Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-])=O.[H][H]>[Pd].C(O)C>[NH:8]1[C:9]2[C:5](=[C:4]([NH2:1])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[N:7]1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc2[nH]ncc12
Yield: 101.3 %

Procedure:
A mixture of 4-nitro-1H-indazole (760 mg, 4.68 mmol), palladium on charcoal (10%, cat.) and ethanol (30 mL) was stirred under a balloon of hydrogen for 4 hours. The reaction mixture was then filtered through celite, and the solvent removed in vacuo to yield 1H-indazol-4-ylamine (631 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14](SC)[NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:24][CH:25]([NH2:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[NH:30][CH:25]([CH3:24])[C:26]([CH3:29])([CH3:28])[CH3:27])[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(N)C(C)(C)C
Reactant: CSC(Nc1cccnc1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Product: CC(NC(Nc1cccnc1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1)C(C)(C)C
Yield: 58 %

Procedure:
2-(4-Chloro-phenylsulfonyl)-3-methylsulfanyl-3-(pyridin-3-ylamino)-2-propenenitrile (0.186 g, 0.5 mmol) was stirred in 1,2,2-trimethylpropylamine (1 ml) for 22 h at 100° C. under nitrogen. The reaction mixture was concentrated. The residue was dissolved in DCM, washed with water, dried (sodium sulfate) and concentrated. The crude product was purified by flash chromatography using ethyl acetate as eluent to give 124 mg (58%) of the title compound as a syrup, which could be crystallised from ethyl acetate/heptane 2:1 to give 65 mg (30%). Mp 172-174° C. 1H NMR (300 MHz, CDCl3): δ=0.85 (s, 9H), 0.9 (d, 3H), 3.03 (m, 1H), 7.35 (m, 2H), 7.48 (d, 2H), 7.80 (d, 2H), 8.33 (br s, 1H), 8.5 (br s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]3[O:23][CH2:22][CH:21]([CH:24]4[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:25]4)[CH2:20][CH:19]=3)=[C:12]([F:33])[C:11]=2[F:34])=[C:6]([F:35])[C:5]=1[F:36])[CH3:2]>C1(C)C=CC=CC=1.CC(O)C.[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH:18]3[CH2:19][CH2:20][CH:21]([CH:24]4[CH2:29][CH2:28][CH:27]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:25]4)[CH2:22][O:23]3)=[C:12]([F:33])[C:11]=2[F:34])=[C:6]([F:35])[C:5]=1[F:36])[CH3:2]
Reactant: CCCC1CCC(C2CC=C(CCc3ccc(-c4ccc(OCC)c(F)c4F)c(F)c3F)OC2)CC1
Agent: [Pd]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCCC1CCC(C2CCC(CCc3ccc(-c4ccc(OCC)c(F)c4F)c(F)c3F)OC2)CC1
Reaction time: 12 h
Yield: 27.9 %

Procedure:
6-(2-(4′-Ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)ethyl)-3-(4-propylcyclohexyl)-3,4-dihydro-2H-pyran (31) (2.5 g) prepared in the second step was dissolved in a mixture of toluene (5 ml) and IPA (5 ml), and 5%-Pd/C 125 mg) was added. The stirring was continued under a hydrogen atmosphere at room temperature for 12 hours. 5%-Pd/C was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 20 g, eluent: toluene), and then by recrystallization (heptane/toluene=50/50 by volume) to give 2-(2-(4′-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)ethyl)-5-(4-propylcyclohexyl)tetrahydro-2H-pyran (32) (0.7 g) in 30.1% yield.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:44])[C:12](=[C:23]2[NH:27][C:26]3[CH:28]=[CH:29][C:30]([NH:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:43])[CH3:42])=[CH:36][CH:35]=4)=[CH:31][C:25]=3[NH:24]2)[C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=2)=[O:14])[CH:6]=1)(=O)C.[OH-].[Na+].[Cl-].[NH4+]>C1COCC1>[F:22][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([F:21])[CH:18]=1)[C:13]([C:12](=[C:23]1[NH:27][C:26]2[CH:28]=[CH:29][C:30]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:43])[CH3:42])=[CH:36][CH:35]=3)=[CH:31][C:25]=2[NH:24]1)[C:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([OH:4])[CH:6]=1)=[O:44])=[O:14]
Reactant: CC(=O)Nc1ccc(CNc2ccc3c(c2)NC(=C(C(=O)c2cc(F)cc(F)c2)C(=O)c2cccc(OC(C)=O)c2)N3)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(CNc2ccc3c(c2)NC(=C(C(=O)c2cccc(O)c2)C(=O)c2cc(F)cc(F)c2)N3)cc1
Reaction time: 24 h
Yield: 85.7 %

