Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1.[C@H:21]12[CH2:27][C@H:24]([NH:25][CH2:26]1)[CH2:23][N:22]2[CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][N:25]3[CH2:26][C@@H:21]4[CH2:27][C@H:24]3[CH2:23][N:22]4[CH2:28][C:29]3[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=3)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(CN2C[C@@H]3C[C@H]2CN3)cc1
Reactant: O=Cc1ccc(Oc2ccc(-c3ncco3)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(CN2C[C@@H]3C[C@H]2CN3Cc2ccc(Oc3ccc(-c4ncco4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 99.6 %

Procedure:
4-[4-(2-oxazolyl)phenoxy]benzaldehyde (10.2 g, 38.5 mmol) and methyl 4-[[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate (9.9 g, 40.4 mmol, 1.05 equiv.) were dissolved in dichloroethane (200 mL). After 75 minutes, sodium triacetoxyborohydride (9.8 g, 46.1 mmol, 1.2 equiv.) was added. The reaction mixture was stirred overnight at ambient temperature. Then, 1N NaOH was added. The reaction mixture was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with 0.5 M H2SO4, and MeOH was added to the mixture until the precipitated gummy solid dissolved. The layers were separated and the aqueous layer was cooled to −5 C and saturated K2CO3 was added slowly enough to keep the temperature below 0 C to prevent ester hydrolysis. Once the pH was 11, the solution was extracted with EtOAc (2×), and the combined EtOAc fractions were dried and concentrated to give 19.0 g (100%) of methyl 4-[[(1S,4S)-5-[[4-[4-(2-oxazolyl)phenoxy]phenyl]methyl]-2,5-diazabicyclo[2.2.1]hept-2-yl]methyl]benzoate as the free base, which was 98% pure by HPLC; 1H NMR (300 MHz, CDCl3) δ 8.02 (d, 2H), 8.02 (d, 2H), 7.69 (d, 1H), 7.47 (d, 2H), 7.40 (d, 2H), 7.22 (d, 1H), 7.08 (d, 2H), 7.05 (d, 2H), 3.92 (s, 3H), 3.84 (d, 1H), 3.78 (d, 1H), 3.77 (d, 1H), 3.71 (d, 1H), 3.35 (s, 1H), 3.31 (s, 1H), 2.89 (d, 1H), 2.88 (d, 1H), 2.71 (dd, 1H), 2.70 (dd, 1H), 1.79 (s, 2H) ppm.
Reaction SMILES: [C:1]([C:4]1[N:12]2[C:7]([C:8]([NH2:13])=[N:9][CH:10]=[N:11]2)=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=3[F:34])=[O:22])=[CH:16][CH:15]=2)[CH:5]=1)(=[O:3])[CH3:2].C(N(C(C)C)CC)(C)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[Br:56]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1>[Br:56][CH2:2][C:1]([C:4]1[N:12]2[C:7]([C:8]([NH2:13])=[N:9][CH:10]=[N:11]2)=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=3[F:34])=[O:22])=[CH:16][CH:15]=2)[CH:5]=1)=[O:3]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(=O)c1cc(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn12
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1ncnn2c(C(=O)CBr)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A suspension of Example 100 in THF (5 mL) was cooled to −78° C. and treated with diisopropylethyl amine (0.424 mL, 2.57 mmol) followed by trimethylsilyltriflate (0.421 mL, 2.177 mmol). The reaction was allowed to warm to rt over 30 min, then cooled again to −78° C. and treated with 1,3-dibromo-5,5-dimethylhydantoin (62 mg, 0.218 mmol). The reaction was allowed to stir for 1 h at −78 C, then warmed to rt and quenched with methanol (200 uL) and diluted with ethyl acetate and 1N sodium sulfite solution. The organic layer was separated, washed with 1 N bisulfate buffer (pH 2), dried with sodium sulfate and passed thru a silica plug. Evaporation of the solvent gave a yellow solid which was triturated with Et2O:hexanes (1:1) to provide the title compound as a yellow solid (154 mg, 70% Yield). 1H-NMR (DMSO-d6) 9.18 (s, 1H), 8.45 to 8.48 (m, 1H), 8.02 (s, 1H), 7.43 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 7.27 (s, 1H), 7.20 to 7.37 (m, 4H), 4.77 (s, 2H). MS [M+H]+=551.2; LCMS RT=3.63.
Reaction SMILES: Cl.[NH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([C:13]([OH:15])=[O:14])([CH2:6]3)[CH2:4]1)[CH2:10]2.S(Cl)([Cl:18])=O.[CH3:20]O>>[ClH:18].[CH3:20][O:14][C:13]([C:5]12[CH2:11][CH:9]3[CH2:8][CH:7]([CH2:12][C:3]([NH2:2])([CH2:10]3)[CH2:4]1)[CH2:6]2)=[O:15]
Reactant: NC12CC3CC(C1)CC(C(=O)O)(C3)C2
Reactant: O=S(Cl)Cl
Reactant: CO
Agent: Cl
Product: COC(=O)C12CC3CC(CC(N)(C3)C1)C2
Temperature: 60 °C
Yield: 92 %

