Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[CH:25][C:26](=[O:32])[NH:27]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:14])([F:15])[F:16])[CH:11]=[N:21][C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH:24]=[CH:25][C:26](=[O:32])[NH:27]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc2[nH]c(=O)ccc12
Reactant: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=O)C(F)(F)F
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=Nc1cccc2[nH]c(=O)ccc12)C(F)(F)F

Procedure:
In the same way as in Example 1, 250 mg (0.46 mmol) of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 132 mg (0.63 mmol) of 5-aminoquinolone and 0.4 ml of titanium tetraethoxide are reacted to give 5-{[(2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentylidene]amino}quinolin-2(1H)-one. 64 mg of imine purified by column chromatography (silica gel, hexane/ethyl acetate 0-75%) are cyclized in the same way as in Example 1 at −30° C. using 1.5 ml (1.5 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-75%) yields 52 mg of product.
Reaction SMILES: CCCCCCCCCCCCCCCCCC(N[C@H]([C@H](O)/C=C/CCCCCCCCCCCCC)CO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O[C@@H]4O[C@H](CO)[C@H](O)[C@H](O)[C@H]4O)[C@H]3NC(C)=O)[C@H](O[C@@:68]3(C(O)=O)[O:73][C@@H:72]([C@H:74](O)[C@H:75](O)[CH2:76]O)[C@H:71](NC(C)=O)[C@@H:70]([OH:84])[CH2:69]3)[C@H]2O)[C@H](O)[C@H]1O)=O.[CH2:108]([OH:110])[CH3:109]>>[CH3:76][C:75]1[C:74]2[CH:72]=[CH:71][C:70]([OH:84])=[CH:69][C:68]=2[O:73][C:108](=[O:110])[CH:109]=1
Reactant: CCO
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@H](CO[C@@H]1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O[C@@H]4O[C@H](CO)[C@H](O)[C@H](O)[C@H]4O)[C@H]3NC(C)=O)[C@H](O[C@]3(C(=O)O)C[C@H](O)[C@@H](NC(C)=O)[C@H]([C@H](O)[C@H](O)CO)O3)[C@H]2O)[C@H](O)[C@H]1O)NC(=O)CCCCCCCCCCCCCCCCC
Product: Cc1cc(=O)oc2cc(O)ccc12
Reaction time: 0.5 h

