Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:9][N:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:7]1)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:19]([N:8]1[CH2:9][C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C@@H:6]([CH:4]=[O:5])[CH2:7]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CON(C)C(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of (3R,4S)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid methoxy-methyl-amide 6.58 g (0.017 mol) dissolved in THF (100 mL) was added 16 mL (0.017 mol) of lithiumaluminiumhydride (1.0M in THF) dropwise at 0° C. and stirred for one hour. The reaction was quenched by aq. ammonium chloride solution and extracted with ethylacetate twice. The combined organic layers were dired on anhydrous sodium sulfate and concentrated in vaccuo. The residue was purified by silica gel column chromatography eluted by a mixture of heptane and ethyl acetate (3:2) yielding 5.21 g (93%) of the title compound as a light yellow oil. ES-MS m/e: 334.2 (M+H+). compound as a light yellow oil. ES-MS m/e: 393.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:11]([O:13]CC)=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[OH-].[K+]>O.C(O)C>[CH3:1][C:2]1[S:3][C:4]([C:11]([OH:13])=[O:12])=[C:5]([C:7]([F:8])([F:9])[F:10])[N:6]=1
Reactant: CCOC(=O)c1sc(C)nc1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(C(F)(F)F)c(C(=O)O)s1
Reaction time: 8 h
Yield: 77.6 %

Procedure:
1.3 g of ethyl 2-methyl-4-trifluoromethylthiazole-5-carboxylate and 0.4 g of potassium hydroxide were dissolved in a mixture of 5 ml each of water and ethanol and reaction was effected at room temperature overnight. After the reaction, the reaction mixture was concentrated and acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract was concentrated to obtain 0.89 g of 2-methyl-4-trifluoromethylthiazole-5-carboxylic acid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:20][C:19](=O)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:24])=O>CN(C)C=O>[Cl:24][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[N:20]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1ccc(-c2nc3ccccc3c(=O)[nH]2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2nc(Cl)c3ccccc3n2)cc1

Procedure:
A mixture of 8.9 g of 2-(4-tert-butylphenyl)quinazolin-4(3H)-one and 60 ml of thionyl chloride was treated with 2.34 g of dimethylformamide as described in Example VI. The initial solid was triturated with cyclohexane, filtered, and the filtrate concentrated to give an oil which solidified on standing to give a solid, m.p. 74°-77°. This solid was recrystallized twice from petroleum ether (30°-60° fraction) using a low-temperature recrystallization apparatus to give 6.3 g of 4-chloro-2-(4-tert-butylphenyl)quinazoline, m.p. 75°-76.5°; ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([O:26][CH2:27][CH2:28][OH:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH3:15])=[CH:9][CH:8]=1)(OC)=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].Cl>O1CCCC1.O>[ClH:25].[OH:2][CH2:1][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([O:26][CH2:27][CH2:28][OH:29])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH3:15])=[CH:9][CH:8]=1
Reactant: COC(=O)COc1ccc(CC(C)NCC(OCCO)c2cccc(Cl)c2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC(Cc1ccc(OCCO)cc1)NCC(OCCO)c1cccc(Cl)c1

Procedure:
N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-hydroxyethoxy)-2-(3-chlorophenyl)ethanamine (3.0 g) in dry tetrahydrofuran (30 ml) was added dropwise, with stirring, to a suspension of lithium aluminium hydride (1.0 g) in dry tetrahydrofuran (30 ml) and the resultant mixture heated under reflux for 3 hours. After cooling, water (1 ml), 10% aqueous sodium hydroxide (1 ml) and water (2 ml) were added carefully. Filtration and evaporation of the filtrate to dryness gave an oil which was converted to its hydrochloride salt by treatment with ethereal hydrogen chloride. Recrystallisation from ethyl acetate-methanoldiethyl ether gave the title compound, mp 86°-90° C. as a 49:51 mixture of diastereoisomers.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16]Cl)=[CH:12][N:11]=1.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=1>O.CN(C=O)C>[Cl:9][C:10]1[N:11]=[CH:12][C:13]([CH2:16][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:24]=2)=[CH:14][CH:15]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OCc2ccc(Cl)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
Potassium carbonate (1.3 g) and sodium iodide (93 mg) were added to a DMF solution (20 mL) of 2-chloro-5-chloromethylpyridine (1.0 g) and ethyl 4-hydroxybenzenecarboxylate (1.0 g), and stirred overnight at room temperature. Water was added to the reaction solution, and extracted with diethyl ether. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated off under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=9/1 to 3/2) to obtain the entitled compound (1.7 g).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[CH3:21][C:22]1([CH3:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([N:25]3[CH2:26][CH2:27][C:22]([CH3:28])([CH3:21])[CH2:23][CH2:24]3)=[O:20])=[N:8][C:9]=2[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(Cc2ccc(F)cc2)n1
Reactant: CC1(C)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCN(C(=O)c2ccc(C3CC3)c(Cc3ccc(F)cc3)n2)CC1

