Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:23])[CH2:16][CH2:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=O)C.[OH-].[K+].O>CO.C1C=CC=CC=1>[OH:4][C@H:5]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:23])[CH2:16][CH2:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH2:6]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)C(C)C)[C@@]4(C)CC[C@@H]32)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Solvent: CO
Product: CC(C)C(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 90 %

Procedure:
Specifically, the crude 3β-acetoxy-24-oxocholest-5-ene was dissolved in 100 ml of a mixture of methanol and benzene (1:1). To the solution was added dropwise a 10% methanol solution of potassium hydroxide at room temperature with stirring. After the addition, the mixture was stirred at 70° C. for 4 hours. After the reaction, 100 mg of water was added to separate the reaction mixture into layers. The resulting aqueous layer was extracted twice with benzene. The benzene extracts were combined with the organic layer. The mixture was washed successively with dilute hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to form 3.6 g (yield: 90% based on 3β-acetoxychol-5-enic acid) of 3β-hydroxy-24-oxocholest-5-ene as a white solid. The properties of the product were as follows:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[CH:13][C:14]2[CH2:18][O:17][B:16]([OH:19])[C:15]=2[CH:20]=1)[C:5]#[N:6].C([O-])([O-])=O.[K+].[K+].[Cl:27]C1C=C(C=CC=1F)C#N.CCOC(C)=O>CS(C)=O>[Cl:27][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[CH:13][C:14]2[CH2:18][O:17][B:16]([OH:19])[C:15]=2[CH:20]=1)[C:5]#[N:6]
Reactant: N#Cc1ccc(Oc2ccc3c(c2)B(O)OC3)c(F)c1
Reactant: N#Cc1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Oc2ccc3c(c2)B(O)OC3)c(Cl)c1
Temperature: 90 °C
Yield: 33.3 %

Procedure:
To a solution of 3H-benzo[c][1,2]oxaborole-1,6-diol (5) (300 mg, 2 mmol) in DMSO (30 mL) were added K2CO3 (828 mg, 6 mmol) and 3-chloro-4-fluoro-benzonitrile (933 mg, 6 mmol). The reaction was heated at 90° C. for 7 hours. After the cooling of reaction solution, EtOAc (50 mL) was added. The organic layer was washed with water (5×50 mL). The organic layer was evaporated under vacuum. The residue was purified by reverse phase chromatography to afford 3-chloro-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yloxy)-benzonitrile (6) 190 mg in 33.3% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (s, 1 H), 8.22 (s, 1 H), 7.77 (d, J=7.81 Hz, 1 H), 7.50 (d, J=8.20 Hz, 1 H), 7.34 (s, 1 H), 7.28 (d, J=8.20 Hz, 1 H), 7.01 (d, J=8.59 Hz, 1 H), 4.99 (s, 2 H). ESMS (m/z): 284 (M−H)−. HPLC: 96.41% (220 nm), 96.0% (maxplot).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]#[C:9][C:10](=O)[CH3:11].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[N:29]=[C:28]([NH:30][NH2:31])[N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][N:25]3[CH3:32])=[CH:16][CH:15]=1.[CH2:33](O)C>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[N:29]=[C:28]([N:30]3[C:9]([CH2:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[CH:10][C:11]([CH3:33])=[N:31]3)[N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][N:25]3[CH3:32])=[CH:16][CH:15]=1
Reactant: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(NN)nc21
Reactant: CC(=O)C#COC1CCCCO1
Reactant: CCO
Product: Cc1cc(COC2CCCCO2)n(-c2nc(Nc3ccc(Cl)cc3)c3ncn(C)c3n2)n1
Yield: 12 %

