Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]([CH3:15])([C:12](Cl)=[O:13])[C:9](Cl)=[O:10].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][NH:24][OH:25]>C(Cl)Cl>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][N:24]1[C:9](=[O:10])[C:8]([CH3:15])([CH3:7])[C:12](=[O:13])[O:25]1
Reactant: ONCc1ccccc1F
Reactant: CC(C)(C(=O)Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)C(=O)ON(Cc2ccccc2F)C1=O
Temperature: -25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
The procedure of Example III was utilized with 10.2 ml (0.128 mole) pyridine, 10.2 grams (0.060 mole) dimethylmalonyl chloride and 120 ml methylene chloride in solution under argon at -72° C., to which 8.5 grams (0.060 mole) of N-(2-fluorophenylmethyl)hydroxylamine (Intermediate F) in 25 ml methylene chloride was added in a single portion, raising the temperature immediately to -25° C., and stirring was continued at 0° C. for two hours. Gas chromatography on a sample of the reaction mixture showed only one major peak. The reaction mixture was washed with 2 N hydrochloric acid and water, the methylene chloride layer was separated and dried over sodium sulfate, and after removal of sodium sulfate by filtration, the solvent was removed under reduced pressure, leaving 13.0 grams of a yellow viscous liquid (91% yield). The nmr and ir spectra were consistent with the assigned structure.
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6]([CH3:14])=[C:7]2[C:11]([OH:13])=[O:12].[C:15](=O)([O:21]C(C)(C)C)[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]>C(=O)(O)[O-].[Na+].O.O1CCOCC1>[C:17]([O:16][C:15]([NH:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6]([CH3:14])=[C:7]2[C:11]([OH:13])=[O:12])=[O:21])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)OC(C)(C)C)C2SC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.3 %

Procedure:
7-Amino-2-carboxy-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (371 g) is dissolved in a solution of sodium bicarbonate (307 g) in a mixture of distilled water (2 liters) and dioxane (2 liters). A solution of di-tert.-butyl carbonate (421 g) in dioxane (2 liters) is added in the course of 10 minutes. The reaction mixture is stirred for 48 hours at 25° C. The suspension obtained is concentrated under reduced pressure (20 mm Hg) at 50° C. to a residual volume of about 2 liters, and is then diluted with ethyl acetate (1 liter) and distilled water (2 liters). The aqueous phase is decanted, washed with ethyl acetate (500 cc) and acidified to pH 2 with 6 N hydrochloric acid in the presence of ethyl acetate (1500 cc). The aqueous phase is extracted with ethyl acetate (2×1 liter). The combined organic phases are washed with a saturated sodium chloride solution (2×250 cc) and dried over sodium sulphate. After filtration, the solvent is evaporated under reduced pressure (20 mm Hg) at 50° C. 7-tert.-Butoxycarbonylamino-2-carboxy-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (486 g) is obtained in the form of yellow crystals (m.p.=190° C., with decomposition).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=O)[O:18]C2C=CC([N+]([O-])=O)=CC=2)=[CH:12][CH:11]=1)([O-:9])=[O:8]>C(Cl)Cl.O>[O:4]1[CH2:5][CH2:6][CH:2]([O:1][C:17](=[O:18])[O:16][C:13]2[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:15][CH:14]=2)[CH2:3]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: O[C@H]1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCOC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.9 %

Procedure:
(S)-(+)-3-Hydroxy-tetrahydrofuran (0.88 mL, 13 mmol) was dissolved in DCM (5 mL) and H2O (40 mL), carbonic acid bis-(4-nitro-phenyl) ester (5.8 g 19 mmol) and TEA (2.8 mL, 20 mmol) were added slowly. The reaction was allowed to stir at room temperature for 24 h. After concentrated, diluted with EtOAc, washed with brine and H2O, dried over Na2SO4, the crude product was purified on silica (12 g, 25-75% EtOAc/hexanes) to give carbonic acid 4-nitro-phenyl ester tetrahydro-furan-3-yl ester as light yellow solid (2.3 g, 71%).
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:5]=[C:6]([S:10]([O-:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.[Na+].Br[C:16]1[CH:24]=[CH:23][C:22]2[N:21]([CH3:25])[C:20]3[CH2:26][CH:27]4[NH:31][CH:30]([C:19]=3[C:18]=2[C:17]=1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28]4>>[F:13][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([S:10]([C:16]2[CH:24]=[CH:23][C:22]3[N:21]([CH3:25])[C:20]4[CH2:26][CH:27]5[NH:31][CH:30]([C:19]=4[C:18]=3[C:17]=2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28]5)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=S([O-])c1cccc(OC(F)F)c1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cccc(OC(F)F)c4)ccc31)C1CCC(C2)N1
Yield: 43 %

