Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:20](/B(O)O)=[CH:21]\[CH3:22].C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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.O>[CH:20](/[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[CH:21]\[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: C/C=C/B(O)O
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: C/C=C/c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Temperature: 95 °C
Reaction time: 12 h
Yield: 96.3 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (400 mg, 1.22 mmol), trans-1-propen-1-ylboronic acid (157 mg, 1.82 mmol), ethanol (1.4 ml), 2N aqueous sodium carbonate solution (5 ml), and tetrakis(triphenylphosphine)palladium(0) (170 mg, 0.147 mmol) in toluene (10 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (340 mg, 97.1%) as an oil.
Reaction SMILES: C1COCC1.[OH-].[Na+].C([O:10][C:11](=[O:46])[C:12]([CH3:45])=[CH:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([C:21](=[O:43])[NH:22][C:23]2[S:24][CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([O:40][CH3:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:29]=3[F:42])[N:27]=2)=[CH:16][C:15]=1[F:44])C.Cl>CO>[F:44][C:15]1[CH:16]=[C:17]([C:21](=[O:43])[NH:22][C:23]2[S:24][CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]([O:40][CH3:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:29]=3[F:42])[N:27]=2)[CH:18]=[C:19]([F:20])[C:14]=1[CH:13]=[C:12]([CH3:45])[C:11]([OH:46])=[O:10]
Reactant: CCCCCC(OC)c1cccc(-c2csc(NC(=O)c3cc(F)c(C=C(C)C(=O)OCC)c(F)c3)n2)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCC(OC)c1cccc(-c2csc(NC(=O)c3cc(F)c(C=C(C)C(=O)O)c(F)c3)n2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
To a mixture of THF (2 mL), methanol (2 mL), and 2N sodium hydroxide aqueous solution of 3-(2,6-difluoro-4-{4-[2-fluoro-3-(1-methyloxyhexyl)phenyl]thiazol-2-ylcarbamoyl}phenyl}-2-methylacrylic acid ethyl ester (500 mg) was stirred at room temperature for 3 h. The reaction mixture was acidified with hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, and brine, dried over magnesium sulfate, and evaporated. The residue was recrystallized from ethyl acetate to obtain the compoumd (B1) 370 mg.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12](OC)=[O:13].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[CH2:12][OH:13]
Reactant: COC(=O)c1ccccc1Nc1cccc(C)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1cccc(Nc2ccccc2CO)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
A solution of 2-[(2,3-dimethylphenyl) amino]benzoic acid, methyl ester (31 g, 121.5 mmol) in dry ether (600 ml) is added dropwise to a suspension of lithium aluminum hydride (6.9 g, 0.18 mmol) in dry ether (200 ml) under an atmosphere of dry nitrogen. The reaction mixture is stirred at room temperature overnight and quenched by the careful dropwise addition of water (7 ml), 15% NaOH (7 ml) and water (20 ml). The resulting suspension is filtered and the filtrate is evaporated to an oil which crystallizes upon addition of hexane to give pure 2-[(2,3-dimethylphenyl)amino]benzyl alcohol (26 g, 94%); mp 65°-69° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH2:9][C:10]1[NH:14][N:13]=[N:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:18](I)[CH3:19]>C1COCC1.C(OC(=O)C)C>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH2:9][C:10]1[N:11]=[N:12][N:13]([CH2:18][CH3:19])[N:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)NCCc1nnn[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCn1nnc(CCNC(=O)OC(C)(C)C)n1

Procedure:
A solution of [2-(1H-Tetrazol-5-yl)-ethyl]-carbamic acid tert-butyl ester (EP 449523) (1.0 g, 4.69 mmol) in dry THF (20 ml) is treated with a 60% dispersion of sodium hydride in mineral. oil (0.19 g, 4.69 mmol) and stirred at ambient temperature for 10 minutes. Ethyliodide (0.375 ml, 4.69 mmol) is added and the reaction mixture is heated at reflux for 7 hours, then diluted with ethylacetate and filtered. The filtrate is evaporated and the residue purified by flash silica chromatography (elution 3:2 hexanelethylacetate) to afford [2-(2-Ethyl-2H-tetrazol-5-yl)-ethyl]-carbamic acid tert-butyl ester, which elutes first, and the titled compound, [2-(1-Ethyl-1H-tetrazol-5-yl)-ethyl]-carbamic acid tert-butyl ester, which elutes next.