Procedure:
To a 3-neck 2-L flask equipped with a reflux condenser and a temperature probe was added 3-amino-adamantane-1-carboxylic acid hydrochloride (100 g, 432 mmol) and methanol (1.0 L). To this solution was slowly added thionyl chloride (15.7 mL, 216 mmol) and the reaction was heated at 60° C. for 4 hours. Once cooled to room temperature, the crude reaction mixture was concentrated under reduced pressure to remove most of the methanol. Heptane (about 1-L) was then added and the mixture was once again concentrated under reduced pressure at which point a solid began to precipitate. This process was repeated three more times, then the solids were filtered off, washed with heptane and allowed to dry in open air to afford 97.2 g (92%) of the title compound, 3-amino-adamantane-1-carboxylic acid methyl ester hydrochloride, as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.46 (br s, 3H), 3.65 (s, 3H), 2.33-2.24 (m, 2H), 2.23-2.16 (m, 2H), 2.11-1.95 (m, 4H), 1.94-1.78 (m, 4H), 1.75-1.62 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.[CH:11](=O)[CH3:12].[BH3-]C#N.[Na+].[C:18](#N)[CH3:19]>>[CH2:18]([N:1]([CH2:11][CH3:12])[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12)[CH3:19]
Reactant: Nc1cnn2ccccc12
Reactant: CC=O
Reactant: CC#N
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CC)c1cnn2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 58 %

Procedure:
A solution of 3-aminopyrazolo[1,5-a]pyridine (0.74 g, 5.55 mmol) in acetonitrile (15.0 mL) was treated with acetaldehyde (6.2 mL, 4.89 g, 111 mmol) and NaCNBH3 (0.84 g, 13.3 mmol) and stirred at room temperature for 3 days. The reaction was concentrated in vacuo and the residue partitioned between ethyl acetate and saturated NaHCO3 solution. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×). The organic layers were combined, washed with brine, dried over MgSO4 and concentrated in vacuo to dryness. The residue was subjected to column chromatography (15% ethyl acetate/hexane) to give 0.61 g (58%) of a yellow oil as the title compound: MS (EI) m/z 190 (M++H).
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2].[NH2:19][CH2:20][CH2:21][CH2:22][S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[N+:1]([CH:4]=[C:5]([NH:19][CH2:20][CH2:21][CH2:22][S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Reactant: NCCCSc1ccccn1
Product: Cc1nc[nH]c1CSCCNC(=C[N+](=O)[O-])NCCCSc1ccccn1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)-methylthio)ethylamino]ethylene with 2-(3-aminopropylthio)pyridine according to the procedure of Example 1 (a) (ii) yields the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:25][S:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[CH3:24][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([S:26][CH3:25])[CH:32]=3)[N:7]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: CSc1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)n2)n1
Product: CSc1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1