Procedure:
To a THF solution (5 ml) of 3-{2-[5-(4-acetylaminobenzylamino)-1,3-dihydro-2H-benzimidazol-2-ylidene]-3-(3,5-difluorophenyl)-3-oxopropionyl}phenyl acetate (123 mg) was added 1M sodium hydroxide aqueous solution (0.5 ml), followed by 24 hours of stirring. A saturated ammonium chloride aqueous solution was added thereto, followed by extraction with ethyl acetate and drying over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol=20:1 (v/v)) to obtain N-[4-({2-[1-(3,5-difluorobenzoyl)-2-(3-hydroxyphenyl)-2-oxoethylidene]-2,3-dihydro-1H-benzimidazol-5-ylamino}methyl)phenyl]acetamide (98 mg, 86%). Hereinafter, the compound of Example 438 was obtained similarly.
Reaction SMILES: [CH3:1][C:2]([S:30]([CH3:33])(=[O:32])=[O:31])([CH2:13][CH2:14]C1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1)[C:3]([NH:5]OC1CCCCO1)=[O:4].BrC1C=CC(C2ON=C(CO)C=2)=CC=1.[F-].[Cs+].O>C(OCC)(=O)C.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.O1CCOCC1>[CH3:1][C:2]([S:30]([CH3:33])(=[O:31])=[O:32])([CH2:13][CH3:14])[C:3]([NH2:5])=[O:4]
Reactant: CC1(C)OB(c2ccc(CCC(C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OCc1cc(-c2ccc(Br)cc2)on1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCC(C)(C(N)=O)S(C)(=O)=O
Temperature: 115 °C
Reaction time: 3 h

Procedure:
To flask containing 2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanamide, which may be prepared as in Preparation 3, (100 mg, 0.208 mmol) was added [5-(4-Bromo-phenyl)-isoxazol-3-yl]-methanol (58.2 mg, 0.229 mmol), cesium fluoride (126 mg, 0.832 mmol), water (200 uL) and 1,4-dioxane (2 mL). To this mixture was added Palladium tetrakis (35.8 mg, 0.031 mmol) and the mixture was heated to 115° C. with stirring for 3 hours. The mixture was diluted with ethyl acetate and washed with aqueous HCl (0.1 N). The phases were separated and the crude organic extract was concentrated to dryness. The crude material was purified via silica gel chromatography eluting with ethyl acetate/heptanes to afford N-hydroxy-4-{4′-[3-hhydroxymethyl)isoxazol-5-yl]biphenyl-4-yl}-2-methyl-2-(methylsulfonyl)butanamide as a solid 21 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[NH:9]C(O[C:13](=[O:14])[C:7]=2[CH:6]=[CH:5][CH:4]=1)=O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1>C(O)C.CN(C)C1C=CN=CC=1>[NH2:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=1[C:13]([NH:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[O:14]
Reactant: COc1ccc(N)cc1
Reactant: COc1cccc2c(=O)oc(=O)[nH]c12
Agent: CN(C)c1ccncc1
Solvent: CCO
Product: COc1ccc(NC(=O)c2cccc(OC)c2N)cc1

Procedure:
To a solution of 27.17 g (0.141 mol) of 8-methoxyisatoic anhydride in 200 mL of ethanol was added a catalytic amount of 4-dimethylaminopyridine and 350 mL of a 1M solution containing 43.0 g (0.350 mol) of p-anisidine. The reaction mixture was stirred and heated under reflux overnight. The reaction flask was then chilled on ice. The precipitate that formed was collected by vacuum filtration and amounted to 34.7 g. An analytical sample (mp 168-169° C.) was obtained by recrystallization from ethanol.
Reaction SMILES: N.[K].[CH2:3]([O:5][CH:6]([O:10][CH2:11][CH3:12])[C:7](=[CH2:9])[CH3:8])[CH3:4]>CCOCC>[CH2:3]([O:5][C:6]([O:10][CH2:11][CH3:12])=[C:7]([CH3:9])[CH3:8])[CH3:4]
Reactant: C=C(C)C(OCC)OCC
Agent: N
Agent: [K]
Solvent: CCOCC
Product: CCOC(OCC)=C(C)C
Temperature: -35 °C
Reaction time: 72 h
Yield: 42.2 %

