Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([N:7]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:3][CH:2]=1.[Br:21]N1C(=O)CCC1=O>ClCCl>[Br:21][C:11]1[CH:10]=[CH:9][C:8]2[N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:20])=[CH:6][CH:5]=3)[C:19]3[C:14]([C:13]=2[CH:12]=1)=[CH:15][CH:16]=[CH:17][CH:18]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-n2c3ccccc3c3ccccc32)cc1
Solvent: ClCCl
Product: Cc1ccc(-n2c3ccccc3c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of 9-p-tolyl-9H-carbazole (0.82 g, 3.2 mmol) in dichloromethane (DCM)(30 mL) was added N-bromosuccinimide (NBS) at about 0° C. The whole was stirred at about 0° C. to about room temperature (RT) overnight. The resulting solution was purified by flash column (silica gel, hexanes to hexanes/dichloromethane 8:1). After removal of solvent, a white solid (Compound 13) was obtained (1.0 gram, in 93% yield).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:36])[N:24]([CH2:32][CH2:33][C:34]#[N:35])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH:20]=[C:19]([Cl:37])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[OH2:39].[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>ClCCl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[C:34]([CH2:33][CH2:32][N:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])[C:23](=[O:36])[C:21]1[CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=[C:19]([Cl:37])[CH:20]=1)(=[O:39])[NH2:35]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCC#N)c2ccccc2F)c1)c1ccncc1
Reactant: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)CCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (2-{3-chloro-5-[(2-cyano-ethyl)-(2-fluoro-phenyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.055 g) and water (0.020 ml) in a mixture of trifluoroacetic acid (1 ml) and dichloromethane (1 ml) was stirred at room temperature for 2 h and then the solvent removed under reduced pressure. The residue was purified by preparative hplc to give the title compound (0.035 g) as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [C:1]([S:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]O)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([NH2:40])(=[O:39])[C:30]1[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:32](N)=[O:33].S1C=CC=C1P.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([S:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][N:40]1[C:29](=[O:39])[C:30]2[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:32]1=[O:33])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccccc1C(N)=O
Reactant: OCc1ccccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Pc1cccs1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To a solution of (2-tritylsulfanylphenyl)-methanol (4.7 g, 12.3 mmol), phthalamide (2.29 g, 15.6 mmol) and thiphenylphosphine (4.09 g, 15.6 mmol) in THF (70 mL) at 0° C. under an argon atmosphere, was slowly added DEAD (2.4 mL, 15 mmol). The reaction mixture was stirred at RT for 30 min, then partitioned between aqueous saturated NaHCO3 and EtOAc. The organic layer was separated, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to afford the title compound (4.7 g, 75%) as yellow foam. 1H NMR (300 MHz, CDCl3): δ 7.82 (2H, m), 7.70 (2H, m), 7.38-7.33 (5H, m), 7.27-7.22 (10H, m), 7.12 (1H, dd, J 1.4, 0.5), 7.08 (1H, dt, J 1.4, 0.5), 6.96 (1H, dd, J 7.6, 1.5), 6.88 (1H, dt, J 7.6, 1.5), 4.47 (2H, s).
Reaction SMILES: C1N=C[N:3](C(N2C=NC=C2)=O)C=1.[F:13][C:14]1[CH:19]=[C:18]([C:20]2[C:21]([O:28][CH3:29])=[N:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])[C:17]([F:30])=[CH:16][C:15]=1[C:31]1[N:35]([C@H:36]2[CH2:40][CH2:39][O:38][CH2:37]2)[N:34]=[CH:33][C:32]=1[C:41]([OH:43])=O.N>CN(C=O)C>[F:13][C:14]1[CH:19]=[C:18]([C:20]2[C:21]([O:28][CH3:29])=[N:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])[C:17]([F:30])=[CH:16][C:15]=1[C:31]1[N:35]([C@H:36]2[CH2:40][CH2:39][O:38][CH2:37]2)[N:34]=[CH:33][C:32]=1[C:41]([NH2:3])=[O:43]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1nc(C)cc(C)c1-c1cc(F)c(-c2c(C(=O)O)cnn2[C@H]2CCOC2)cc1F
Agent: N
Solvent: CN(C)C=O
Product: COc1nc(C)cc(C)c1-c1cc(F)c(-c2c(C(N)=O)cnn2[C@H]2CCOC2)cc1F
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 43.6 %