Procedure:
The saliva of each experimental group of Test Example 1 in the present specification was used to examine inhibitory activity against cholera toxin binding. 200 μl of an ethanol solution containing 0.1% ganglioside GM1 (w/v) was added to a 96-well plate for ELISA test. Then, the ganglioside GM1 was adsorbed thereonto by air-drying. The saliva of each experimental group was diluted 10 times with PBS containing 1% bovine serum albumin (BSA) and then reacted for 1 hour by the addition of a biotin-conjugated cholera toxin. 100 μl of the reaction solution was added to the plate for ELISA test, and the plate was left for 30 minutes. Then, the supernatant was removed. The plate for ELISA test was washed several times with PBS containing 0.05% Tween 20. Biotin-binding β-galactosidase was added thereto. The plate for ELISA test was left for a given length of time. Then, the supernatant was removed. The plate for ELISA test was washed several times again with PBS containing 0.05% Tween 20, and the contents in the plate were reacted for 30 minutes by the addition of 4-methylumbelliferyl galactose. Then, 4-methylumbelliferone produced was measured with a fluorophotometer (excitation wavelength: 360 nm, measurement wavelength: 460 nm). Then, an inhibition rate was calculated according to the following formula: Inhibition rate (%)={1−(A/B)}×100, wherein
Reaction SMILES: ClC1N=CC([CH2:8][N:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3=[N:19][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:21](=[O:22])[C:11]3=[CH:10]2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:36][N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1>O1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[C:21](=[O:22])[C:11]2=[CH:10][N:9]([CH2:8][C:12]3[CH:13]=[C:18]([C:40]4[CH:39]=[N:38][N:37]([CH3:36])[CH:41]=4)[N:9]=[CH:10][CH:11]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]2=[N:19]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=c1c2cn(Cc3ccc(Cl)nc3)c3ccccc3c-2nn1-c1ccccc1F
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(Cn3cc4c(=O)n(-c5ccccc5F)nc-4c4ccccc43)ccn2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-[(6-Chloropyridin-3-yl)methyl]-2-(2-fluorophenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 225, 40 mg, 0.10 mmol), bis(tri-tert-butylphosphine)palladium(0) (5.0 mg, 0.010 mmol, 0.1 equiv), cesium carbonate (0.20 mL, 1 M aqueous, 0.20 mmol, 2 equiv) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (35 mg, 0.17 mmol, 1.7 equiv) were suspended in tetrahydrofuran (1 mL) and the mixture was irradiated (high setting) for 10 minutes at 140° C. The mixture was cooled to ambient temperature, the organic layer removed, stirred with Quadrapure® (40 mg, 1 wt equiv) for 1 hour, filtered and purified by reverse phase HPLC (80:20 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.16 (1H, s), 8.65 (1H, d, J=2.2 Hz), 829 (1H, s), 8.20 (1H, dd, J=7.8, 1.4 Hz), 7.99 (1H, s), 7.83 (1H, d, J=8.7 Hz), 7.76 (1H, dd, J=8.2, 2.0 Hz), 7.66-7.58 (3H, m), 7.54 (1H, t, J=7.5 Hz), 7.48-7.37 (2H, m), 7.34 (1H, td, J=7.7, 1.5 Hz), 5.76 (2H, s), 3.87 (3H, s) ppm; low resolution mass spectrometry (ES+) m/z 451.0 [(M+H)+; calculated for C26H20FN6O: 451.2].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[CH:6]=[CH:7][C:8]=1[CH3:9])#[N:2].[Br:20]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:18])([F:17])[F:19])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2C(F)(F)F)cc1C#N
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(-c2ccccc2C(F)(F)F)ccc1CBr

Procedure:
A mixture of 3-cyano-4-methyl-2'-trifluoromethylbiphenyl (420 mg, 1.61 mmol), N-bromosuccinimide (286 mg, 1.61 mmol), AIBN (10 mg), and carbon tetrachloride (20 mL) was refluxed for 1 hour. The resultant mixture was concentrated, and the residue subjected to column chromatography on silica gel eluting with a mixture of ethyl acetate in hexane (7.5 to 92.5 v/v). Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [C:1]1(=[O:11])[N:5]([CH2:6][C:7]([OH:9])=[O:8])[C:4](=[O:10])[CH:3]=[CH:2]1.[C:12]1(C)[CH:17]=[CH:16]C(S(O)(=O)=O)=[CH:14][CH:13]=1.C1(C)C=CC=CC=1.C(O)CCCC>O>[C:4]1(=[O:10])[N:5]([CH2:6][C:7]([O:9][CH2:14][CH2:13][CH2:12][CH2:17][CH3:16])=[O:8])[C:1](=[O:11])[CH:2]=[CH:3]1
Reactant: O=C(O)CN1C(=O)C=CC1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCO
Solvent: O
Product: CCCCCOC(=O)CN1C(=O)C=CC1=O
Yield: 643.8 %