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-(4-fluoro-benzyl)-pyridine-2-carboxylic acid (Example 5 g)) was reacted with 4,4-dimethyl-piperidine (4045-30-1) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=367.5 [MH+].
Reaction SMILES: [CH:1]1([O:4][C@H:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14]([NH:15][C:16](=[O:24])[CH2:17][CH2:18]2)=[CH:13][C:12]4=[O:25])[CH2:3][CH2:2]1.[BH4-].[Na+]>C1COCC1.C(O)C.CCOC(C)=O>[CH:1]1([O:4][C@H:5]2[CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14]([NH:15][C:16](=[O:24])[CH2:17][CH2:18]2)=[CH:13][C@@H:12]4[OH:25])[CH2:3][CH2:2]1
Reactant: C[C@]12CC[C@H]3[C@@H](C(=O)C=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@]12CC[C@H]3[C@@H]([C@@H](O)C=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2OC1CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
17β-Cyclopropyloxy-4-aza-androst-5-en-3,7-dione (1.000 g, 2.9115 mmol) prepared in Example 18B or otherwise obtained, dissolved in a mixture of THF (25 mL) and ethanol (25 mL) is added to a solution of sodium borohydride (NaBH4; 1.000 g, 26.43 mmol) in ethanol (50 mL). The reaction mixture is stirred 5 hours at ambient temperature. At the end of this time, the reaction solution is diluted with EtOAc (100 mL) and washed with brine (NaCl; 3×100 mL). The organic solution is dried over MgSO4, filtered, concentrated and purified by flash chromatography (1:1 EtOAc/CH2Cl2) to give the title compound.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[C:5]([C:12]([NH2:14])=[O:13])[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)#[N:2].[C:22]([N:26]=[C:27]=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:1]([C:3]1[N:7]2[CH2:8][CH2:9][N:10]([C:27]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[CH2:11][C:6]2=[C:5]([C:12]([NH2:14])=[O:13])[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)#[N:2]
Reactant: CC(C)(C)N=C=O
Reactant: N#Cc1c(-c2cccc(F)c2)c(C(N)=O)c2n1CCNC2
Product: CC(C)(C)NC(=O)N1CCn2c(C#N)c(-c3cccc(F)c3)c(C(N)=O)c2C1
Yield: 78.7 %

Procedure:
To a suspension of 0.50 g (0.53 mmol) of 6-cyano-7-(3-fluorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide is added 0.07 ml (0.6 mmol) of tert-butyl isocyanate. After reaction for 2 hours at room temperature, the solvent is evaporated off under reduced pressure and the solid residue is recrystallized from acetonitrile, to give 0.16 g of 6-cyano-7-(3-fluorophenyl)-N2-(tert-butyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide in the form of a white powder after filtering off and drying under reduced pressure.
Reaction SMILES: B.[Na].[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].Cl.O>C(O)(C)C>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][OH:16])=[CH:17][CH:18]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCOc1ccc(C=O)cc1
Agent: B
Agent: Cl
Agent: [Na]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCOc1ccc(CO)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 62.4 %

