([F:35])[CH:31]=1
Reactant: COC(=O)c1cc([C@H]2CCCN2)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: Fc1cc(F)cc(Br)c1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cc([C@H]2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 100 °C
Reaction time: 15 h
Yield: 67.1 %

Procedure:
Diacetoxypalladium (0.028 g, 0.13 mmol) was added to a stirred mixture of methyl 2-morpholino-4-oxo-8-[(2R)-pyrrolidin-2-yl]chromene-6-carboxylate (0.9 g, 2.51 mmol), 1-bromo-3,5-difluorobenzene (0.361 ml, 3.14 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (145 mg, 0.25 mmol) and cesium carbonate (1.227 g, 3.77 mmol) dissolved in 1,4-dioxane (16 mL). The resulting suspension was degassed with argon and then stirred at 100° C. for 15 h. 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% MeOH in EtAc. The solvent was evaporated to dryness to afford methyl 8-[(2R)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-2-morpholino-4-oxo-chromene-6-carboxylate (0.792 g, 67%) as an yellow foam. Mass Spectrum: m/z [M+H]+=471.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][S:23](=[O:30])(=[O:29])[NH:24][CH:25]3[CH2:28][O:27][CH2:26]3)[C:11](=[O:33])[C@:10]([CH2:35][C:36]([O:38]C)=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][S:23](=[O:29])(=[O:30])[NH:24][CH:25]3[CH2:26][O:27][CH2:28]3)[C:11](=[O:33])[C@:10]([CH2:35][C:36]([OH:38])=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CS(=O)(=O)NC1COC1)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@@H](CS(=O)(=O)NC1COC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-(oxetan-3-yl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acetate (41.1 mg, 0.069 mmol; Example 372, Step C) in THF (2.0 ml) and MeOH (1.0 ml) was added 1 N lithium hydroxide (3.0 ml, 3.0 mmol). The suspension was stirred at room temperature for 15 hours, then acidified to pH 4 using 1 N HCl, and then concentrated in vacuo. Purification of the residue by chromatography on silica gel (4 g SiO2, 5 to 25% gradient of a 1:6.5 MeOH/acetone mixture in hexanes) provided the title compound. The material was purified further by reversed phase preparatory HPLC (Eclipse Plus C18, 30×250 mm, 5 um column; Agilent, Santa Clara, Calif.) (eluent: 0.1% TFA in acetonitrile/water, gradient 30% to 60% over 25 min) to provide the title compound, as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]2[C:4](O)([CH:5]3[CH2:13][CH2:12][CH2:11][CH:6]3[NH:7]2)[C:3]=1[F:15].C(=O)([O-])O.[Na+]>ClCCl.FC(F)(F)C(O)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][CH2:13][C:5]=3[C:4]=2[C:3]=1[F:15]
Reactant: OC12C(F)=C(F)C=CC1NC1CCCC12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc2[nH]c3c(c2c1F)CCC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.6 %

Procedure:
A stirred solution of 7,8-difluoro-1,2,3,3a,4,8a-hexahydro-8a-hydroxy-cyclopent[b]indole (1.1 g, 5.2 mmol), in dichloromethane (150 mL) was cooled to 0° C. Trifluoroacetic acid (20 drops) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured onto saturated sodium hydrogen carbonate solution (20 mL) and extracted with dichloromethane (3×50 mL). The organic extracts were combined, dried (magnesium sulfate), filtered, concentrated in vacuo and purified by column chromatography [SiO2; ethyl acetate-heptane (1:5)]to give the product (0.78 g, 78%) as a white crystalline solid. IR νmax (Nujol)/cm−1 3467, 2925, 2854, 1565, 1515, 1450, 1348, 1327, 1244, 1053, 1025, 977, 857, 783, 630 and 516; NMR δH (400 MHz, CDCl3) 2.49-2.58 (2H, m), 2.79-2.87 (2H, m), 2.9-2.96 (2H, m), 6.81-6.95 (2H, m), and 7.83 (1H), br s).
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[NH:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[C:1]1([NH:7][C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[NH:17][C@H:18]2[CH2:23][CH2:22][CH2:21][N:20]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=3)[CH2:19]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccccc1)N[C@@H]1CCCC[C@H]1NC1CCCNC1
Reactant: Fc1ccc(C(F)(F)F)cn1
Product: O=C(Nc1ccccc1)N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2ccc(C(F)(F)F)cn2)C1

Procedure:
1-Phenyl-3-((1R,2R)-2-((S)-1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-3-ylamino)cyclohexyl)urea was synthesized using 1-phenyl-3-((1R,2R)-2-(piperidin-3-ylamino)cyclohexyl)urea (from intermediate C, Example 1) (100 mg, 0.32 mmol) and 2-fluoro-5-(trifluoromethyl)pyridine (57.4 mg, 0.35 mmol) according to General Procedure A to give 15 mg (10.3%) of white solid. Anal. Calcd. for C24H30F3N5O m/z 461.2, found: 462.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 8.18 (m, 1H), 7.30 (m, 1H), 7.21 (m, 4H), 7.00 (m, 1H), 6.67 (d, J=8.9 Hz, 1H), 6.18 (d, J=5.4 Hz, 1H), 4.47 (m, 1H), 3.79 (m, 1H), 3.59 (m, 3H), 3.23 (m, 1H), 2.33 (m, 1H), 2.07 (m, 4H), 1.87 (m, 3H), 1.67 (d, J=7 Hz, 2H), 1.49 (m, 4H).