Procedure:
In a separable flask equipped with a Dean-Stark trap, maleimidoacetic acid (reagent grade) (31.0 g, 0.2 mol), p-toluenesulfonic acid (reagent grade) (5.2 g, 0.03 mol), and toluene (reagent grade) (300 ml) were charged. Then, the mixture was stirred and reacted under reduced pressure at 80° C. for 1 hour with dropwise addition of n-pentanol (reagent grade) (17.6 g, 0.2 mol). After the dropwise addition, the mixture was stirred for another 4 hours for allowing the reaction to be continued. During the reaction, the water formed was removed with the Dean-Stark trap. After the reaction, toluene (300 ml) was added and the mixture was washed three times with ion-exchanged water (100 ml). Then, the organic phase obtained was collected and subjected to removal of the toluene by evaporation using an evaporator and a vacuum dryer to give n-pentyl maleimidoacetate (43.5 g). (Yield: ca. 91%. The absence of maleimidoacetic acid and n-pentanol was verified by GPC measurement. The presence of n-pentyl maleimidoacetate was verified by 1H-NMR measurement using DMSO-d6. This compound is referred to hereinafter as Compound A1).
Reaction SMILES: Cl[CH:2]([CH2:5][C:6]1[CH:16]=[CH:15][C:9]2[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=2[CH:7]=1)[CH:3]=O.[CH3:17][O:18][C:19]1[N:24]=[N:23][C:22]([NH2:25])=[CH:21][CH:20]=1.O>C(O)CCC>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:2]([CH2:5][C:6]3[CH:16]=[CH:15][C:9]4[N:10]=[C:11]([S:13][CH3:14])[S:12][C:8]=4[CH:7]=3)=[CH:3][N:25]=2)[N:24]=1
Reactant: COc1ccc(N)nn1
Reactant: CSc1nc2ccc(CC(Cl)C=O)cc2s1
Solvent: O
Solvent: CCCCO
Product: COc1ccc2ncc(Cc3ccc4nc(SC)sc4c3)n2n1
Temperature: 25 °C
Yield: 66.4 %

Procedure:
A stirred mixture of 2-chloro-3-(2-(methylthio)benzo[d]thiazol-6-yl)propanal from Step 4 of Example 117 (600 mg, 2.2 mmol) and 6-methoxypyridazin-3-amine (550 mg, 4.4 mmol) in 1-butanol (20 mL) was heated at reflux overnight. The mixture was cooled to rt and water (40 mL) was added. The mixture was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford 6-((6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole as a light brown solid (500 mg, 66%). 1H NMR (300 MHz, CDCl3) δ 7.79-7.73 (m, 2H), 7.67 (d, J=1.2 Hz, 1H), 7.43 (s, 1H), 7.38 (dd, J=1.5, 8.4 Hz, 1H), 6.64 (d, J=9.6 Hz, 1H), 4.33 (s, 2H), 3.94 (s, 3H), 2.78 (s, 3H). LCMS (ESI) m/z 343 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[N:10]([C:20](=[O:21])[CH2:19][Cl:18])[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1
Reactant: Cc1ccc(Nc2c(F)cc(F)cc2Cl)cc1
Reactant: O=C(Cl)CCl
Product: Cc1ccc(N(C(=O)CCl)c2c(F)cc(F)cc2Cl)cc1

Procedure:
A mixture of 230 g (0.9 mol) N-(2′-chloro-4′,6′-difluorophenyl)-4-methylaniline and 325 ml (4.06 mol) of chloroacetyl chloride is heated under a nitrogen atmosphere for one hour at 50°. The solvent is evaporated under reduced pressure to give an oil to which 200 ml of chlorobenzene is added. The solvent is evaporated under reduced pressure to completely remove the chloroacetyl chloride, giving N-(2′-chloro-4′,6′-difluorophenyl)-N-chloroacetyl-4-methylaniline as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Br[CH2:13][C:14]#[N:15]>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:13][C:14]#[N:15])[CH2:8][CH2:7]1
Reactant: N#CCBr
Reactant: COCCOC1CCNCC1
Product: COCCOC1CCN(CC#N)CC1