Procedure:
A 5 N aqueous sodium hydroxide solution (0.8 mL) was added to a solution of ethyl 5-(2,5-difluoro-4-(2-methoxy-4,6-dimethylpyridin-3-yl)phenyl)-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate (397 mg) in ethanol (5 mL), and the reaction mixture was stirred at 70° C. for 1 hour. After cooling the reaction mixture to room temperature, chloroform and brine were added, and the mixture was adjusted to pH 6 with 5 N hydrochloric acid and a saturated aqueous ammonium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and the desiccant was removed by filtration. The filtrates was concentrated under reduced pressure to give 5-(2,5-difluoro-4-(2-methoxy-4,6-dimethylpyridin-3-yl)phenyl)-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylic acid (457 mg) as a crude. CDI (211 mg) was added to a solution of the carboxylic acid (457 mg) in DMF (6 mL), and the reaction mixture was stirred at room temperature. After 75 minutes, a 28% aqueous ammonia solution (0.88 mL) was added to the reaction mixture and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding ethyl acetate and a saturated aqueous ammonium chloride solution. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and the desiccant was removed by filtration. After the filtrate was concentrated under reduced pressure, the precipitated solid was removed by filtration and washed with dichloromethane and ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate/n-heptane, 60% to 80% to 85%) to give title compound (199 mg). This title compound was used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][CH3:14])[N:11]=[CH:12][C:3]=12.S(=O)(=O)(O)[OH:16]>>[Cl:1][C:2]1[C:7]([C:8]([NH2:9])=[O:16])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][CH3:14])[N:11]=[CH:12][C:3]=12
Reactant: CCn1ncc2c(Cl)c(C#N)cnc21
Reactant: O=S(=O)(O)O
Product: CCn1ncc2c(Cl)c(C(N)=O)cnc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 46 %

Procedure:
4.25 g. of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]-pyridine-5-carbonitrile (0.02 mol.) are added to 21 ml. of concentrated sulfuric acid. The mixture is stirred at room temperature for 3 days. Then 200 ml. of ice-water are introduced, while cooling with ice-water, and the mixture is allowed to stand overnight in a refrigerator. 2.04 g. (46%) of pure 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]-pyridine-5-carboxamide are obtained, m.p. 192°-193°.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[OH-].[K+].[CH3:20][C:21]1[N:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1>CN1CCCC1=O.O>[CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([CH3:20])=[N:26][CH:25]=3)[C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: C=Cc1cnc(C)nc1
Reactant: CC(C)c1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ncc(CCn2c3c(c4cc(C(C)C)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.6 %

Procedure:
To a solution of 8-Isopropyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g. 0.000438 mol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.122 g, 0.00021 mol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyrimidine (0.13 g, 0.00109 mol) was added and stirred for further 3 h. At 80 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) then purified through preparative TLC. To get the desired compound as yellow oil (0.036 g, 24% yield). 8-Isopropyl-2-methyl-5-[2-(2-methyl-pyrimidin-5-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 0.036 g, 0.000103 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.013 g, 0.000103 mol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.022 g, 49% yield).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:19]([N:21]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:29][CH:28]=2)[CH2:22][C:23](O)=[O:24])=[O:20])[CH2:13][C:14]2[N:18]=[CH:17][NH:16][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.[N:84]1[CH:89]=[CH:88][CH:87]=[CH:86][C:85]=1[CH2:90][CH2:91][NH2:92]>C(Cl)Cl>[CH2:7]([O:8][C:9](=[O:10])[NH:11][CH:12]([C:19](=[O:20])[N:21]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:31][CH:32]=1)[CH2:22][C:23](=[O:24])[NH:92][CH2:91][CH2:90][C:85]1[CH:86]=[CH:87][CH:88]=[CH:89][N:84]=1)[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CN(Cc1ccc(OCc2ccccc2)cc1)C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Reactant: NCCc1ccccn1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN(Cc1ccc(OCc2ccccc2)cc1)C(=O)C(Cc1c[nH]cn1)NC(=O)OCc1ccccc1)NCCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
To a solution of the acid from Step 3 (0.33 g, 0.61 mmol) in methylene chloride was added PyBOP (0.67 g, 1.3 mmol) and diisopropylethylamine (0.23 mL, 1.3 mmol) followed by 2-pyridineethaneamine hydrochloride (0.082 g, 0.67 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, the residue taken up in ethyl acetate, which was washed 3 times with saturated NaHCO3, brine, dried over MgSO4, and concentrated. Flash chromatography gave 0.156 g (37%) of the title compound as a white foam; ES-MS 647 (m+1).
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[CH:26]=2)=[CH:18][CH:17]=1>>[Br:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[C:26]=2[C:1](=[O:10])[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: BrCCOc1ccc(-c2cc3ccccc3o2)cc1
Product: COc1ccc(C(=O)c2c(-c3ccc(OCCBr)cc3)oc3ccccc23)cc1