Procedure:
4-(Tetrahydro-pyran-2-yloxy)-but-3-yn-2-on (824 mg, 4.5 mmol) and (4-chloro-phenyl)-(2-hydrazino-9-methyl-9H-purin-6-yl)-amine (1.5 g, 5.2 mmol) were dissolved in ethanol (30 mL) and heated at reflux for 24 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by flash chromatography (dichloromethane/methanol/ammonia) to give (4-chloro-phenyl)-{9-methyl-2-[3-methyl-5-(tetrahydro-pyran-2-yloxymethyl)-pyrazol-1-yl]-9H-purin-6-yl}-amine (240 mg, 12%) as an yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.[CH3:32][N:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)N>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:33]([CH3:32])[C:35]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Cl)c3)CC2)c1
Reactant: CN(N)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(Cl)c4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 528.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12](/[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][CH:21]=3)\[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[CH3:33][S:34]([NH:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12](/[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)=[CH:22][CH:21]=3)\[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Product: CS(=O)(=O)Nc1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 6-amino-3-(Z)-{1-[4-(piperidin-1-yl-methyl)-anilino]-1-phenyl-methylidene}-2-indolinone and methanesulphonylchloride
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([CH:11]=O)=[CH:4][CH:3]=1.Cl.[NH2:14][OH:15].C(=O)([O-])O.[Na+]>C(O)C.C(OCC)(=O)C.O>[Br:1][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([CH:11]=[N:14][OH:15])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(Br)c2nsnc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(Br)c2nsnc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.2 %

Procedure:
To a solution of 7-bromo-benzo[1,2,5]thiadiazole-4-carbaldehyde (16.65 g) (Example I3) in ethanol (150 ml) were added hydroxylamine hydrochloride (9.52 g), sodium hydrogen carbonate (11.51 g) and water (15 ml). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (1500 ml) and water (400 ml). After separation of the phases, the aqueous layer was extracted with ethyl acetate (200 ml). The combined organic layers were washed with water (200 ml) and brine (200 ml), dried over sodium sulfate and concentrated to give 7-bromo-benzo[1,2,5]-thiadiazole-4-carbaldehyde oxime (16.65 g) as a brown solid. 1H-NMR (DMSO-d6, 400 MHz): 11.94 (s, 1H), 8.66 (s, 1H), 8.09-9.90 (m, 2H) ppm.
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[CH:12][C:7](N[N+]([O-])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(O)C.S(=O)(=O)(O)O.[N:22]([O-:24])=[O:23].[Na+]>C(Cl)(Cl)Cl.O>[CH:1]([C:4]1[CH:5]=[C:6]([N+:22]([O-:24])=[O:23])[CH:7]=[CH:12][CH:13]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1ccc(N[N+](=O)[O-])cc1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: CC(C)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.56 G. of 4-isopropylnitroaniline is dissolved in 580 ml. of ethanol and stirred. 30.4 Ml. of concentrated sulfuric acid is added dropwise. The reaction mixture is heated to reflux and a solution of 16 g. of sodium nitrite in 25 ml. of water is added dropwise over 5 minutes. Heating is continued for 1 hour and then the reaction mixture is allowed to cool to room temperature. 250 Ml. of water and 1200 ml. of chloroform is added, the layers are separated and the water layer is extracted with an additional 230 ml. of chloroform. The chloroform layers are combined, washed with 250 ml. of water, dried over sodium sulfate and the solvent is removed by distillation through a short vigreau column at atmosphere pressure. The residue is vacuum distilled at from 8.6 to 9.0 mm. of Hg. The fraction taken at 112° to 128° C. is used as is in the next step.
Reaction SMILES: [C:1]1(=O)[CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH2:10]([O:12][C:13](=[O:21])[CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[CH3:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:10]([O:12][C:13](=[O:21])[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH:1]2[CH2:4][CH2:3][CH2:2]2)[CH2:17][CH2:16]1)[CH3:11]
Reactant: CCOC(=O)CC1CCNCC1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)CC1CCN(C2CCC2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
A mixture of cyclobutanone (0.3 mL, 3.94 mmol) in acetic acid (0.19 mL, 3.28 mmol) was added to a stirred solution of piperidin-4-yl acetic acid ethyl ester (562 mg, 3.28 mmol, obtained in above step) in dichloromethane cooled at 0° C. Solid sodium triacetoxyborohydride (1.39 grams, 7.2 mmol) was added portion wise over a period of 15 minutes. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. The reaction mixture was cooled to 0° C. and basified with saturated sodium bicarbonate solution (pH: 7.5). The two layers were separated, the organic layer was washed with brine, dried over anhydrous sodium sulphate and the volatiles were removed under reduced pressure to obtain (1-Cyclobutyl piperidin-4-yl) acetic acid ethyl ester (652 mg).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[CH:16][CH:17]=[N:18][C:11]=3[N:10]=[C:9]2[C@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])=[CH:4][CH:3]=1.[C-:29]#[N:30].[Na+]>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.[Cu]I>[C:29]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[CH:16][CH:17]=[N:18][C:11]=3[N:10]=[C:9]2[C@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH3:20])=[CH:4][CH:3]=1)#[N:30]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1nc2ncccc2c(=O)n1-c1ccc(I)cc1
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Product: C[C@@H](NC(=O)OC(C)(C)C)c1nc2ncccc2c(=O)n1-c1ccc(C#N)cc1
Temperature: 70 °C

