Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:35][C:36]([OH:38])=[O:37])[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14](C1C=CC=CC=1)(=[O:16])=[O:15].[O:39]1[CH2:44][CH2:43][N:42](S(C2C=CC=CC=2C=O)(=O)=O)[CH2:41][CH2:40]1>>[CH3:1][C:2]1[N:3]([CH2:35][C:36]([OH:38])=[O:37])[C:4]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:5]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:42]1[CH2:43][CH2:44][O:39][CH2:40][CH2:41]1)(=[O:16])=[O:15]
Reactant: Cc1c(Cc2ccccc2S(=O)(=O)c2ccccc2)c(-c2ccccc2)c(-c2ccccc2)n1CC(=O)O
Reactant: O=Cc1ccccc1S(=O)(=O)N1CCOCC1
Product: Cc1c(Cc2ccccc2S(=O)(=O)N2CCOCC2)c(-c2ccccc2)c(-c2ccccc2)n1CC(=O)O

Procedure:
2-(2-methyl-3-(2-(morpholinosulfonyl)benzyl)-4,5-diphenyl-1H-pyrrol-1-yl)acetic acid was synthesized according to 2-(2-methyl-4,5-diphenyl-3-(2-(phenylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetic acid using 2-(morpholinosulfonyl)benzaldehyde in the general procedure X (step 1). 1H NMR (CDCl3/400 MHz) δ (ppm) 7.95 (d, 1H), 7.52 (t, 1H), 7.37-7.24 (m, 5H), 7.19-7.15 (m, 2H), 7.08-7.04 (m, 3H), 6.95-6.91 (m, 2H), 4.65 (s, 2H), 4.23 (s, 2H), 3.52 (t, 4H), 3.02 (t, 4H), 2.09 (s, 3H). MS m/z: 531.35 (M+1).
Reaction SMILES: [NH2:1][CH:2]([CH3:15])[CH2:3][N:4]([CH3:14])[NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[CH:7]=1.Cl[C:17](OC1C=CC=CC=1)=[O:18]>>[Cl:13][C:8]1[CH:7]=[C:6]([N:5]2[C:17](=[O:18])[NH:1][CH:2]([CH3:15])[CH2:3][N:4]2[CH3:14])[CH:11]=[C:10]([Cl:12])[CH:9]=1
Reactant: CC(N)CN(C)Nc1cc(Cl)cc(Cl)c1
Reactant: O=C(Cl)Oc1ccccc1
Product: CC1CN(C)N(c2cc(Cl)cc(Cl)c2)C(=O)N1

Procedure:
Reacting 1-(2-aminopropyl)-1-methyl-2-(3,5-dichlorophenyl)hydrazine with phenyl chloroformate under presence of base to provide the title compound. m.p. 129-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.O.[C:11](=[O:13])=O.[CH3:14][C:15]([CH3:17])=O>O1CCCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([C:15]2[CH:17]=[CH:6][C:5]([CH2:8][O:13][CH3:11])=[CH:4][CH:14]=2)[OH:7])=[CH:4][CH:3]=1
Reactant: O=C=O
Reactant: CC(C)=O
Reactant: O=Cc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: O
Product: COCc1ccc(C(O)c2ccc(Cl)cc2)cc1
Reaction time: 0.17 h
Yield: 68 %

Procedure:
To a solution of the compound obtained in the above step (2) (515 mg) in tetrahydrofaran (4 mL) was added dropwise 1.59M butyl lithium-hexane solution (1.61 mL) under nitrogen gas atmosphere and cooling in dry ice/acetone bath and the mixture was stirred for 10 minutes. Thereto was added a solution of 4-chlorobenzaldehyde (360 mg) in tetrahydrofuran (1 mL) and the mixture was stirred at room temperature overnight. To the reaction mixture was added water and the mixture was extracted with ethyl acetate (×2). The organic layer was concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=80:20→60:40) to give (4-chlorophenyl)[4-(methoxymethyl)phenyl]methanol (459 mg, yield: 68%) as an oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](Cl)(=[O:32])[C:29](Cl)=[O:30].[CH2:34]([OH:36])[CH3:35]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=2)[C:10]([C:28](=[O:32])[C:29]([O:36][CH2:34][CH3:35])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCO
Reactant: FC(F)(F)Oc1ccc(-c2cccc3ccn(Cc4ccccc4)c23)cc1
Product: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2c(-c3ccc(OC(F)(F)F)cc3)cccc12
Yield: 61 %

Procedure:
Ethyl {1-benzyl-7-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetate was prepared from 1-benzyl-7-[4-(trifluoromethoxy)phenyl]-1H-indole (0.421 g, 1.15 mmol), oxalyl chloride (0.60 mL, 6.9 mmol), and ethanol (3 mL) following the procedure described in Step 3 of Example 1. Purification by flash chromatography (Biotage apparatus) using 3-7.5% ethyl acetate in hexane as an eluant yielded the title compound as a yellow gum (0.328 g, 61%). 1 HNMR (300 MHz, DMSO-d6): δ 8.7 (s, 1H), 8.35 (d, 1H, J=7.7 Hz), 7.35 (t, 1H, J=7.7 Hz), 7.0-7.3 (m, 8H), 6.3 (d, 2H, J=7.7 Hz), 5.25 (s, 2H), 4.35 (q, 2H, J=7.4 Hz), and 1.35 ppm (t, 3H, J=7.3 Hz).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[C:10]([NH2:11])=[CH:9][S:8][CH:7]=1)=[O:5].C(N(CC)CC)C.[Cl:19][C:20]1[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=1[O:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>ClCCl>[CH3:2][O:3][C:4]([C:6]1[C:10]([NH:11][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][O:22][C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[Cl:19])=[CH:9][S:8][CH:7]=1)=[O:5]
Reactant: COC(=O)c1cscc1N
Reactant: O=C(Cl)CCCOc1ccccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cscc1NC(=O)CCCOc1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
To 4-amino-thiophene-3-carboxylic acid methyl ester hydrochloride (199 mg, 0.994 mmol) in dichloromethane (1.9 mL) and triethylamine (0.29 mL, 2.08 mmol), was slowly added a crude solution of 4-(2-chloro-phenoxy)-butyryl chloride (271 mg, approximately 1.16 mmol) in dichloromethane (1.9 mL). The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was then further diluted with dichloromethane (50 mL) and washed with water. The aqueous phase was then extracted with dichloromethane and the combined organic phases were dried with sodium sulfate, and concentrated in vacuo. The residue was then purified by column chromatography (SiO2, Heptane/EtOAc: 0-80%) to yield the title compound as a white solid (281 mg, 80%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:15])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O[CH:20]([NH:22]C(=O)C)[CH3:21])(C)C>FC(F)(F)C(O)=O>[NH2:22][CH:20]([C:8]1[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=1[OH:15])[CH3:21]
Reactant: CC(=O)NC(C)OC(C)C
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(N)c1c(O)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.06 g (10.0 mmol) of 3,5-di-tert-butylphenol in 10 mL of trifluoroacetic acid was added 1.6 g (11.0 mmol) of N-(1-isopropoxyethyl)acetamide and the resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layers were separated and then extracted with EtOAc. The organic layers were combined, dried (Na2SO4), filtered and evaporated in vacuo. The product was purified on a silica gel flash chromatography column eluted with 0-25% EtOAc in CH2Cl2. Evaporation of the purified fraction and drying in vacuo afforded the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([NH2:12])[C:7]1[O:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[O:11]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH2:6][NH:12][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: NCc1ccco1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCc1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
Methanesulfonyl chloride (3.2 mL, 42 mmol) was slowly added to a stirring solution of furfurylamine (4.2 g, 43.2 mmol) and triethylamine (6 mL, 43 mmol) in anhydrous methylene chloride (110 mL). The reaction was stirred overnight at ambient temperature and then diluted with ethyl acetate. The organic solution was successively washed with 1N aqueous hydrochloric acid three times, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride solutions, dried (anhydrous sodium sulfate), and filtered. The solution was concentrated under reduced pressure to give the desired product as a tan liquid (6.6 g, 89%). 1H NMR (CDCl3, 300 MHz) δ 7.39-7.38 (m, 1H), 6.33-6.31 (m, 2H), 5.02 (br s, 1H), 4.33-4.31 (d, 2H, J=6 Hz).