Procedure:
When p-anisoyl chloride and 2-[4'-(2-bromoethoxy)phenyl]benzofuran are reacted by the procedure described in Example 11 and the 2-[4'-(2-bromoethoxy)phenyl]-3-p-anisoylbenzofuran thus obtained is treated with piperidine as described in Example 11, the title compound is obtained.
Reaction SMILES: [C:1]([OH:15])(=[O:14])[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C@H:6]([C:8]([CH2:11][OH:12])([CH3:10])[CH3:9])[OH:7].S(=O)(=O)(O)O>>[C:1]([OH:15])(=[O:14])[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C@@H:6]([C:8]([CH2:11][OH:12])([CH3:10])[CH3:9])[OH:7]
Reactant: CC(C)(CO)[C@H](O)C(=O)NCCC(=O)O
Agent: O=S(=O)(O)O
Product: CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)O

Procedure:
D-pantothenic acid was quantified by high performance liquid chromatography [column: Shimadzu SCR101H (7.9 mm dia.×30 cm); mobile phase: 0.008N sulfuric acid; flow rate: 0.8 ml/min; detector: differential refractometer] and/or microbial bioassay [indicator strain: Lactobacillus plantatum IFO 3070; medium: commercially available pantothenic acid assay medium (produced by DIFCO)]. Quantitative determination and optical purity determination of pantoic acid were conducted by high performance liquid chromatography [column: SUMICHIRAL OA-1200; mobile phase: n-hexane/1,2-dichloroethane/ethanol=90/8/2; flow rate: 1.0 ml/min; detector: UV] of the ethyl acetate extract after cell removal from the culture broth by centrifugation, addition of 6N hydrochloric acid to the supernatant and subsequent heating in a water bath at 80° C. for 15 minutes (by this operation, pantoic acid in an equilibrium is converted to pantolactone).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH:19]([CH:25](OC)OC)[CH:20](OC)OC)[CH2:15][C@H:14]1[C@@H:13]([CH3:30])[S:12][C:11]([NH:31]C(=O)C1C=CC=CC=1)=[N:10]2.[CH3:40][NH:41][NH2:42].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O.C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([C:19]3[CH:25]=[N:42][N:41]([CH3:40])[CH:20]=3)[CH2:15][C@H:14]1[C@@H:13]([CH3:30])[S:12][C:11]([NH2:31])=[N:10]2
Reactant: COC(OC)C(C(OC)OC)[C@H]1C[C@H]2[C@@H](C)SC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Reactant: CNN
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@H]1SC(N)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](c3cnn(C)c3)C[C@@H]12
Temperature: 70 °C