Procedure:
A3 (2.02 g, 4.10 mmol), (Ph3P)4Pd (439 mg, 0.38 mmol), CuI (157 mg, 0.82 mmol) and NaCN (406 mg, 8.29 mmol) were combined in a 25 mL pear shaped flask equipped with a reflux condenser. The mixture was evacuated under high vacuum and backfilled with dry N2 three times. Acetonitrile (6 mL) was then added and the resulting suspension heated to 70° C. for 30 min. at which point TLC and HPLC analysis indicated near complete consumption of A3. The mixture was diluted with EtOAc (100 mL) and filtered through a pad of celite. The filtrate was washed with saturated NaHCO3 (100 mL). The aqueous wash was extracted with additional EtOAc (2×50 mL). The combined extracts were dried over Na2SO4 and concentrated. Purification of the residue by silica gel chromatography (50×400 mm column; 80% EtOAc/hexanes to 100% EtOAc) gave 1 (1.42 g, 89%; purity 96% AUC; 92% e.e. by chiral HPLC analysis). Rf=0.35 (80% EtOAc/hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]([F:13])[F:12])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]([F:13])[F:12])[C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1c(Cl)cccc1OC(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1c(Cl)cccc1OC(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a solution of 2-chloro-6-difluoromethoxy-benzaldehyde (0.65 g; 3.15 mmol) in MeOH (10 mL) was added NaBH4 (357.13 mg; 9.44 mmol), at −15° C. After complete addition the mixture was allowed to warm to RT and stirred for 30 minutes. Subsequently, water (5 mL) was added and the volatiles were removed in vacuo. The residue was partitioned between Et2O and 5% aqueous NaHCO3. The layers were separated and the organic layer was dried (Na2SO4), filtered, and concentrated in vacuo to afford (2-chloro-6-difluoromethoxy-phenyl)-methanol (0.52 g), which was used as such.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH:20]4[CH:15]([CH2:16][CH2:17][NH:18][CH2:19]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[CH3:37][O:38][C:39]1[CH:47]=[CH:46][CH:45]=[C:44]([O:48][CH3:49])[C:40]=1[C:41](O)=[O:42].S1C=CC=C1C1C=CC=CC=1C(O)=O>>[CH3:49][O:48][C:44]1[CH:45]=[CH:46][CH:47]=[C:39]([O:38][CH3:37])[C:40]=1[C:41]([N:18]1[CH2:17][CH2:16][CH:15]2[CH:20]([N:13]([C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][N:10]=3)[CH2:14]2)[CH2:19]1)=[O:42]
Reactant: COc1cccc(OC)c1C(=O)O
Reactant: c1ccc(-c2ccnc(N3CC4CCNCC43)n2)cc1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: COc1cccc(OC)c1C(=O)N1CCC2CN(c3nccc(-c4ccccc4)n3)C2C1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting 8-(4-phenyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane (Intermediate 6) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2,6-dimethoxy-benzoic acid for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. for C25H26N4O3, 430.50; m/z found, 431.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.60-7.27 (m, 7H), 7.25-6.66 (m, 3H), 4.84-2.46 (m, 12H), 2.18-1.15 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH2:6][CH:5]([N:8]([C:20]([CH:22]2[CH2:26][CH2:25][CH2:24][O:23]2)=[O:21])[C@@H:9]2[CH2:13][NH:12][C@H:11]([C:14]([N:16]([CH2:18][CH3:19])[CH3:17])=[O:15])[CH2:10]2)[CH2:4][CH2:3]1.C(O[C:33]([N:35]1[CH2:39][C@@H:38]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)[C@H:37]([C:47]([OH:49])=O)[CH2:36]1)=O)(C)(C)C.[O:50]1[CH2:55][CH2:54]C(=O)[CH2:52][CH2:51]1>>[ClH:46].[Cl:46][C:43]1[CH:42]=[CH:41][C:40]([C@@H:38]2[CH2:39][N:35]([CH:33]3[CH2:54][CH2:55][O:50][CH2:51][CH2:52]3)[CH2:36][C@H:37]2[C:47]([N:12]2[CH2:13][C@@H:9]([N:8]([CH:5]3[CH2:6][CH2:7][C:2]([CH3:1])([CH3:27])[CH2:3][CH2:4]3)[C:20]([C@@H:22]3[CH2:26][CH2:25][CH2:24][O:23]3)=[O:21])[CH2:10][C@H:11]2[C:14]([N:16]([CH2:18][CH3:19])[CH3:17])=[O:15])=[O:49])=[CH:45][CH:44]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)cc2)C1
Reactant: O=C1CCOCC1
Reactant: CCN(C)C(=O)[C@@H]1C[C@H](N(C(=O)C2CCCO2)C2CCC(C)(C)CC2)CN1
Product: CCN(C)C(=O)[C@@H]1C[C@H](N(C(=O)[C@@H]2CCCO2)C2CCC(C)(C)CC2)CN1C(=O)[C@@H]1CN(C2CCOCC2)C[C@H]1c1ccc(Cl)cc1
Product: Cl
Yield: 80 %