Procedure:
Intermediate 6 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude material was purified by flash column chromatography (SiO2, 7:3 hexane/ethyl acetate) to give tert-butyl 2-(3-difluoromethoxyphenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (155 mg, 43%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 8.12-8.22 (m, 1H), 7.76-7.82 (m, 1H), 7.62-7.72 (m, 2H), 7.46 (t, J=8.1 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.21-7.26 (m, 1H), 6.52 (t, J=72.9 Hz, 1H), 5.19-5.38 (m, 1H), 4.55-4.80 (m, 1H), 3.61 (s, 3H), 3.20-3.51 (m, 1H), 2.50 (d, J=8.1 Hz, 1H), 2.12-2.40 (m, 2H), 1.89-1.99 (m, 1H), 1.55-1.67 (m, 1H), 1.37 (s, 9H).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6].[CH3:9][C:10]([CH2:25][CH2:26][CH2:27][CH:28]([CH3:40])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:39])[CH2:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[CH:11][CH2:12][CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O>[CH3:9][C:10]([CH2:25][CH2:26][CH2:27][CH:28]([CH3:40])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:39])[CH2:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[CH:11][CH2:12][CH2:13][O:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6]
Reactant: OCC(O)CO
Reactant: CC(=CCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)CCCC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=CCCOCC(O)CO)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 4 %

Procedure:
0.21 g (55%, 4.8 mmol) of sodium hydride was added to a solution of 0.44 g (4.8 mmol) of glycerol in dry N,N-dimethylformamide (5 mL) with cooling on ice. After the mixture was stirred for 30 min at 50° C., the above (4,8,12,16-tetramethylheptadec-3-enyl)tosylate was added dropwise with additional stirring for 12 hours at the same temperature. After addition of water at 0° C., the reaction mixture was extracted with ethyl acetate. The extract was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane mixture) to obtain 44 mg of the title compound (4% yield in 2 steps) as a colorless transparent viscous product. The results of NMR analysis of the obtained compound are as shown below.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.Cl[CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH3:16])=[O:14]>CO>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[N:1]=2)[N:4]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: Nc1ccc(Cl)nn1
Solvent: CO
Product: COC(=O)Cc1cn2nc(Cl)ccc2n1
Yield: 52 %

Procedure:
10.1 g of 3-amino-6-chloropyridazine was suspended in 120 ml of methanol; 23.5 g of methyl 4-chloroacetoacetate was added, followed by heating and refluxing for 20 hours. After cooling, the mixture was concentrated under reduced pressure; the residue was ajusted to pH 7 by the addition of an aqueous solution of sodium hydrogen carbonate, followed by extraction with ethyl ether; the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (1:4). The desired fraction was collected to yield 9.15 g of methyl 6-chloroimidazo[1,2-b]pyridazin-2-acetate was dissolved in 10 ml of N,N-dimethylformamide; while the solution was stirred under ice water cooling conditions, 3.5 g of a 60% sodium hydride dispersion in mineral oil was add little by little, followed by stirring at room temperature for 30 minutes. Under ice water cooling conditions, 6.3 ml of methyl iodide was added, followed by stirring at room temperature for 5 hours. Ice water was poured, followed by extraction with ethyl acetate; the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (1:1). The desired fraction was collected and concentrated to yield 14.1 g of the title compound.
Reaction SMILES: Cl.[CH:2]([N:15]1[CH2:18][CH:17]([NH:19][NH2:20])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[C:32](=O)/[CH:33]=[CH:34]/N(C)C>C(O)C.C(O)(=O)C>[CH:2]([N:15]1[CH2:16][CH:17]([N:19]2[C:32]([C:23]3[CH:24]=[C:25]([C:28]([F:29])([F:30])[F:31])[CH:26]=[CH:27][C:22]=3[Br:21])=[CH:33][CH:34]=[N:20]2)[CH2:18]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NNC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CN(C)/C=C/C(=O)c1cc(C(F)(F)F)ccc1Br
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(Br)c(-c2ccnn2C2CN(C(c3ccccc3)c3ccccc3)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
To a solution of compound 1-benzhydryl-3-hydrazinylazetidine hydrochloride (15.5 g, 49.6 mmol) in ethanol (150 mL), a mixture of (E)-1-(2-bromo-5-(trifluoromethyl)phenyl)-3-(dimethylamino)prop-2-en-1-one (16 g, 49.6 mmol) in acetic acid (15 mL) was added slowly at 0° C. The reaction was stirred at the same temperature for 8 h. After warming to rt, the solvent was completely evaporated off. The residue was diluted with ethyl acetate (500 mL), washed with water (500 mL), and saturated aqueous sodium bicarbonate (30 mL). Organic part was dried over sodium sulfate, filtered and concentrated under a vacuum to give the crude which was further purified by column chromatography using silica gel (100 to 200 mesh) eluting with 0% to 10% ethyl acetate in hexanes to obtain 1-(1-benzhydrylazetidin-3-yl)-5-(2-bromo-5-(trifluoromethyl)phenyl)-1H-pyrazole (10 g, 39.3%) as a sticky yellow solid. MS (ESI, positive ion) m/z (M+1): 512.01. 1H NMR (400 MHz, DMSO) δ 8.03 (d, J=8.3 Hz, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.77 (s, 1H), 7.68 (d, J=1.5 Hz, 1H), 7.43 (d, J=7.4 Hz, 4H), 7.26 (t, J=7.5 Hz, 4H), 7.17 (t, J=7.3 Hz, 2H), 6.41 (d, J=1.5 Hz, 1H), 4.66-4.59 (m, 1H), 4.57 (s, 1H), 3.46 (dt, J=26.3, 7.3 Hz, 4H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[N:14][N:15]([CH2:16][C@H:17](O)[CH3:18])[C:9]=3[C:7]=2[N:8]=1.C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[N-:36]=[N+:37]=[N-:38].[Na+]>O1CCCC1>[N:36]([C@@H:17]([CH3:18])[CH2:16][N:15]1[C:9]2[C:7]3[N:8]=[C:4]([CH2:3][O:2][CH3:1])[O:5][C:6]=3[CH:12]=[CH:11][C:10]=2[CH:13]=[N:14]1)=[N+:37]=[N-:38]
Reactant: COCc1nc2c(ccc3cnn(C[C@@H](C)O)c32)o1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCc1nc2c(ccc3cnn(C[C@H](C)N=[N+]=[N-])c32)o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 37 %