Procedure:
The title compound is synthesized by coupling of 4-(2-Methoxy-ethoxy)-piperidine (commercially available from ChemBridge Corporation) and bromoacetonitrile analogously to the preparation of intermediate 149.2 as a colorless oil; ES-MS: M+=199.2; 1HNMR(DMSO-d6) 3.65 (s, 2H), 3.50 (dd, 2H), 3.40 (dd, 2H), 3.30-3.25 (m, 1H), 3.20 (s, 3H), 2.70-2.60 (m, 2H), 2.25-2.20 (m, 2H), 1.85-1.80 (m, 2H), 1.50-1.40 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9](O)=[O:10])=[CH:4][CH:3]=1.B.Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Cl)nc1
Agent: B
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: OCCc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To solid (6-chloro-pyridin-3-yl)-acetic acid (172 mg, 1 mmol) was added borane in THF (1M, 5 ml) and the reaction was stirred at room temperature. After 2 hours, the reaction was heated to 50 degC for 90 minutes. Aqueous hydrochloric acid (2N, 8 ml) was added to the reaction and it was allowed to cool to room temperature. After 10 minutes the reaction was basified with saturated aqueous sodium bicarbonate and extracted into ethyl acetate. The organic liquors were washed with water (×2) and brine, dried (MgSO4) and concentrated to furnish the crude product as a yellow oil (126 mg). This material was used as such in the coupling reaction. MS: [M+H]+158.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18](C2C=CN=CC=2)[CH2:17][CH2:16]1)=[O:12])([O-])=O>C(O)C.[Pd]>[N:18]1[CH:19]=[CH:20][C:15]([CH:14]([CH:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[O:13][C:11]([NH:10][C:5]2[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:12])=[CH:16][CH:17]=1
Reactant: O=C(Nc1ccccc1[N+](=O)[O-])OCC1CCN(c2ccncc2)CC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1NC(=O)OC(c1ccncc1)C1CCNCC1
Yield: 190.2 %

Procedure:
A solution of 2-nitro-N-[1-(4-pyridyl)piperidin-4-yl-methoxycarbonyl)benzeneamine (7.55 g, 21.2 mmol) and 5% palladium-on-carbon (4.00 g) in ethanol (250 mL) was placed under an atmosphere of hydrogen (1 bar). After consumption of the starting material (16-20 h), the mixture was filtered through diatomaceous earth. Hot ethyl acetate was used to wash the filter cake. Concentration of the filtrate in vacuo yielded 6.58 g (96%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6](Cl)(C)[CH:5](Cl)[CH2:4][C:3]=1/[CH:11]=[CH:12]/Cl.[CH:14]1C=C(CN)C=C(CN)C=1.CC(N=NC(C#N)(C)C)(C#N)C>>[CH:1]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:11]=[CH:12][CH:14]=1
Reactant: CC1=C(/C=C/Cl)CC(Cl)C(C)(Cl)C1
Reactant: NCc1cccc(CN)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: c1ccc2ccccc2c1
Reaction time: 1 h