Procedure:
(4S)-4-[(4,4-dimethylcyclohexyl)(tetrahydrofuran-2-ylcarbonyl)amino]-N-ethyl-N-m ethyl-L-prolineamide (100 mg, 0.26 mmol) prepared in Step D of Example A2 and (3S,4R)-1-(tert-butoxycarbonyl)-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid prepared in Preparation Example A9-9 were reacted according to the procedure described in Step F of Example A1, and then according to that in Step E of Example A1. This compound was reacted with tetrahydro-4H-pyran-4-one via reductive amination as described in Step A of Example A1, and purified by HPLC. This TFA salt of the compound was treated according to the procedure described in Step G of Example A1 to give the title compound (139 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([OH:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].[CH3:16]I>CO.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:16])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)O)ccc1Cl
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1

Procedure:
A mixture of 1 g (4 mmol) 2-Chloro-5-sulfino-benzoic acid in 20 ml methanol and 20 ml water was treated with 10N NaOH to pH=9 before adding 1.7 g (12 mmol) methyliodide. The mixture was heated for 48 h to 80° C. with occasional addition of NaOH to maintain pH=9. After removal of all volatiles HCl conc. was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and evaporated to dryness. The residue was taken up in methanol and subjected to reversed phase HPLC purification eluting with an acetonitrile/water gradient to yield after evaporation of the product fractions 323 mg (34%) of the title compound. MS (m/e): 233.0 (M−H, 100%)
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.Br[CH:24]([CH:31]=O)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].CN(C)C(=O)C>O>[CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:14][C:24]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][N:13]=1)=[CH:8]2
Reactant: CCOC(=O)CC(Br)C=O
Reactant: CN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)Cc1cnc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
A mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.40 g), ethyl 3-bromo-4-oxobutyrate (0.48 g) and N,N-dimethylacetamide (25 mL) was stirred at 90° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.28 g, yield 55%) was obtained as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). melting point 126-127° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH:11]2[CH2:13][CH2:12]2)O)=[C:4]([F:14])[CH:3]=1.FC(F)(F)C(O)=O.[CH3:22][S:23]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:35]=1[NH:34][CH:33]=[CH:32]2)(=[O:25])=[O:24]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([CH:11]2[CH2:13][CH2:12]2)[C:32]2[C:31]3[C:35](=[C:27]([CH2:26][S:23]([CH3:22])(=[O:25])=[O:24])[CH:28]=[CH:29][CH:30]=3)[NH:34][CH:33]=2)=[C:4]([F:14])[CH:3]=1
Reactant: CS(=O)(=O)Cc1cccc2cc[nH]c12
Reactant: OC(c1c(F)cc(Cl)cc1F)C1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Cc1cccc2c(C(c3c(F)cc(Cl)cc3F)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