Procedure:
The title compound was prepared from 6′-bromo-6-methyl-4-(4-trifluoromethylphenyl)-[2,2′]bipyridinyl (example E.26) (0.39 g, 1.1 mmol) and commercially available 3-(methylthio)phenylboronic acid (0.183 g, 1.1 mmol) according to the general procedure VI. Obtained as a white solid (0.150 g, 31%). MS (ISP) 437.1 [(M+H)+]; mp 144° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]([NH:16]C(OCC1C=CC=CC=1)=O)=[CH:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][N:10]=[CH:9]2.FC(F)(F)C(O)=O>CO>[CH3:1][O:2][C:3](=[O:27])[CH:4]([NH2:16])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][N:10]=[CH:9]2
Reactant: COC(=O)C(=Cc1cc(Cl)c2[nH]ncc2c1)NC(=O)OCc1ccccc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(N)Cc1cc(Cl)c2[nH]ncc2c1
Reaction time: 96 h

Procedure:
A solution of 2-benzyloxycarbonylamino-3-(7-chloro-1H-indazol-5-yl)-acrylic acid methyl ester (300 mg, 0.78 mmol) in methanol (10 mL) was treated with trifluoroacetic acid (0.2 mL), flushed with nitrogen, and treated with 10% palladium on charcoal (30 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen. After 4 days, all starting material had been consumed. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography gave 78 mg (40%). 1H-NMR (CDCl3, 500 MHz) δ 1.31 (bs, 3H), 2.95 (dd, J=13.7, 7.9, 1H), 3.18 (dd, J=13.7, 5.2, 1H), 3.48 (s, 3H), 3.78 (dd, J=7.9, 5.2, 1H), 7.23 (s, 1H), 7.46 (s, 1H), 8.00 (s, 1H). Mass spec.: 254.06 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])C(F)(F)F)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:24][CH3:25].[OH-:26].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:16])=[O:26])=[CH:7][N:8]2[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c2ccc(Cl)cc21
Temperature: 60 °C
Yield: 92 %

Procedure:
A mixture of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (300 mg, 1.21 mmol), potassium carbonate (419 mg, 3.03 mmol), and iodoethane (0.14 mL, 1.82 mmol) in N,N-dimethylformamide (4 mL) in a sealed reaction vessel was heated at 60° C. for 16 h. At this time, the reaction was cooled to 25° C. and partitioned between water (30 mL) and ethyl acetate (30 mL). This mixture was treated with a 1N aqueous hydrochloric acid solution (6 mL), shaken, and separated. The organic layer was concentrated in vacuo to afford a yellow solid. The resulting solid was then treated with a 20% aqueous sodium hydroxide solution (7 mL) and was heated at 115° C. for 24 h. At this time, the reaction was cooled to 25° C. and was partitioned between water (75 mL) and ethyl acetate (75 mL). This solution was treated with a 1N aqueous hydrochloric acid solution (25 mL), shaken, and separated. The organic layer was washed with a saturated aqueous sodium chloride solution (1×50 ml), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 6-chloro-1-ethyl-1H-indole-3-carboxylic acid (250 mg, 92%) as a pale yellow solid: mp 225-227° C.; EI-HRMS m/e calcd for C11H10ClNO2 (M+) 223.0400, found 223.0400.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[CH:34]([C@@H:36]1[CH2:41][CH2:40][C@H:39]([C:42]([O:44][CH3:45])=[O:43])[CH2:38][CH2:37]1)=O.O>C1COCC1>[C:3]1(/[CH:2]=[CH:34]/[C@@H:36]2[CH2:41][CH2:40][C@H:39]([C:42]([O:44][CH3:45])=[O:43])[CH2:38][CH2:37]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)[C@H]1CC[C@@H](C=O)CC1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H]1CC[C@@H](/C=C/c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyltriphenylphosphonium bromide (2.94 g) was dissolved in THF (23.0 mL), added at −20° C. with potassium tert-butoxide (1.07 g) in small portions, and stirred for 1 hour at the same temperature. Subsequently, a THF (6.0 mL) solution of methyl cis-4-formylcyclohexane carboxylate (1.00 g) was added dropwise over 35 minutes, and stirred for 1.6 hours at the same temperature. After raising the temperature to room temperature, it was stirred after adding water and extracted with toluene. The organic layer was washed with water and saturated brine in order. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The residues were purified by silica gel column chromatography (9% ethyl acetate/hexane) to obtain the title compound (268 mg) as a colorless oil.
Reaction SMILES: C[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.Br[CH2:17]C1C=CC=CC=1C.CC[O-].[Na+].SCC(OCC)=O>C(O)C>[CH3:17][C:4]1[CH:3]=[CH:2][CH:15]=[CH:14][C:5]=1[CH2:6][S:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: Cc1ccccc1CBr
Reactant: CCOC(=O)CSCc1ccc(C)cc1
Agent: CCOC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSCc1ccccc1C