Procedure:
N-[(4R,4aR,6R,8aS)-8a-(2,4-Difluorophenyl)-4-methyl-6-(1,1,3,3-tetramethoxypropan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C75) [prepared from P4 via a method similar to that used for the conversion of P1 to C44 in Preparation P3 and Example 5] (297 mg, 0.526 mmol) was combined with ethanol (1.75 mL) and methyl hydrazine (36.4 mg, 0.789 mmol) followed by addition of water (0.6 mL). Concentrated sulfuric acid (55 μL, 1.0 mmol) was slowly added and the reaction mixture was heated at 70° C. for 18 hours. Saturated aqueous sodium bicarbonate solution was added, and the aqueous layer was extracted three times with ethyl acetate; the combined organic layers were extracted three times with 0.2 M aqueous hydrochloric acid, and the combined aqueous layers were washed with ethyl acetate. The pH was adjusted to 9-10 by addition of 1 M aqueous sodium hydroxide solution, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (Gradient: 0% to 15% methanol in dichloromethane) provided the product as an off-white solid. Yield: 109 mg, 0.287 mmol, 55%. LCMS m/z 379.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.48 (s, 1H), 7.36 (s, 1H), 7.22-7.28 (m, 1H), 6.85-6.92 (m, 2H), 4.57 (dd, J=11.3, 2.3 Hz, 1H), 4.16 (dd, J=11.1, 2.1 Hz, 1H), 3.76 (s, 3H), 3.69 (d, J=11.3, 1H), 3.01-3.06 (m, 1H), 2.78 (dt, J=11.9, 3.8 Hz, 1H), 1.75-1.80 (m, 1H), 1.59-1.68 (m, 1H), 1.10 (d, J=7 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C@@H:8]([NH:13][C:14](=[O:28])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]3[CH2:27][CH2:26][CH2:25][O:24]3)=[CH:17][CH:16]=1)[CH2:7][CH2:6]2)=O.[CH3:29][C:30]([S@:33]([NH2:35])=[O:34])([CH3:32])[CH3:31].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>S([O-])([O-])(=O)=O.[Cu+2].ClCCl>[CH3:29][C:30]([S@:33](/[N:35]=[CH:1]/[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C@@H:8]([NH:13][C:14](=[O:28])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]3[CH2:27][CH2:26][CH2:25][O:24]3)=[CH:17][CH:16]=1)[CH2:7][CH2:6]2)=[O:34])([CH3:32])[CH3:31]
Reactant: O=Cc1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Reaction time: 24 h

Procedure:
A mixture of N-((S)-6-formyl-1,2,3,4-tetrahydronaphthalen-2-yl)-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (1.0 g), (R)-2-methylpropane-2-sulfinic acid amide (0.32 g), pyridinium para-toluenesulfonate (165 mg), copper(II) sulfate (1.0 g; anhydrous) and dichloromethane (10 ml) was stirred for 24 hours. Solid fractions were filtered off and the filtrate was concentrated. The residue was purified by chromatography on silica gel. The product was thus obtained with the molecular weight of 482.65 (C27H34N2O4S); MS (ESI): 483 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1.[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[S:37](Cl)(=[O:39])=[O:38]>C1COCC1>[Cl:26][C:27]1[CH:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[CH:30]=[CH:29][C:28]=1[S:37]([NH:19][C:4]1[CH:5]=[CH:6][C:7]([S:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)=[C:2]([Cl:1])[CH:3]=1)(=[O:39])=[O:38]
Reactant: Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(Sc2ccc3ccccc3c2)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl
Yield: 89.3 %

Procedure:
The title compound was prepared using the method of example 94, starting with 3-chloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (150 mg, 0.53 mmol), pyridine (Aldrich, 0.21 mL, 2.63 mmol) and 2-chloro-4-trifluoromethylbenzenesulfonyl chloride (Maybridge, 162 mg, 0.58 mmol) in THF. 250 mg (90%) of title compound (95) was obtained as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[CH:9]=[C:8]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=1)[CH3:2].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[C:10]([C:34]2[CH:35]=[CH:36][C:31]([C:30]([F:41])([F:40])[F:29])=[CH:32][CH:33]=2)[CH:9]=[C:8]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:7]=1)[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cc1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 95 °C
Yield: 99.3 %