Procedure:
A laminate-type organic electrophotographic photoreceptor was produced in the same manner and in the same ratios of starting materials as in Example 24 except that (PC-1) was replaced by (PC-2), MXDA by azobisisobutylonitrile (AIBN), and the conditions of the reaction after the drying were changed to 120° C., 1 hour.
Reaction SMILES: [Li]CCCC.C[Si](C)(C)[C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[CH2:15]([O:22][C:23]1[CH:28]=[C:27](I)[CH:26]=[CH:25][C:24]=1[N:30]1[S:34](=[O:36])(=[O:35])[N:33]([CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:32](=[O:43])[CH2:31]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOCC.C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([O:22][C:23]1[CH:28]=[C:27]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH:26]=[CH:25][C:24]=1[N:30]1[S:34](=[O:35])(=[O:36])[N:33]([CH2:37][CH2:38][Si:39]([CH3:41])([CH3:40])[CH3:42])[C:32](=[O:43])[CH2:31]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: C[Si](C)(C)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(-c3nccs3)cc2OCc2ccccc2)S1(=O)=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of n-BuLi (2.5M in hexane, 0.44 mL, 1.1 mmol) in Et2O (1 mL) at −78° C. is added 2-(trimethylsilyl)thiazole (0.16 mL, 1.0 mmol) and the reaction mixture is stirred at −78° C. for 30 min. Zinc chloride (1.0 M in Et2O1 3.0 mL, 3.0 mmol) is added and the mixture is warmed to RT over 30 min. The ether is removed under reduced pressure then a solution of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (250 mg, 0.46 mmol) and Pd(PPh3)4 (55 mg, 0.046 mmol) in THF (1 mL) is added. The yellow solution is stirred at RT for 1 h then is heated at reflux for 2 h. The mixture is quenched with 1N HCl, extracted with EtOAc, washed with brine, dried over MgSO4 and concentrated. The residue is purified by chromatography using EtOAc/hexane as eluent to afford the title compound as a yellow solid: 1H NMR (CDCl3) δ 0.01 (s, 9H), 0.83 (m, 2H), 3.51 (m, 2H), 4.33 (s, 2H), 5.13 (s, 2H), 7.27-7.37 (m, 6H) 7.48 (m, 2H), 7.73 (br s, 1H), 7.82 (d, J=4 Hz, 1H); (M+1)+=502.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([F:17])[CH:13]=[CH:12][CH:11]=3)[C:5]([OH:18])=[CH:4][CH:3]=1.[OH-].[Na+]>CCO>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[F:17])[NH:9]2)[C:5]([OH:18])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1ccc(Cl)nc1C1Cc2c(F)cccc2N1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
A mixture of 6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-ol (10 g, 38 mmol) and metal Sn (23 g, 190 mmol) in CH3CH2OH/concentrated HCl (60 mL/40 mL) was stirred under reflux for 3 h. The mixture was cooled to room temperature and adjusted to pH=7 by saturated NaOH and filtered though a Celite pad. The filtrate was extracted with EtOAc, washed by brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=10:1) to get 6-chloro-2-(4-fluoroindolin-2-yl)pyridin-3-ol (8 g, yield: 80%). 1H-NMR (CDCl3, 400 MHz) δ 9.86 (s, 1H), 7.10˜7.20 (m, 3H), 6.33˜6.91 (m, 2H), 5.15˜5.21 (m, 1H), 4.61 (s, 1H), 3.65˜3.71 (m, 1H), 3.04˜3.11 (m, 1H). MS (M+H)+: 265.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.CC[O:24][C:25]([CH2:27][CH:28]1[C:33](=O)[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:26]>>[Cl:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:29]3[CH:28]([CH2:27][C:25]([OH:26])=[O:24])[CH2:33][CH2:32][CH2:31][C:30]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(C(F)(F)F)cc1
Agent: Cl
Product: O=C(O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(C(F)(F)F)cc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-trifluoromethylphenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared. m.p. 167°-168° C.
Reaction SMILES: C1COCC1.[O:6]([C:13]1[S:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O>[O:6]([C:13]1[S:17][C:16]([CH2:18][OH:19])=[CH:15][CH:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=Cc1ccc(Oc2ccccc2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(Oc2ccccc2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
To a solution of THF (60 mL) and 5-phenoxy-thiophene-2-carbaldehyde (2.8 g) was added LAH (390 mg) at 0° C., which was stirred for 10 minutes at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate. The solvent was evaporated under a reduced pressure and the organic layer was purified by NH silica gel chromatography (ethyl acetate), and then purified by silica gel chromatography (hexane:ethyl acetate=4:1, then 2:1) to obtain the titled compound (2.0 g).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].O[C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][C:27](=[O:33])[NH:28]2>ClCCl>[F:7][C:8]([F:21])([F:20])[S:9]([O:12][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][C:27](=[O:33])[NH:28]2)(=[O:11])=[O:10]
Reactant: O=C1CCc2c(O)cccc2N1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1CCc2c(cccc2OS(=O)(=O)C(F)(F)F)N1
Reaction time: 2 h
Yield: 107 %