Procedure:
A solution of the product from Step B (0.20 g, 0.77 mmol in tetrahydrofuran (10 mL) was cooled (ice bath), triethylamine (0.43 mL, 3.06 mmol) and methanesulfonic anhydride (0.24 g, 1.38 mmol) were added and the mixture was stirred at 0° C. for 20 minutes. Sodium azide (0.50 g, 7.66 mmol) was added to the reaction mixture, which was evaporated to a residue that was dissolved in dimethyl sulfoxide (10 mL) and heated at 90–100° C. for 2 hours. The reaction mixture was cooled to room temperature, water (200 mL) was added, and the mixture was extracted with ethyl acetate (2×100 mL). The combined extracts were dried (magnesium sulfate), filtered, and evaporated to give a residue which was purified by chromatography (silica gel, hexane/ethyl acetate) to give a yellow oil (80 mg, 37%): LC/MS m/z 287.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([S:9](=[O:12])(=[O:11])[NH2:10])=[CH:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>CC(C)=O>[C:22]([O:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([S:9](=[O:11])(=[O:12])[NH2:10])=[CH:8][C:4]=2[CH:3]=1)(=[O:24])[CH3:23]
Reactant: NS(=O)(=O)c1cc2cc(O)ccc2s1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)Oc1ccc2sc(S(N)(=O)=O)cc2c1
Temperature: -5 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
A solution of 5-hydroxy-2-sulfamoylbenzo[b]thiophene (4.00 g, 0.017 m) in acetone (70 ml) was cooled to -5° C., triethylamine (1.92 g, 0.019 m) was added, followed by the dropwise addition of a solution of acetyl chloride (1.49 g, 0.019 m) in acetone (10 ml) over 15 minutes, maintaining the temperature at -5° to -3° C. After stirring at -5° C. for 21/4 hours, the mixture was filtered and the solid was washed with acetone. The combined filtrate and washings were concentrated under reduced pressure, the residue was dissolved in ethyl acetate (7.5 ml) washed with water (2×20 ml), dried and evaporated under reduced pressure. The residue was crystallized from 1,2-dichloroethane to yield 4.01 g (87%) of product melting at 129°-132° C. An analytical sample melted at 131.5°-133° C. after recrystallization from 1,2-dichloroethane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:11]([O:20][CH2:21][C:22]([OH:24])=[O:23])[C:10]([C:25](=[O:39])[NH:26][C@@H:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[CH3:28])=[N:9]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:47](C)[C:48](OCC)=O>CC(C)=O>[CH2:47]([O:23][C:22](=[O:24])[CH2:21][O:20][C:11]1[C:10]([C:25](=[O:39])[NH:26][C@@H:27]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:34]=2)[CH3:28])=[N:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH3:48]
Reactant: C[C@@H](NC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1OCC(=O)O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1c(C(=O)N[C@H](C)c2ccc(C(F)(F)F)cc2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [E1] (156 mg, 0.28 mmol) in acetone was added potassium carbonate (26 mg) and ethyl 2-bromopropionate (11.7 ul, 0.10 mmol). The resulting suspension was stirred overnight at room temperature then partitioned between dichloromethane and brine. The organic phase was dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. The residue was purified by column chromatography over silica (2 g) silica, eluting with dichloromethane then ethyl acetate/heptane (1/1) to give 142 mg of {1-(2-Chloro-phenyl)-5-(4-chloro-phenyl)-3-[(R)-1-(4-trifluoromethyl-phenyl)-ethylcarbamoyl]-1H-pyrazol-4-yloxy}-acetic acid ethyl ester
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[C:10]([O:14][C:15]([NH:17][CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].[H-].[Na+].O>CN(C=O)C>[C:10]([O:14][C:15]([NH:17][C:18]([CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([I:1])[CH:3]=1)([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)OCC
Reactant: BrCc1cccc(I)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1cccc(I)c1)(NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
25 g (84.2 mmol) of 3-iodobenzyl bromide are added to a solution of 24.3 g (88.4 mmol) of diethyl [(tert-butoxycarbonyl)amino]malonate and 3.7 g (92.6 mmol) of sodium hydride in 300 ml of DMF while cooling in ice. After stirring the mixture at RT for 4 h, 5 ml of water are added cautiously while cooling in ice. The mixture is extracted several times with ethyl acetate, and the combined organic phases are washed with a saturated sodium chloride solution and water, dried over magnesium sulfate and concentrated in vacuo. The crude product is dried under high vacuum.
Reaction SMILES: FC(F)(F)C1C=CC(COC2C=CC=CC=2CO)=CC=1.C[O:22][C:23](=[O:55])[CH2:24][O:25][C:26]1[CH:34]=[CH:33][C:32]([S:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)=[C:31]2[C:27]=1[CH2:28][CH2:29][CH2:30]2>>[F:53][C:51]([F:52])([F:54])[C:48]1[CH:49]=[CH:50][C:45]([CH2:44][O:43][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[CH2:36][S:35][C:32]2[CH:33]=[CH:34][C:26]([O:25][CH2:24][C:23]([OH:55])=[O:22])=[C:27]3[C:31]=2[CH2:30][CH2:29][CH2:28]3)=[CH:46][CH:47]=1
Reactant: COC(=O)COc1ccc(SCc2ccccc2OCc2ccc(C(F)(F)F)cc2)c2c1CCC2
Agent: OCc1ccccc1OCc1ccc(C(F)(F)F)cc1
Product: O=C(O)COc1ccc(SCc2ccccc2OCc2ccc(C(F)(F)F)cc2)c2c1CCC2