Reaction SMILES: [CH2:1]([C:4]1([OH:17])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].CN(C1C=CC=CN=1)C.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C>ClCCl>[C:27]([O:17][C:4]1([CH2:1][CH:2]=[CH2:3])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC1(OC(C)=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
A solution of tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate (3.7 g, 14.51 mmol) in dichloromethane (20 mL) was treated with dimethylaminopyridine (1.8 g, 14.51 mmol), acetic anhydride (4.1 mL, 43.53 mmol) and triethylamine (6.1 mL, 43.53 mmol), and was stirred overnight at 20° C. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. Combined organic extracts were washed with water, dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure, and purified by a standard method to provide the title compound 44B (3.4 g). LC-MS: m/z 284.4 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH2:9]O)=[C:6]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[N:5]=[CH:4][N:3]=1.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:7]([CH2:8][CH2:9][N:25]2[C:21](=[O:31])[C:22]3[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:24]2=[O:26])=[C:6]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[N:5]=[CH:4][N:3]=1
Reactant: OCCc1c(Cl)ncnc1N[C@H]1CCc2ccccc21
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCc1c(Cl)ncnc1N[C@H]1CCc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
2-{4-chloro-6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-5-yl}ethanol (2.80 g, 9.66 mmol), phthalimide (1.56 g, 10.6 mmol) and triphenylphosphine (2.79 g, 10.6 mmol) were dissolved in THF (105 mL) and the solution was cooled at 0° C. DIAD (2.09 mL, 10.6 mmol) was added dropwise and the mixture was stirred 23° C. for 1 hour. The solvent was removed in vacuo and the residue was purified using chromatography on silica gel using gradient 10 to 50% ethyl acetate in hexane to afford the title compound (3.50 g, 86%). LC/MS: Rt=2.12 min, ES+ 419 (AA standard).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[C:8]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:10])=[CH:11][CH:12]=1
Reactant: C1CCNC1
Reactant: O=C(O)C=Cc1ccc(Br)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(Br)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5.0 g (22.0 mmol) of 4-bromocinnamic acid, 6 mL of oxalyl chloride and 3 drops of DMF in 40 mL of CH2Cl2 was heated to gentle reflux until gas evolution ceased. The volatiles were removed in vacuo and the residue was taken up in 50 mL of CH2Cl2. Pyrrolidine (10 mL; 120 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated in vacuo and chromatographed to afford 5.36 g (19.1 mmol; 87%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8]O)=[C:6]([CH3:10])[C:5]([I:11])=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>C1C=CC=CC=1>[Cl:14][CH2:8][C:7]1[C:6]([CH3:10])=[C:5]([I:11])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Cc1c(I)ccc(F)c1CO
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1c(I)ccc(F)c1CCl
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of the product of Step C (4.01 g, 15.4 mmol) in anhydrous benzene (40 mL) was added dropwise thionyl chloride (3.7 g, 30.8 mmol). The mixture was stirred 80° C. overnight. The mixture was cooled to rt, washed with saturated aqueous sodium bicarbonate solution, water and brine, and dried over magnesium sulfate, and concentrated to dryness to give the title compound as a colorless oil.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O-:12])([O-])=O.[K+].[K+].[OH2:15]>CN(C=O)C>[CH2:1]([O:15][C:3]1[CH:4]=[CH:5][C:9]([OH:12])=[C:7]([CH3:6])[C:2]=1[CH3:1])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(O)ccc(OCc2ccccc2)c1C