Reaction SMILES: [OH-].[K+].[CH2:3]([C:9]1[S:10][C:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24]C(=O)C)[CH:20]=3)[CH:15]=2)=[N:12][N:13]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.Cl>C(O)C>[CH2:3]([C:9]1[S:10][C:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([OH:24])[CH:20]=3)[CH:15]=2)=[N:12][N:13]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCc1nnc(-c2ccc3cc(OC(C)=O)ccc3c2)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCc1nnc(-c2ccc3cc(O)ccc3c2)s1
Reaction time: 0.33 h
Yield: 74.3 %

Procedure:
1.50 g (22.7 mM) of potassium hydroxide was dissolved in 72 ml of ethanol at 60°-65° C. To the solution, 2.90 g (8.18 mM) of 2-hexyl-5-(6-acetoxynaphthalene-2-yl)-1,3,4-thiadiazole was added, followed by stirring for 20 minutes at 60°-65° C. The reaction mixture was poured into 200 ml of iced water and 3 ml of concentrated hydrochloric acid was added thereto to precipitate a crystal. The crystal was recovered by filtration and washed with water to obtain 1.90 g of 2-hexyl-5-(6-hydroxynaphthalene-2-yl)-1,3,4-thiadiazole (Yield: 71.9 %). ##STR138##
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH:3]=1.[CH3:20][N:21]1[CH:25]=[C:24]([C:26]2[CH:27]=[N:28][CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=2)[CH:23]=[N:22]1.C(=O)(O)[O-].[Na+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([F:19])=[C:12]([C:4]2[CH:3]=[C:2]([C:30]3[CH:29]=[N:28][CH:27]=[C:26]([C:24]4[CH:23]=[N:22][N:21]([CH3:20])[CH:25]=4)[CH:31]=3)[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=1
Reactant: Fc1ccc(Cl)cc1-c1cc(Cl)c2cccnc2n1
Reactant: Cn1cc(-c2cncc(B3OC(C)(C)C(C)(C)O3)c2)cn1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cncc(-c3cc(-c4cc(Cl)ccc4F)nc4ncccc34)c2)cn1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A slurry of 147 mg (0.5 mmol) 4-chloro-2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine, 171 mg (0.6 mmol) 3-(1-methyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine and 50.4 mg (0.6 mmol) sodium bicarbonate in 1 ml DMF and 0.5 ml water was heated to 80° C. under nitrogen. Then 7.0 mg (0.01 mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added. The reaction mixture was stirred for 16 hours at 80° C. Water was then added to the reaction mixture and the resulting precipitate was filtered off. The residue was chromatographed on a silica gel column with dichloromethane/methanol as eluent yielding 2-(5-chloro-2-fluoro-phenyl)-4-[5-(1-methyl-1H-pyrazol-4-yl)-pyridin-3-yl]-[1,8]naphthyridine als yellow crystals; HPLC-MS: 2.09 min, [M+H] 416.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>>[CH3:44][S:45]([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)(=[O:47])=[O:46]
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NS(C)(=O)=O)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 33 in Step A and methylsulfonyl chloride in Step B, the title compound was prepared.