Procedure:
Pyridine (30 ml) and trifluoromethanesulfonic anhydride (25 g) were added with stirring at 0° C. to an anhydrous dichloromethane solution (200 ml) of 5-hydroxy-3,4-dihydro-1H-quinolin-2-one (15.9 g), followed by stirring for 2 hours. The resulting mixture was concentrated under reduced pressure, water was added to the residue, and extraction with dichloromethane was performed. The extract was washed with water, an aqueous potassium hydrogensulfate solution and water in this order, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was recrystallized from an ethyl acetate-diisopropyl ether mixed solvent to thereby obtain 28 g (yield: 97%) of 5-trifluoromethanesulfonyloxy-3,4-dihydro-1H-quinolin-2-one as a light brown powder.
Reaction SMILES: COC(=O)CC[C@H]([C@@H]1[C@]2(C)[C@H]([C@H]3[C@H](CC2)[C@]2(C)C(C[C@@H](OCOCCOC)CC2)=CC3)CC1)C.COCCO[AlH2-]OCCOC.[Na+].O1CCCCC1OC1CCCCO1.[CH3:60][O:61][CH2:62][CH2:63][O:64][CH2:65][O:66][C@H:67]1[CH2:89][CH2:88][C@@:87]2([CH3:90])[C:69](=[CH:70][CH2:71][C@@H:72]3[C@@H:86]2[CH2:85][CH2:84][C@@:83]2([CH3:91])[C@H:73]3[CH2:74][CH2:75][C@@H:76]2[C@H:77]([CH3:82])[CH2:78][CH2:79][CH2:80][OH:81])[CH2:68]1.[S:92](Cl)([C:95]1[CH:101]=[CH:100][C:98]([CH3:99])=[CH:97][CH:96]=1)(=[O:94])=[O:93]>N1C=CC=CC=1>[CH3:60][O:61][CH2:62][CH2:63][O:64][CH2:65][O:66][C@H:67]1[CH2:89][CH2:88][C@@:87]2([CH3:90])[C:69](=[CH:70][CH2:71][C@@H:72]3[C@@H:86]2[CH2:85][CH2:84][C@@:83]2([CH3:91])[C@H:73]3[CH2:74][CH2:75][C@@H:76]2[C@H:77]([CH3:82])[CH2:78][CH2:79][CH2:80][O:81][S:92]([C:95]2[CH:101]=[CH:100][C:98]([CH3:99])=[CH:97][CH:96]=2)(=[O:94])=[O:93])[CH2:68]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCOCO[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCO)[C@@]4(C)CC[C@@H]32)C1
Agent: C1CCC(OC2CCCCO2)OC1
Agent: COCCOCO[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)OC)[C@@]4(C)CC[C@@H]32)C1
Agent: COCCO[AlH2-]OCCOC
Solvent: c1ccncc1
Product: COCCOCO[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCOS(=O)(=O)c5ccc(C)cc5)[C@@]4(C)CC[C@@H]32)C1

Procedure:
The 3β-(methoxyethoxymethoxy)-5-cholenic acid methyl ester was reduced with Vitride as described for the tetrahydropyranyl ether in Example 3. The resulting compound, the 3β-(methoxyethoxymethoxy)-24-hydroxy-5-cholene, was treated with tosyl chloride in pyridine and the 3β-(methoxyethoxymethoxy)-24-tosyloxy-5-cholene obtained. The tosyloxy compound was heated in dimethylformamide with potassium cyanide, and the tosyloxy group exchanged for the cyano group. 2.1 mmole of the 3β-(methoxyethoxymethoxy)-25-cyano-5-cholene was stirred with 2.36 g (10.5 mmole) of zinc bromide in 15 ml of methylene chloride. The insoluble material was removed by filtration, washed with ether, and the combined filtrates extracted with saturated aqueous solutions of sodium bicarbonate and sodium chloride. After drying, the solvents were evaporated, and the residue sponified with alkali. The 3β-hydroxy-5-homocholenic acid was obtained from the acidified saponification mixture.