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of 2,3-dimethyl-1,4-dihydroquinone (5 g) and benzyl bromide (6.2 g) and K2CO3 (10 g) in DMF (50 mL) was stirred at 120° C. for 5 h. The mixture was poured into water and extracted with EtOAc. The EtOAc was washed with water, dried and evaporated. The residue was purified by silica gel column eluting with 10% EtOAc in hexane to give 3.2 g of 4-benzyloxy-2,3-dimethyl-phenol as a pale solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:13][CH:12]([CH3:14])[CH2:11][C@H:3]([NH:2][S:23]([CH3:22])(=[O:25])=[O:24])[C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NS(C)(=O)=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-tert-Butyl 2-amino-4-methylpentanoate hydrochloride (1.53 g, 6.84 mmol) was dissolved in dichloromethane and triethylamine (3.15 mL, 22.57 mmol). Methanesulfonyl chloride (0.638 mL, 8.21 mmol) was added dropwise, and the reaction stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous NaHCO3 and extracted with dichloromethane (3×50 mL). The solvent was removed in vacuo to give (S)-tert-butyl 4-methyl-2-(methylsulfonamido)pentanoate: 1H NMR (300 MHz, CDCl3) δ ppm 4.71 (d, J=9.7, 1H), 3.98 (td, J=9.5, 5.5, 1H), 2.92 (s, 3H), 1.84 (dt, J=13.1, 6.6, 1H), 1.54 (s, 9H), 1.44-1.48 br s, 1H), 0.96 (dd, J=6.6, 2.4, 6H); MS (ESI−) m/z 264 (M−H)−. (S)-tert-Butyl 4-methyl-2-(methylsulfonamido)pentanoate was dissolved in 10 mL of 4 N HCl in dioxane and stirred at room temperature overnight. The solvent was removed under a stream of nitrogen and under high vacuum to give (S)-4-methyl-2-(methylsulfonamido)pentanoic acid: 1H NMR (300 MHz, CDCl3) δ ppm 4.86 (d, J=9.6, 1H), 4.17 (td, J=9.6, 4.8, 1H), 3.18-3.07 (m, 1H), 2.99 (s, 3H), 1.96-1.80 (m, 1H), 1.64 (dddd, J=23.4, 13.9, 9.1, 5.0, 2H), 1.40 (t, J=7.3, 1H), 0.98 (dd, J=6.6, 3.3, 6H).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH2:7]([O:14][C:15](Cl)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[CH2:7]([O:14][C:15]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(N)CO
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(CO)NC(=O)OCc1ccccc1
Yield: 100.3 %

Procedure:
A procedure similar to that described in Preparation 7 was repeated, except that 7.00 g of 2-amino-2-methylpropanol, 13.47 g of benzyloxycarbonyl chloride, 13.13 g of potassium carbonate, 35 ml of ethyl acetate and 35 ml of water were used, to give 17.59 g of the title compound having an Rf value of 0.72 (on silica gel thin layer chromatography, using a 3:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])/[CH:14]=[C:15](\[C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)/[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2].C(O)(=[S:33])C.C(N(CC)CC)C>C(N(CC)CC)C.O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])[CH2:14][C:15]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)([SH:33])[C:16]([F:17])([F:19])[F:18])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Reactant: CC(O)=S
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)CC(S)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl ester (25 g) was added thioacetic acid (6 eq.) and triethylamine (200 μL) The solution was stirred at room temperature 2 drops of triethylamine were added. After stirring at room temperature for 24 hours, the mixture was poured in a mixture of water and ethyl acetate, extracted with ethyl acetate and washed with brine. The collected organic phases were dried over magnesium sulfate, filtered and the filtrate was evaporated under vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane/dichloromethane) to give 4-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-mercapto-butyryl]-2-methyl-benzoic acid tert-butyl ester (3.78 g) 1H NMR (CDCl3, 400 MHz): δ=7.89 (d, J=8.8 Hz, 1 H), 7.72-7.79 (m, 2 H), 7.53-7.57 (m, 2 H), 7.35 (t, J=1.8 Hz, 1 H), 4.30 (d, J=18.3 Hz, 1 H), 3.97 (d, J=18.3 Hz, 1 H), 3.30 (s, 1 H), 2.59-2.65 (m, 3 H), 1.58-1.66 (m, 10 H), 1.56 ppm (s, 1 H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[S:11](=O)(=[O:14])([OH:13])[OH:12]>>[C:9]1([S:11]([OH:14])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: c1ccc2ccccc2c1
Product: O=S(=O)(O)c1cccc2ccccc12
Temperature: 150 °C
Reaction time: 3 h
Yield: 133 %

Procedure:
500 g naphthalene (3.9 m) and 624 g sulfuric acid 98% (6.23 m) were charged to a reactor and mixed. The resulting mixture was then heated rapidly to 150° C. and agitated at 150° C. for 3 hours to obtain 1080 g of naphthalenesulfonic acid having the following properties:
Reaction SMILES: Br[C:2]1[C:7]([N:8](COC)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:39]=[CH:38][C:31]([C:32](N(OC)C)=[O:33])=[CH:30][CH:29]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:7]2[C:2]([C:32](=[O:33])[C:31]3[CH:38]=[CH:39][C:28]([Cl:27])=[CH:29][CH:30]=3)=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)(=[O:10])=[O:11])=[CH:13][C:14]=1[C:19]([F:21])([F:22])[F:20]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1
Product: O=C(c1ccc(Cl)cc1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by procedure analogous to that described in Example 29 using N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide and 4-chloro-N-methoxy-N-methyl-benzamide 1H NMR (400 MHz, CDCl3) δ10.61 (s, 1H), 8.37 (m, 1H), 8.16 (m, 1H), 8.09 (m, 1H), 7.84 (m, 1H), 7.77-7.75 (m, 2H), 7.53 (m, 1H), 7.42-7.40 (m, 2H), 7.23 (m, 1H) MS: (M+H)/z=509.0.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl-].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:12]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)c1ccc(F)cc1

Procedure:
A mixture of 4-fluorobenzoic acid (5.0 g, 36 mmol) in CH2Cl2 was treated with oxallyl chloride (6.2 mL, 72 mmol) and a catalytic amount of DMF. The mixture was stirred until the evolution of gas stopped and then concentrated under reduced pressure. The residue was re-dissolved in CH2Cl2 and the solution was added in a drop wise manner to a mixture of benzyl alcohol (3.9 g, 36 mmol), diisopropyl ethyl amine (12.6 mL, 72 mmol) and a catalytic amount of DMAP in CH2Cl2. After stirring overnight the reaction mixture was concentrated and the residue was passed through a silica gel plug with 10% Et2O in hexanes. The intermediate 4-fluoro benzoic acid benzyl ester obtained from the above procedure was dissolved in DMSO (25 mL). Followed addition of piperazine (14 g, and the mixture was heated in a sealed tube at 120° C. overnight. Next morning the reaction mixture was partitioned between EtOAc and water. The water layer was basified to pH 12 with solid NaOH, extracted once again with EtOAc and the combined EtOAc layer was dried over Na2SO4, filtered and concentrated to afford the product (8.5 g, Yield: 80%). HRMS m/z calcd for C18H20N2O2 [M+H]: 297.1598. Found: 297.1597.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=2)[CH2:3]1.C[O:19][C:20]([CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[S:31](Cl)(=[O:33])=[O:32])[CH2:23]1)=[O:21]>>[CH3:1][C@H:2]1[CH2:3][N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][N:9]=2)[CH2:5][CH2:6][N:7]1[S:31]([C:28]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:29]=1[CH2:30][CH:22]([C:20]([OH:21])=[O:19])[CH2:23]2)(=[O:33])=[O:32]
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)Cl)c2C1
Reactant: C[C@H]1CN(c2ccc(C(F)(F)F)cn2)CCN1
Product: C[C@H]1CN(c2ccc(C(F)(F)F)cn2)CCN1S(=O)(=O)c1cccc2c1CC(C(=O)O)C2

Procedure:
The compound 4-[2-(S)-Methyl-4-(5-trifluoromethyl-pyridin-2-yl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid was prepared from 3-(S)-methyl-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine and 4-chlorosulfonyl-indan-2-carboxylic acid methyl ester following the procedure outlined in Example 79. 1H NMR (400 MHz, DMSO-d6): 8.38 (s, 1H), 7.82-7.76 (m, 1H), 7.65 (d, 1H), 7.52 (d, 1H), 7.37 (t, 1H), 6.93-6.88 (m, 1H), 4.35-4.18 (m, 2H), 4.18-4.02 (m, 1H), 3.60-3.46 (m, 1H), 3.45-3.10 (m, 7H), 2.97-2.80 (m, 1H), 1.06-1.01 (m, 3H); MS (ESI): 470.0 (M+H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15].C1N2CCN(CC2)C1.C(N=C=O)CCC>C1(C)C(C)=CC=CC=1.C(Cl)Cl>[CH3:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]=[C:1]=[O:2])(=[O:16])=[O:15]
Reactant: CSCc1ccccc1S(N)(=O)=O
Reactant: O=C(Cl)Cl
Agent: C1CN2CCN1CC2
Agent: CCCCN=C=O
Solvent: Cc1ccccc1C
Solvent: ClCCl
Product: CSCc1ccccc1S(=O)(=O)N=C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosgene (2.5 ml, 35 mmol) was added portionwise into a nitrogen-purged mixture containing 6.8 g (31 mmol) of o-methylthiomethylbenzenesulfonamide, 0.1 g of DABCO, and 3.8 g (38 mmol) of n-butyl isocyanate in 60 ml of dry xylene, while the temperature was maintained at 130°-135° C. between additions. Stirring was continued for 1 hour at 130°-135° C. The mixture was cooled to room temperature and the solid was filtered off under nitrogen. The filtrate was concentrated to yield 9.0 g (theo 7.6 g) of oil: IR cm-1 2240 (N=C=O), no NH at ca 3300. The oil was taken up in 90 ml of dry methylene chloride.