Procedure:
To ammonia (500 mL) at -35° C. was added FeCl3 ·6H2O (0.1 g),then potassium metal (24.26 g), and then methacrolein diethylacetal (109 g, 0.756 mol) in ether (150 mL). The mixture was stirred at --35° C. for 3 days, then the ammonia was evaporated, additional ether (100 mL) was added and stirring was continued for another day. The mixture was filtered and the filtrate was distilled at 65° C. and 55 mm Hg to afford 46.05 g of 1,1-diethoxy-2,2-dimethylethylene (Formula V: R3 =R4 =CH3 ; R5 =R6 =OC2H5).
Reaction SMILES: O.[OH-].[Na+].[CH2:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH3:5].[O:14]1[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]1[CH2:16][OH:17]>[Cl-].C([N+](CCCC)(CCCC)C)CCC.C(Cl)Cl>[CH2:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:15]([OH:14])[CH2:16][OH:17])[CH3:5]
Reactant: OCC1OC1c1ccccc1
Reactant: CCOc1ccccc1O
Agent: CCCC[N+](C)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOc1ccccc1OC(c1ccccc1)C(O)CO
Temperature: 22.5 °C
Yield: 60.5 %

Procedure:
Water (800 mL), sodium hydroxide (50%, 83.1 mL), tributylmethyl-ammonium chloride (75%, 27.5 ml), and 2-ethoxyphenol (306.72 g) were combined and stirred at 20-25° C. The methylene chloride solution of 2,3-epoxy-3-phenylpropanol from Example 1 was added, and the two phase mixture was stirred and heated to 40° C. internal temperature. The methylene chloride was distilled at atmospheric pressure over a 3-4 hour period. When the methylene chloride had been removed, the internal temperature was raised to 60° C. for 2 hours. The mixture was cooled to below 30° C., toluene (1200 ml) was added, and the mixture was stirred for 5 minutes. The phases were separated and the aqueous phase was extracted with toluene (800 mL). The toluene solutions were combined and washed with 1 N NaOH (2×400 ml) and with water (400 mL) at approximately 25° C. The toluene solution was concentrated under partial vacuum maintaining an internal temperature of 40-50° C. The residual oil was dissolved in methyl t-butyl ether (760 ml), and water content was verified to be less than 0.1% by potassium fluoride assay. The solution was seeded with crystals of the title compound at 20-25° C., stirred for 1 hour, and cooled to 0° C. for 2 hours. The resulting solids were filtered, washed with methyl t-butylether (2×200 mL, cooled to −15° C.), and dried under vacuum to yield 256.1 g of the title compound (60.5% from cinnamyl alcohol).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH3:10][CH:11]([NH2:14])[CH2:12][OH:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CC(O)=O>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:14][CH:11]([CH3:10])[CH2:12][OH:13])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(N)CO
Reactant: O=Cc1cccc(Br)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CC(CO)NCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 56 h

Procedure:
To a stirred solution of the (6-bromo-2-pyridyl)-formaldehyde (0.52 g, 2.8 mmol) in toluene (14 mL) was added DL-2-amino-1-propanol (0.67 mL). The resulting mixture was heated to reflux with a Dean-Stark trap for 3 h under N2 until complete formation of the imine was observed. The mixture was brought to RT followed by the addition of a solution of NaBH(OAc)3 (2.0 g, 9.8 mmol) in AcOH (6 mL). The resulting mixture was stirred at RT and under N2 for 56 h. The mixture was neutralized (pH 7.0) with a saturated solution of NaHCO3 (aq) and extracted with CH2Cl2 (3×50 mL). The aqueous layer was concentrated by rotary evaporation and the residue obtained was extracted with CH2Cl2 (3×50 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated by rotary evaporation to afford the title compound as a pale yellow oil. EI-MS m/z 245 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N+:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[N+:12]([C:15]1[CH:20]=[C:19]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[CH2:5]3)[CH:18]=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: O=C1Cc2cc(Br)ccc2N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: O=C1Cc2cc(-c3cccc([N+](=O)[O-])c3)ccc2N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 6.5 %