104 mg (0.48 mmol) of the compound from Example 156A and 0.04 ml (0.57 mmol) of trifluoroacetic acid were added to 100 mg (0.48 mmol) of the compound from Example 86A in 4 ml of dichloromethane. The reaction mixture was stirred at RT for 45 min, the solvent was removed in vacuo, and the crude product was then purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 100 mg (51% of theory) of the title compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH:8]([C:12]([O:14][CH3:15])=[O:13])[C:7](=O)[C:6]=2[CH:17]=1.[BH4-].[Na+].O>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:17]=1
Reactant: COC(=O)C1CCSc2ccc(Br)cc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1=Cc2cc(Br)ccc2SCC1
Reaction time: 1 h
Yield: 46.5 %

Procedure:
A solution of methyl 7-bromo-5-oxo-2,3,4,5-tetrahydro-1-benzothiepine-4-carboxylate (24.94 g) in THF (200 ml) was cooled to −20° C., and to the mixture was added dropwise a solution of sodium boro hydride (2.99 g) in methanol (30 ml). While the temperature of the mixture was kept at −15 to 20° C., the mixture was stirred for 1 hour. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue (24.38 g) was dissolved in THF (200 ml). To the mixture was added triethylamine (26 ml) and then to the mixture was added dropwise at 0° C. methanesulfonyl chloride (9.2 ml). The mixture was stirred at 0° C. for 30 minutes and then at room temperature for 15 hours. To the mixture was added dropwise 1,8-diaza-bicyclo[5,4,0]-7-undecene (17.9 g), and the mixture was stirred for 3 hours. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the residue was purified with column chromatography (ethyl acetate/hexane=1:10). Under reduced pressure, the mixture was concentrated, and the resulting crystals were recrystallized from ethyl acetate/hexane to give pale yellow crystals of methyl 7-bromo-2,3-dihydro-1-benzothiepine-4-carboxylate (11.00 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].[CH:14]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:13])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH:5][C:20]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:21]
Reactant: O=C(Cl)C1CCCCC1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)C1CCCCC1
Reaction time: 2 h

Procedure:
Phenylalanine methyl ester (1 g., 0.0046 moles) is dissolved in pyridine 5 mL. Cyclohexanoyl chloride (0.62 mL) is added and the mixture is stirred for 2 hours. The reaction mixture is poured onto hydrochloric acid (IN) and crushed ice. The aqueous mixture is extracted twice with toluene. The combined toluene extracts are concentrated in vacuo to give 1.1 g of crude N-cyclohexanoylphenylalanine methyl ester.
Reaction SMILES: [CH2:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[S:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26]O>S(=O)(=O)(O)O>[CH2:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([O:14][CH3:26])=[O:13])=[CH:10][C:9]=1[S:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Cc1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCCCSc1cc(C(=O)OC)cc(S(N)(=O)=O)c1Cc1ccccc1

Procedure:
A solution of 4-benzyl-3-n-butylthio-5-sulfamylbenzoic acid (0.85 g) in dry methanol (10 ml) and conc. sulfuric acid (0.2 ml) is refluxed for 20 hours. The methanol is removed in vacuo and the residue is triturated with 1 N sodium hydrogen carbonate (15 ml). The resulting crystalline material is collected by filtration, washed with water and dried. After recrystallization from methanol, methyl 4-benzyl-3-n-butylthio-5-sulfamylbenzoate is obtained with a melting point of 118°-120° C.