Procedure:
Preparation of [2-(4-Trifluoromethyl-benzyloxy)-phenyl]-methanol (compound 81A) The title compound was prepared in the manner analogous to Example 14A using 1-bromomethyl-4-trifluoromethyl-benzene and 2-hydroxymethyl-phenol. MS m/z 265 (M-OH). Step 2. Preparation of 1-(4-trifluoromethyl-benzyloxy)-2-chloromethyl-benzene (compound 81B) The title compound was prepared in the manner analogous to Example 3B using 81A. MS m/z 265 (M-Cl). Step 3. Preparation of {7-[2-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acid methyl ester (compound 81C) The title compound was prepared in the manner analogous to Example 1F using 81B and 12C. MS m/z 503 (M+1). Step 4. Preparation of {7-[2-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acid (compound 81) The title compound was prepared in the manner analogous to Example 1 using 81C. mp 150-152° C.; IR (KBr) cm−1: 3074, 3042, 1701, 1324, 1124, 1099; 400 MHz 1H NMR (DMSO-d6): δ 7.58-7.75 (m, 2H), 6.92-7.20 (m, 4H), 6.80 (t, 1H, J=7.5 Hz), 6.51 (d, 1H, J=8.5 Hz), 5.16 (s, 2H), 4.57 (s, 2H), 3.99 (s, 2H), 2.70 (t, 2H, J=7.5 Hz), 2.62 (t, 2H, J=7.5 Hz), 1.80 (pentet, 2H); MS m/z 487 (M−1). Anal. Calc'd for C26H23F3O4S: C, 63.92; H, 4.75; found: C, 63.54; H, 4.52.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([S:22]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11]2)(=[O:23])=[O:24])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(CCCOc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCCOc3ccccc3)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid ethyl ester (4.2 g, 9.1 mmol) dissolved in THF:Methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.0 g (75%); off white powder, mp 195° C.; MS: 434.5 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[CH:4]=1)#[N:2].[CH3:15][O:16]C(Cl)Cl.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]2[C:10]([CH:9]=[CH:8][C:7]([O:13][CH3:14])=[C:6]2[CH:15]=[O:16])=[CH:11][CH:12]=1)#[N:2]
Reactant: COc1ccc2ccc(C#N)cc2c1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc2ccc(C#N)cc2c1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 3.7 g of 2-cyano-7-methoxynaphthalene was dissolved in 40 ml of dichloro- methane, and 6.6 ml of titanium tetrachloride and 4.6 ml of dichloromethyl methyl ether were added dropwise into the resulting solution at 0° in this order. The resulting mixture was stirred at room temperature for 30 minutes and cooled to 0° C. again. Water was added to the resulting mixture to cease the reaction, and the resulting mixture was extracted with dichloromethane (100 ml×2) The organic layers were combined, washed with water, a saturated aqueous solution of sodium bicarbonate and brine successively, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the resulting crude crystal was washed with ether and dried to give 3.3 g of the title compound as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=3)[N:7]([C:18]([O:20][CH:21](Cl)[CH3:22])=[O:19])[C:6]=2[CH:5]=[C:4]([O:24][CH3:25])[C:3]=1[OH:26].[C:27]([OH:30])(=[O:29])[CH3:28]>C(OCC)(=O)C>[C:27]([O:30][CH:21]([O:20][C:18]([N:7]1[C:6]2[CH:5]=[C:4]([O:24][CH3:25])[C:3]([OH:26])=[C:2]([Br:1])[C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)=[O:19])[CH3:22])(=[O:29])[CH3:28]
Reactant: COc1ccc2c(c1)Sc1c(cc(OC)c(O)c1Br)N2C(=O)OC(C)Cl
Reactant: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)Sc1c(cc(OC)c(O)c1Br)N2C(=O)OC(C)OC(C)=O