Procedure:
5-bromo-2-indolinone (1.08 g, 5.09 mmol) and tetrakistriphenyl phosphine Pd (0) (0.273 g) were stirred under an atmosphere of nitrogen in ethylene glycol dimethyl ether (35 mL). After 15 minutes, 3-nitrophenyl boronic acid (1.70 g, 10.2 mmol) was added, followed by potassium carbonate (4.24 g, 30.7 mmol) in water (15 mL). The reaction was heated to reflux overnight, cooled to room temperature and then filtered. Saturated ammonium chloride was added. The water layer was extracted with ethyl acetate (3×20 mnL). The combined organic layer was dried with MgSO4, filtered, and solvent removed in vacuo. The product was purified by flash silica gel chromatography (3:2 hexane; ethyl acetate) to give 5-(3-Nitro-phenyl)-1,3-dihydro-indol -2-one (0.084 g, 65%), Mp=269° C.; 1H NMR (DMSO) δ10.5 (s, 1H), 8.38-8.36 (m:, 1H) 8.17-8.14 (m, 1H), 8.10-8.07 (m, 1H), 7.75-7.60 (m, 3H), 6.95 (d, 1H, J=8.1 Hz), 3.57 (s, 2H); IR (KBr) 3420, 3190, 1700 c/m−; MS (EI) m/z 253 (M−H)−; CHN calculated for C14H10N2O: C, 66.14; H, 3.96; N, 11.02; Found: C, 64.59; H,4.16; N,9.43.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].[Cl:14]N1C(=O)CCC1=O.Cl.C(OCC)(=O)C>C(Cl)(Cl)Cl.CO>[Cl:14][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([C:1]#[N:2])[C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(Cl)c(O)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
Methyl 3-cyano-4-hydroxybenzoate (2.00 g) was dissolved in chloroform (15 mL) and methanol (5 mL), and N-chlorosuccinimide (3.62 g) and 4N hydrochloric acid-ethyl acetate (6.8 mL) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and a mixture of methanol and water in a mixing ratio of 9:1 was added, and then the precipitated crystal was washed with water and isopropyl alcohol to obtain the title compound (1.27 g) as a colorless crystal.
Reaction SMILES: [F:1][CH:2]([F:19])[N:3]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([O:16][CH3:17])[CH:10]=2)[N:5]=[C:4]1[CH3:18].S(Cl)([Cl:23])(=O)=O>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:23][C:14]1[CH:13]=[C:12]([CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[N:6]1[C:7](=[O:8])[N:3]([CH:2]([F:1])[F:19])[C:4]([CH3:18])=[N:5]1
Reactant: COc1cc(-n2nc(C)n(C(F)F)c2=O)ccc1C
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc(-n2nc(C)n(C(F)F)c2=O)c(Cl)cc1C
Yield: 97 %

Procedure:
A solution of 15.0 g (0.056 mole) of 4-difluoromethyl-4,5-dihydro-1-(4-methyl-3-methoxyphenyl)-3-methyl-1,2,4-triazol-5(1H)-one and 7.5 g (0.056 mole) of sulfuryl chloride in 100 mL of chloroform was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure to leave a residue. This residue was dissolved in methylene chloride and washed with an aqueous 10% sodium hydroxide solution. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield 16.5 g of 1-(2-chloro-4-methyl-5-methoxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one as a solid.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][C@@H:8]([O:10][C:11]2[CH:16]=[N:15][C:14]([CH:17]3[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[CH2:7][N:6]1[CH2:20][C:21]([O:23]C)=O)=[N+]=[N-].O>CO.[Ni]>[CH:17]1([C:14]2[N:15]=[CH:16][C:11]([O:10][C@H:8]3[CH2:7][N:6]4[CH2:20][C:21](=[O:23])[NH:1][CH2:4][C@@H:5]4[CH2:9]3)=[N:12][CH:13]=2)[CH2:19][CH2:18]1
Reactant: COC(=O)CN1C[C@H](Oc2cnc(C3CC3)cn2)C[C@H]1CN=[N+]=[N-]
Agent: [Ni]
Solvent: CO
Solvent: O
Product: O=C1CN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2CN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the product from Example 201B (203 mg, 0.611 mmol) in methanol (20 mL) was added to Raney®-nickel 2800, water slurry (2030 mg, 34.6 mmol) in a 50 mL pressure bottle. The mixture was stirred at ambient temperature for 16 hours under hydrogen (30 psi). The mixture was filtered and concentrated in vacuo to give the title compound. MS (ESI) m/z 275 (M+H)+.
Reaction SMILES: I[C:2]1[S:3][C:4]([CH3:7])=[CH:5][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:27]([OH:30])[C:28]#[CH:29].C(N(C(C)C)CC)(C)C>[Cu]I.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.C(Cl)(Cl)Cl.[Pd].[Pd].O.O1CCCC1>[CH3:7][C:4]1[S:3][C:2]([C:29]#[C:28][CH2:27][OH:30])=[CH:6][CH:5]=1
Reactant: Cc1ccc(I)s1
Reactant: C#CCO
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C#CCO)s1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2-iodo-5-methylthiophene (5.00 g), copper(I) iodide (82 mg), triphenylphosphine (286 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (445 mg), propargyl alcohol (1.91 ml), diisopropylethylamine (15.1 ml) and tetrahydrofuran (30 ml) was stirred at room temperature for 20 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1-2:1) to give the object product (1.48 g) as a brown oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: OCCCCCCBr
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Yield: 47.6 %