Reaction SMILES: C(OC([N:11]1[CH:16]2[CH2:17][CH:18]([CH:20]([OH:25])[C:21]([O:23][CH3:24])=[O:22])[CH2:19][CH:12]1[CH2:13][O:14][CH2:15]2)=O)C1C=CC=CC=1>CO.[Pd]>[CH3:24][O:23][C:21](=[O:22])[CH:20]([OH:25])[CH:18]1[CH2:19][CH:12]2[NH:11][CH:16]([CH2:15][O:14][CH2:13]2)[CH2:17]1
Reactant: COC(=O)C(O)C1CC2COCC(C1)N2C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(O)C1CC2COCC(C1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.8 %

Procedure:
A mixture of 7-(hydroxy-methoxycarbonyl-methyl)-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (Compound AJ) (300 mg, 0.86 mmol) and 10% palladium on active carbon (100 mg) in methanol (10 mL) was stirred at room temperature under hydrogen (30 psi) for 16 hours. The catalyst was filtered off. The filtrate was concentrate in vacuo to afford hydroxy-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-acetic acid methyl ester (Compound AH) (107 mg, 57%) which was used for the next step without further purification. MS: calc'd (MH+) 216, measured (MH+) 216.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[O:15][CH3:16])=[O:5])C.Br[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[CH3:16][O:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[N:7]([CH2:18][C:19]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=1)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]2
Reactant: BrCc1cccc2ccccc12
Reactant: CCOC(=O)c1cc2cccc(OC)c2[nH]1
Product: COc1cccc2cc(C(=O)O)n(Cc3cccc4ccccc34)c12

Procedure:
Using general procedure B, 7-methoxy-1H-indole-2-carboxylic acid ethyl ester (Lit. 6) was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 330.3 ([M−H]−).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:30][CH2:29][C:11]2([N:15]([CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:14][N:13]([CH2:23][C:24]([O:26]C)=[O:25])[C:12]2=[O:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].CO>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([CH2:16][CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[CH2:14][N:13]([CH2:23][C:24]([OH:26])=[O:25])[C:12]2=[O:28])[CH2:29][CH2:30]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CN1CN(CC2CCCCC2)C2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(CC(=O)O)CN2CC1CCCCC1
Yield: 71.1 %

Procedure:
A stirred mixture of 4 g (9.45 mmol) of methyl 8-(t-butoxycarbonyl)-1-cyclohexylmethyl-4-keto-1,3,8-triazaspiro [4.5]decan-3-acetate, 4 g (72 mmol) carbonate 60 ml of methanol and 40 ml of water was heated at reflux for 3 hours. The resulting solution was concentrated to about one-half of its original volume and then it was carefully acidified with 2N HCl at 0° C. The resulting mixture was extracted with ethyl acetate. After the extracts were dried over magnesium sulfate, they were concentrated. The residue solid was recrystallized from hexane to give the product as 2.75 g (69.5%) of colorless crystals, mp 148°-149° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[S:8])[NH2:7])=[CH:4][CH:3]=1.Br[CH2:12][CH:13](OC)OC.CC1C=CC(S(O)(=O)=O)=CC=1>CCO>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[S:8][CH:12]=[CH:13][N:7]=2)=[CH:4][CH:3]=1
Reactant: COC(CBr)OC
Reactant: NC(=S)c1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Oc1ccc(-c2nccs2)cc1
Temperature: 25 °C

Procedure:
To a mixture of 4-hydroxybenzothioamide (30.64 g, 0.20 mol) and 2-bromo-1,1-dimethoxyethane (31.00 g, 0.20 mol) in EtOH (600 mL) was added 4-methylbenzenesulfonic acid (34.44 g, 0.20 mol) with stirring at rt. The reaction mixture was heated at 90° C. for 24 h, then cooled to rt and concentrated in vacuo. The mixture was diluted with H2O (200 mL), adjusted to pH 10 with saturated NaHCO3 aqueous solution and extracted with DCM (200 mL×3). The combined organic phases were concentrated in vacuo to give the title compound as s yellow solid (21.3 g, 60%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:5][CH:4]=1)#[N:2].CO.[CH3:19]CN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:19][O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1
Reactant: N#Cc1ccc(CCCCCC(=O)O)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCCCCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