Procedure:
A mixture of 4-bromo-10-(1-chloroethoxycarbonyl)-2,7-dimethoxy-3-hydroxy-10H-phenothiazine (1g) and mercuric acetate (1.46g) in glacial acetic acid (30 ml) was stirred and heated at 85° for 10 minutes. After cooling the mixture was diluted with ethyl acetate, washed with water, aqueous NaHCO3 solution, and brine, dried and evaporated. Flash chromatography on a column of silica gel, eluting with a 1:3 mixture of ethyl acetate and hexane, afforded the pure title product (599 mg) m.p.: 162°-164° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[O:12]=[C:13]([N:29]1[CH2:34][CH2:33][CH:32]([S:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]([F:45])([F:44])[F:43])[CH2:31][CH2:30]1)[CH2:14][NH:15][C:16]([C:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:20][N:19]=1)=[O:17]>C(Cl)Cl>[O:12]=[C:13]([N:29]1[CH2:30][CH2:31][CH:32]([S:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]([F:44])([F:43])[F:45])=[O:9])[CH2:33][CH2:34]1)[CH2:14][NH:15][C:16]([C:18]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:20][N:19]=1)=[O:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(NCC(=O)N1CCC(Sc2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2)[nH]n1
Solvent: ClCCl
Product: O=C(NCC(=O)N1CCC(S(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 1 h
Yield: 59.5 %

Procedure:
m-Chloroperbenzoic acid (18.5 mg, 0.1 mmol) was added to a cold (0-4° C.) solution of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-phenylsulfanyl)-piperidin-1-yl]-ethyl}-amide (50 mg, 0.1 mmol) in DCM (10 mL) and stirring was continued for 1 hr. The reaction mixture was concentrated. Purification by column chromatography (using 60-120 silica gel and 0.6% MeOH in CHCl3 as eluent) afforded 30 mg (58.35% yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzenesulfinyl)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 505.15, 95.9%. 1H NMR (300 MHz, DMSO-d6): δ 13.8 (s, 1H), 8.2-7.9 (m, 4H), 7.9-7.8 (m, 3H), 7.6-7.4 (t, 2H), 7.4 (t, 1H), 7.1 (s, 1H), 4.5 (d, 1H), 4.2 (d, 2H), 4.0 (d, 1H), 3.1 (m, 2H), 2.8-2.5 (m, 2H), 1.9 (d, 1H), 1.7 (dd, 1H), δ 1.6-1.4 (m, 2H).