Procedure:
The procedure is as in Example 29 for the preparation of ethyl (4-methylbenzylthio)acetate, starting with 2-bromomethyltoluene (10 g), a 2M ethanolic solution of sodium ethylate (30 cc) and ethyl 2-mercaptoacetate (6.5 g), in ethanol (100 cc). Ethyl (2-methylbenzylthio)acetate (8.9 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH2:12])[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[C:20](Cl)(Cl)=[S:21].C(OCC)C>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]=[C:20]=[S:21])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: S=C(Cl)Cl
Reactant: NCCCc1cc(F)cc(F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Fc1cc(F)cc(CCCN=C=S)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
A solution of 3-(3,5-difluorophenyl)propylamine (0.0327 mol) and triethylamine (0.072 mol) in tetrahydrofuran (20 ml) was added dropwise to a solution of thiophosgene (0.0392 mol) in tetrahydrofuran at 0°. The reaction was stirred 2 hours at room temperature then ethyl ether was added and the mixture filtered. The filtrate was concentrated and distilled (Kugelrohr) to yield 3.8 g (55%) of a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:9]1([CH2:15][SH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH2:15]([S:16][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: SCc1ccccc1
Reactant: Cc1cncc(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1cncc(SCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 95.4 %

Procedure:
To a solution of 3-bromo-5-methylpyridine (888 mg) in toluene (10 mL) were added phenylmethanethiol (705 mg), N,N-diisopropylethylamine (1.47 g), tris(dibenzylideneacetone)dipalladium(0) (189 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (239 mg), and the mixture was stirred under an argon atmosphere at 80° C. for 1.5 hr. The reaction mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→17:3) to give the title compound as a yellow oil (yield 1.06 g, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)([SH:15])[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:25].[OH-].[K+].[NH2:28]OS(O)(=O)=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][C:10]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=3)([C:11]([F:14])([F:13])[F:12])[S:15][N:28]=2)=[CH:4][C:3]=1[CH3:25]
Reactant: NOS(=O)(=O)O
Reactant: Cc1cc(C(=O)CC(S)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1cc(C2=NSC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-Bromo-3-methyl-phenyl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-mercapto-butan-1-one (382 mg) in a solution of potassium hydroxide (162 mg in 8 mL of water) was added a solution of Hydroxylamine-O-sulfonic acid (2 equiv.) in a solution of potassium hydroxide (243 mg in 16 mL of water). After stirring at room temperature for 30 minutes, the mixture was diluted 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 3-(4-Bromo-3-methyl-phenyl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isothiazole (184 mg).
Reaction SMILES: [CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH2:24]([CH2:26][NH2:27])[OH:25]>>[CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:3]=1[C:4]([C:6](=[CH:12][NH:27][CH2:26][CH2:24][OH:25])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: NCCO
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F
Product: CCOC(=O)C(=CNCCO)C(=O)c1c(C)c(F)c(F)c(F)c1F