To a solution of 6-(p-cyanophenyl)hexanoic acid (1.0 g), which is disclosed in J. Med. Chem., 36, 1811 (1993), in methylene chloride (10 ml) are added methanol (0.2 ml), WSC.HCl (883 mg) and 4-dimethylaminopyridine (561 mg), and the mixture is stirred at room temperature for 30 minutes. The mixture is diluted with ethyl acetate, and washed with 1N hydrochloric acid and a saturated aqueous sodium hydrogen carbonate solution, and purified by silica gel column chromatography (n-hexane/ethyl acetate=5:1) to give the title compound (600 mg).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.[OH-].[K+].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]3[CH2:19][CH2:18][N:17]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:16][CH2:15]3)(=[O:12])=[O:13])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: ClCc1ccccc1
Reactant: O=S(=O)(c1cccc2cnccc12)N1CCNCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=S(=O)(c1cccc2cnccc12)N1CCN(Cc2ccccc2)CC1
Yield: 79 %

Procedure:
In 150 ml of ethanol were added 2.77 g of 1-(5-isoquinolinesulfonyl)piperazine, i.e., Compound (35), 1.0 g of potassium hydroxide and 1.9 g of benzyl chloride, and the mixture was refluxed under heating for five hours. After the ethanol was removed from the reaction solution, 100 ml of chloroform was added to the resulting solution, and the solution obtained was washed with a buffer solution having a pH of 5.5 and extracted twice with 20 ml of a 2N aqueous hydrochloric acid solution. The aqueous hydrochloric acid layer was rendered alkaline, extracted twice with 50 ml of chloroform, and the chloroform layer extracted was washed with water and dried with anhydrous magnesium sulfate. After the chloroform was distilled therefrom under reduced pressure, 5 ml of a 10N aqueous hydrochloric acid solution was added to the residue and the mixture was condensed to dryness. The crystalline residue thus obtained was recrystallized from ethanol to give 2.9 g of 1-(5-isoquinolinesulfonyl)-4-benzylpiperazine [i.e., Compound (56)] dihydrochloride in a yield of 66%.
Reaction SMILES: ClC1C([F:8])=CN=C(C)C=1.[Cl:10][C:11]1[C:16]([F:17])=[CH:15][N:14]=[C:13]([CH2:18][CH2:19][CH3:20])[CH:12]=1>>[Cl:10][C:11]1[C:16]([F:17])=[CH:15][N:14]=[C:13]([CH2:18][CH2:19][CH3:20])[C:12]=1[F:8]
Reactant: CCCc1cc(Cl)c(F)cn1
Reactant: Cc1cc(Cl)c(F)cn1
Product: CCCc1ncc(F)c(Cl)c1F

Procedure:
By following the procedures described in Example 69 and replacing 4-chloro-5-fluoro-2-picoline (the product of Example 66) with 4-chloro-5-fluoro-2-propyl-pyridine (the product of Example 70), the title compound can be prepared.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][C:8]([CH:11]=[O:12])=[CH:9][N:10]=1.[C:13](O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[S:7][C:8]([CH:11]([OH:12])[CH3:13])=[CH:9][N:10]=1
Reactant: O=Cc1cnc(C2OCCO2)s1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: CC(O)c1cnc(C2OCCO2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 2-(1,3-dioxolan-2-yl)-1,3-thiazole-5-carbaldehyde (2.25 g) in tetrahydrofuran (20 mL) was slowly added a 1.13M methyllithium diethyl ether solution (12.0 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 30 min, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (1.96 g, yield 80%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). MS: 202 (MH+).
Reaction SMILES: C([Mg]Br)C.[CH:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:13][CH2:14][C:15]#[C:16][CH2:17]Cl.[NH4+].[Cl-]>C1COCC1.[Cu]Cl>[Cl:13][CH2:14][C:15]#[C:16][CH2:17][C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: ClCC#CCCl
Reactant: C#CCCCCCC
Agent: Cl[Cu]
Agent: CC[Mg]Br
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCCCCCC#CCC#CCCl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
38.1 ml of a 1M solution of ethyl magnesium bromide in THF were added dropwise, at room temperature, to a solution of 4 grams of 1-octyne in 15 ml of anhydrous THF, under an inert atmosphere. With the addition complete, the mixture was maintained under stirring for 30 min at room temperature and then heated under reflux for 1 h, 30 min. The mixture was cooled to room temperature and then 287 mg of copper(I) chloride were added and the mixture was again heated under reflux for 1 hour. The mixture was then cooled to room temperature and 9.95 ml of 1,4-dichloro-2-butyne dissolved in 20 ml of anhydrous THF were rapidly added dropwise. The mixture was maintained under stirring for 30 min at room temperature, then it was heated under reflux for 2 h and then maintained under stirring for 15 h at room temperature before being heated under reflux for another 2 h. The reaction medium was then