Procedure:
Using 5 g (25.6 mmol) of 4-cyano-4'-hydroxybiphenyl, 85 ml of acetonitrile, 4.63 g (25.6 mmol) of 6-bromohexanol and 7.09 g (51.2 mmol) of anhydrous potassium carbonate, synthetic treatment was carried out in the same manner as in Example 2. The obtained gray powder was recrystallized from methanol to obtain 3.6 g (yield: 48%) of 4-cyano-4'-(6-hydroxyhexyloxy)biphenyl (24) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C1(C[C:21](O)=[O:22])C=CC=CC=1.C=O>C1C=CC=CC=1>[OH:1][C:2]1[C:3]([CH2:21][OH:22])=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CC(=O)O)cc1O
Reactant: O=C(O)Cc1ccccc1
Agent: C=O
Solvent: c1ccccc1
Product: COc1ccc(CC(=O)O)c(CO)c1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 83 %

Procedure:
11.0 g of 3-hydroxy-4-methoxyphenylacetic acid is dissolved in 550 ml of benzene and refluxed to remove water as azeotrope. Then, 14.0 g of benzeneboronic acid is added thereto, and refluxed for approximately 1 hour while removing the water produced. (In this reaction, the starting phenylacetic acid works as the carboxylic acid catalyst). At 2-3 hour intervals, each 2-3 g of paraformaldehyde is added while continuing the removal of water, and after the lapse of 9 hours an additional 1.0 g of benzeneboronic acid is added thereto. The reaction is completed within a period of 20 hours, and the solvent is completely distilled off under reduced pressure. The crystalline residue after addition of 150 ml of water is kept on an oil bath at 90°-100° C. for 1.5 hours under stirring. The reaction mixture is cooled to room temperature, and the precipitated crystals are collected and recrystallized from acetone-ether to give 9.70 g (83% yield) of 3-hydroxy-2-hydroxymethyl-4-methoxyphenylacetic acid as the δ-lactone having mp. 183°-185° C. IR νmaxCHCl 3 3540, 1740, 1600, 1277, 1030, 983cm-1. NMR (d6 -DMSO) δ 3.80 (3H. singlet), 3.65 (2H, singlet), 5.32 (2H, singlet), 6.70, 6.90 (AB quartet, J = 8.0 Hz), 8.07 (1H, singlet) ppm. Anal. Aclcd. for C10H10O4 : C, 61.85; H, 5.19 (%). Found: C, 61.70; H, 5.17 (%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[OH:12]O>O1CCCC1.[OH-].[Na+]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:12]
Reactant: OB(O)c1cccc(F)c1Cl
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Oc1cccc(F)c1Cl
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-3-fluorophenylboronic acid (5.0 g) in tetrahydrofuran (50 mL) and 1M aqueous NaOH (30 mL) at 0° C. was added 30% hydrogen peroxide solution (4 mL), and the reaction was stirred for 2 hours. The reaction was quenched with saturated aqueous Na2S2O3 solution, acidified with concentrated aqueous HCl, and extracted twice with ethyl acetate. The combined extracts were washed with brine, concentrated, and chromatographed on silica gel using 10% ethyl acetate/hexanes as eluent to give the product.
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:19][O:20][CH3:21])[CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:7][CH:6]=1>O.C1COCC1.C(O)C.CCOC(C)=O>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:19][O:20][CH3:21])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CCC(=NOC)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CON=C(CCC(=O)O)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 69.1 %

Procedure:
Lithium hydroxide monohydrate (9.59 g, 228.57 mmol) was added to ethyl 4-(4-chlorophenyl)-4-(methoxyimino)butanoate (Intermediate 52) (12.33 g, 45.71 mmol) in water (25.4 mL), THF (102 mL) and ethanol (102 mL). The resulting solution was stirred at 20° C. for 1 day. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (200 mL). The aqueous was adjusted to pH5 with 1M citric acid solution then extracted with EtOAc (3×150 mL). The organic extracts were washed with saturated brine (25 mL) then dried over MgSO4, filtered and evaporated to afford desired product 4-(4-chlorophenyl)-4-(methoxyimino)butanoic acid (7.63 g, 69.1%) as a light yellow solid.