Procedure:
Employing ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-ethoxyacrylate (7.0 g) and ethanol amine (1.33 ml), the procedure of Reference Example 21 is repeated to give ethyl 2-(2-methyl-3,4,5,6-tetraflurobenzoyl)-3-(2-hydroxyethyl)aminoacrylate. To the product are added pyridine (70 ml) and acetic anhydride (2.57 ml) and the mixture is stirred at room temperature over-night. After concentration, the resultant is diluted with water, subjected to extraction with dichloromethane, and the extract is washed with water and then with a saturated saline solution and dried to give ethyl 2-(2-methyl-3,4,5,6-tetrafluorobenzoyl)-3-(2-acetyloxyethyl) aminoacrylate, which is then treated with 60% sodium hydride (1.09 g) as in Reference Example 22 to give ethyl 1-(2-acetyloxyethyl)-5-methyl-6,7,8-trifluoro-1,4-dihydro-4 -oxoquinoline-3carboxylate (6.15 g), as colorless prisms (recrystallized from ethyl acetate), m.p. 192°-193° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].[CH3:27][C:28]1[NH:29][CH:30]=[CH:31][N:32]=1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]2[N:6]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:18])=[O:19])[CH:5]([CH2:4][CH2:3][CH2:2][N:29]3[CH:30]=[CH:31][N:32]=[C:28]3[CH3:27])[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCl)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(CCCn3ccnc3C)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=442.2 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 2-methyl-1H-imidazole.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C([S:47][CH2:48][CH:49]([CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([Br:60])[CH:55]=1)[C:50](O)=[O:51])(=O)C>C(Cl)Cl.C(N(CC)CC)C>[Br:60][C:56]1[CH:55]=[C:54]([CH2:53][CH:49]([CH2:48][SH:47])[C:50]([NH:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)=[O:51])[CH:59]=[CH:58][CH:57]=1
Reactant: CC(=O)SCC(Cc1cccc(Br)c1)C(=O)O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(CS)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
1.88 g of L-Tryptophan in the form of the hydrochloride is introduced into 25 ml of anhydrous methylene chloride and 2.14 ml of triethylamine, 3.1 g of BOP then 2.217 g of the product obtained in Stage 4 above, dissolved in 25 ml of anhydrous methylene chloride, are added. The solution is agitated for 2 hours at ambient temperature, then the solvent is evaporated off, the product obtained in the form of a yellow oil, is then purified by chromatography on silica, with chloroform-ethyl acetate: 85-15 as eluant. After evaporation of the solvent and washing, a yellow gum is obtained. In this way 2.69 g of expected product is obtained (mixture of two diastereoisomers).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:27][CH:28]=O)[CH2:10][N:11]([CH3:26])[C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]([C:24]#[N:25])[CH:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:30][S:31]([C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1[CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:33])=[O:32]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:27][CH2:28][N:45]2[CH2:44][CH2:43][CH:42]([C:35]3[CH:36]=[CH:37][C:38]([O:40][CH3:41])=[CH:39][C:34]=3[S:31]([CH3:30])(=[O:33])=[O:32])[CH2:47][CH2:46]2)[CH2:10][N:11]([CH3:26])[C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]([C:24]#[N:25])[CH:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1cc(C#N)cc2ccccc12
Reactant: COc1ccc(C2CCNCC2)c(S(C)(=O)=O)c1
Product: COc1ccc(C2CCN(CC[C@H](CN(C)C(=O)c3cc(C#N)cc4ccccc34)c3ccc(Cl)c(Cl)c3)CC2)c(S(C)(=O)=O)c1
Product: Cl

Procedure:
Using standard reductive amination conditions N-[2-(S)-(3,4-dichlorophenyl)-4-oxobutyl]-N-methyl-3-cyano-1-naphthamide (0.130 g) was reacted with 4-(2-methylsulfonyl-4-methoxyphenyl)piperidine (0.082 g) and the product (0.074 g) was converted to the hydrochloride salt. MS m/z 678 (M+H). 1H NMR (DMSO-d6) δ 10.57 (m, 1H), 8.62 (m, 1H), 8.10 (m, 1H), 7.95-7.00 (m, 10H), 3.83 (s, 3H), 3.32 (s, 3H), 3.64-1.65 (m, 19H).
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(=[O:26])=[O:25])([CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C>CO.[OH-].[Na+]>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([S:24]([C:5]([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)([CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:4]([OH:35])=[O:3])(=[O:25])=[O:26])=[CH:32][CH:31]=1
Reactant: CCOC(=O)C(CCCc1ccccc1)(CCCc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C(CCCc2ccccc2)(CCCc2ccccc2)C(=O)O)cc1

Procedure:
2-(4-Methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoic acid was prepared starting from 2-(4-methoxy-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl)-pentanoic acid ethyl ester (2.0 g, 4 mmol) dissolved in methanol (50 ml) and 10 N NaOH (30 ml). The resulting reaction mixture was worked up as outlined in Example 9. Yield 1.18 g, 63%. Waxy solid; MS: 449.2 (M+H—H2O)+.