cooled to 4° C. and hydrolyzed with care with a saturated aqueous solution of NH4Cl. The medium was then extracted 3 times with diethyl ether and the combined organic phases were washed 3 times with water and then with a saturated aqueous solution of NaCl before being dried over Na2SO4, filtered and concentrated under vacuum in a rotary evaporator. The oily residue containing 1,4-dichloro-2-butyne in excess was purified by distillation under reduced pressure and 1-chloro-2,5-dodecadiyne was isolated in the form of a pale yellow oil (yield 36%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[C:13]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].O>C(OCC)(=O)C>[CH3:8][S:9]([O:28][CH2:27][CH2:26][CH2:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:23][CH:22]=1)(=[O:11])=[O:10]
Reactant: CC(C)(C)Oc1ccc(CCCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)Oc1ccc(CCCCOS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Triethylamine (32.9 ml) and methanesulfonyl chloride (14.6 ml) were added to a solution of 4-(4-tert-butoxyphenyl)butan-1-ol (35.0 g) in ethyl acetate (360 ml) at 0° C., and the mixture was stirred at 0° C. for 1.5 hr. By adding water, the reaction mixture was separated. The organic layer was washed successively with 5% sodium hydrogen carbonate solution and water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crude 4-(4-tert-butoxyphenyl)butyl methanesulfonate (50.2 g). A suspension of the product (50.2 g) and sodium iodide (46.1 g) in acetone (500 ml) was stirred for 4.5 hr. By adding water and diisopropyl ether, the reaction mixture was separated. The organic layer was successively washed with 10% hypo-water and water, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the titled compound (52.1 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]2[CH:3]1[CH:4]=[CH:5][C:6]2=[O:8].C1(C)C=CC=CC=1.C([O:25]OO)(C)(C)C.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.CO>O>[O:25]1[CH:4]2[CH:5]1[C:6](=[O:8])[CH:7]1[CH:3]2[C:2]1([F:1])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CC(C)(C)OOO
Reactant: CCOC(=O)C1(F)C2C=CC(=O)C21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(F)C2C(=O)C3OC3C21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
16.9 g of (1RS,5RS,6RS)ethyl 6-fluoro-2-oxobicyclo[3.1.0]hex-3-ene-6-carboxylate was dissolved into 100 ml of toluene. 30.6 ml of 70% t-butylhydroxyperoxide aqueous solution and 11.5 ml of 10% benzyltrimethylammoniumhydroxide/methanol solution were added thereto, and this was stirred at room temperature for 4 hours. After the reaction solution was poured into water, it was extracted twice with ethyl acetate. The obtained organic layers were consolidated to be washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After filtering off the desiccant, concentration of the filtrate was carried out under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200 (made by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=8:1 to 6:1), yielding 13.4 g of (1RS,3RS,4RS,5SR,6RS)ethyl 3,4-epoxy-6-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylate. The proton NMR and mass spectrograph data are shown below.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17](=[O:32])[CH:18]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C@@H:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])[CH:10]=2)[CH2:8][CH2:7][CH2:6]1.[OH-].[Na+].Cl>O1CCOCC1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2([CH2:4][C:3]([OH:33])=[O:2])[CH2:6][CH2:7][CH2:8]2)=[CH:10][C:11]=1[NH:16][C:17](=[O:32])[CH:18]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C@@H:19]([CH3:24])[C:20]([F:23])([F:22])[F:21]
Reactant: COC(=O)CC1(c2ccc(Cl)c(NC(=O)C(c3ccc(Cl)cc3)[C@@H](C)C(F)(F)F)c2)CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@H](C(C(=O)Nc1cc(C2(CC(=O)O)CCC2)ccc1Cl)c1ccc(Cl)cc1)C(F)(F)F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
38 mg (0.08 mmol) of methyl-[1-(4-chloro-3-{[(3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)cyclobutyl]acetate were dissolved in 9.5 ml of dioxane, and 0.15 ml of 1 N aqueous sodium hydroxide solution was added. The mixture was stirred at 80° C. overnight. The reaction mixture was then acidified with 1 N hydrochloric acid to pH 1 and extracted repeatedly with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by preparative HPLC. This gave 22 mg (0.05 mmol, 60% of theory) of the target compound.