Procedure:
A mixture of (3-benzyloxy-5-trifluoromethanesulfonyloxy-phenyl)-acetic acid ethyl ester (108 g, 0.26 mol), 4-(trifluoromethyl)phenylboronic acid (55.6 g, 0.29 mol), 1,2-dimethoxyethane (1.1 L) and aqueous Na2CO3 (2 M, 129 mL, 0.26 mol) was mechanically stirred while purging N2 at room temperature for 10 min. To this system was added Pd(Ph3)4 (480 mg, 0.42 mmol) and heated to reflux (95° C.) for 2.5 h. The red-brown mixture was diluted with EtOAc (0.5 L) and washed with saturated aqueous NaHCO3 solution (3×200 mL) and brine (2×200 mL). The organic fraction was dried (Na2SO4) and concentrated in vacuo. The crude mixture was purified by ISCO column chromatography to obtain (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (107 g, 100%).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]#[N:14])[CH:11]=2)[NH:6][C:5]=1[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:41]C(Br)(Br)Br>C1COCC1>[Br:41][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]#[N:14])[CH:11]=2)[NH:6][C:5]=1[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17]
Reactant: BrC(Br)(Br)Br
Reactant: CC[Si](CC)(CC)c1[nH]c2ccc(C#N)cc2c1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1[nH]c2ccc(C#N)cc2c1CCBr
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
A solution 3-(2-hydroxyethyl)-2-(triethylsilyl)-1H-indole-5-carbonitrile (0.873 g; 2.91 mmol) in THF (6 mL) was added to a solution of triphenylphosphine (1.52 g; 5.81 mmol) and perbromomethane (1.93 g; 5.81 mmol) in THF (30 mL) pre-stirred for 30 minutes. The resulting mixture was stirred at room temperature overnight, filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 2 to 40% ethyl acetate in heptane) to yield 0.906 g (86%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([O:4][C:5]([NH:7][C@@H:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18](OS(C(F)(F)F)(=O)=O)=[CH:17][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6])[CH3:3].[CH2:30]([O:32][CH2:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[C:37](OB(O)O)=[C:36]([O:46][CH3:47])[CH:35]=1)[CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NC(C)C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1.CN1CCCC1=O>[CH3:1][C:2]([CH3:29])([O:4][C:5]([NH:7][C@@H:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:37]2[C:36]([O:46][CH3:47])=[CH:35][C:34]([CH2:33][O:32][CH2:30][CH3:31])=[CH:39][C:38]=2[O:40][CH3:41])=[CH:17][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6])[CH3:3]
Reactant: CCOCc1cc(OC)c(OB(O)O)c(OC)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Solvent: CN1CCCC1=O
Product: CCOCc1cc(OC)c(-c2ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC)cc2)c(OC)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 123.2 %

Procedure:
Under nitrogen atmosphere, to a mixture of ethyl (αS)-α-[[(1,1-dimethylethoxy)carbonyl]amino]-4-(trifluoromethanesulfonyloxy)benzenepropionate (66.2 g), 4-ethoxymethyl-2,6-dimethoxyphenylboric acid (54.0 g), triphenylphosphine (9.83 g) and N-methylpyrrolidone (330 ml) were added palladium acetate (1.68 g) and diisopropylamine (24.9 g), and the mixture was heated at 90° C. After stirring for 1 hour at the same temperature, the mixture was cooled and toluene and water were added. The organic layers were washed with 10% aqueous citric acid solution and saturated aqueous NaCl solution and dried over magnesium sulfate. The solvent was removed in vacuo to yield ethyl (αS)-α-[[(1,1-dimethylethoxy)carbonyl]amino]-4′-ethoxymethyl-2′,6′-dimethoxy(1,1′-biphenyl)-4-propionate (90.1 g) as oil.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16]CC)=[O:15])=[CH:11][CH:12]=2)[C@@H:7]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].[OH-].[Na+].Cl>C(O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=[O:15])=[CH:11][CH:12]=2)[CH:7]([O:19][C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[CH:24][CH:25]=2)[CH2:6][CH:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)[C@@H](Oc1ccc(N3CCOCC3)cc1)C[C@H](C)N2C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N1c2ccc(C(=O)O)cc2C(Oc2ccc(N3CCOCC3)cc2)CC1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
[Step 7] 59.4 mg of ethyl (2S,4S)-1-acetyl-2-methyl-4-(4-morpholinophenoxy)-1,2,3,4-tetrahydroquinoline-6-carboxylate was dissolved in 1 mL of ethanol, and 163 μL of 4 N sodium hydroxide was added to the solution. The mixture was stirred for 4 hours at room temperature. After completion of the reaction, the reaction liquid was adjusted to pH 7 with 1 N hydrochloric acid, and then was extracted three times with chloroform-methanol. The extraction product was dehydrated over anhydrous sodium sulfate, and then was concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (chloroform:methanol=10:1), and thus 51.7 mg (93.3%, cis:trans=14:1) of the title compound was obtained as a pale peach-colored amorphous substance.