Procedure:
A suspension of sodium boron hydride (6.9 g) in isopropyl alcohol (500 ml) was dropwise added to a solution of p-heptyloxybenzaldehyde (119 g) in isopropyl alcohol (300 ml), followed by heating the mixture to 70° C. to form a uniform solution, which was then agitated at 70° C. for 3 hours and allowed to stand overnight, followed by adding 6N-HCl (100 ml) and water (200 ml), heating the mixture to 60° C., distilling off most of the solvent, extracting with toluene, washing with water, washing with alkali, washing with water to make it neutral, drying, concentrating and recrystallizing the residue from a mixed solvent of ethanol (200 ml) and water (60 ml) to obtain p-heptyloxybenzyl alcohol (74.9 g). This product (40 g) together with 47% aqueous hydrogen bromic acid (200 g) were agitated at 80° C. for 7 hours and allowed to stand overnight, followed by extracting with n-heptane (200 ml), washing the n-heptane layer with water till the washing water became neutral, drying, concentrating and subjecting the residue to vacuum distillation to obtain p-heptyloxybenzyl bromide (IIa-2) (28 g) having a b.p. of 174°-175° C./6 Torr.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C[C:27]([N:29](C)C)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Zn].[C-]#N.[C-]#N.[Zn+2]>[F:23][C:22]([F:25])([F:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:6]=[N:7][C:2]([C:27]#[N:29])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)=[O:15]
Reactant: CC(=O)N(C)C
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(Cl)nn2)CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Temperature: 110 °C
Yield: 59 %

Procedure:
In an oven dried round-bottom flask, [4-(6-chloropyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone (1.80 g, 4.85 mmol), Pd2(dba)3 (0.130 g, 0.14 mmol), 1,1′-bis(diphenylphosphino)ferrocene (0.161 g, 0.29 mmol), Zn powder (0.317 g, 4.85 mmol) and Zn(CN)2 (0.569 g, 4.85 mmol) were placed under nitrogen atmosphere. Dimethylacetamide (10 mL) was added and the suspension was purged with nitrogen. The mixture was then heated at 110° C. overnight, then cooled to room temperature and then concentrated in vacuo. The brown residue was dissolved in ethyl acetate (15 mL) and washed with water (2×10 mL), dried over anhydrous Na2SO4 and then concentrated. The crude product was purified using column chromatography to afford 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carbonitrile as a pale yellow syrup in 59% yield (1.03 g). 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J=7.8 Hz, 1H), 7.63-7.50 (m, 2H), 7.48 (d, J=9.6 Hz, 1H), 7.32 (d, J=7.3 Hz, 1H), 6.89 (d, J=9.6 Hz, 1H), 4.12-3.98 (m, 1H), 3.92-3.70 (m, 5H), 3.31 (t, J=5.3 Hz, 2H), 13C NMR (75 MHz, CDCl3) δ 167.7, 158.4, 132.4, 130.8, 130.0, 129.6, 127.1, 126.9, 126.8, 116.5, 110.2, 46.2, 44.2, 43.9, 41.1. MS (ES+) m/z 362.3 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[CH:2].C(N(CC)CC)C.Br[C:21]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:22]=1[CH:23]=[O:24]>ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:29][C:27]1[CH:28]=[CH:21][C:22]([CH:23]=[O:24])=[C:25]([C:2]#[C:1][C:3]2[CH:4]=[CH:5][C:6]([S:9]([CH3:12])(=[O:10])=[O:11])=[CH:7][CH:8]=2)[CH:26]=1
Reactant: C#Cc1ccc(S(C)(=O)=O)cc1
Reactant: O=Cc1ccc(F)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C#Cc2cc(F)ccc2C=O)cc1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 79.2 %

Procedure:
A degassed mixture of 1-ethynyl-4-methanesulfonyl-benzene (2.5 g, 13.87 mmol), bis(triphenylphosphine)palladium(II) chloride (0.49 g, 0.69 mmol), copper(I) iodide (0.13 g, 0.69 mmol), triethylamine (28 mL), and 2-bromo-4-fluorobenzaldehyde (3.38 g, 16 mmol) in dichloromethane (10 mL) was stirred at 80° C. for 3.5 hours, then at room temperature overnight. The reaction mixture was partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (RediSep® Flash column, 230-400 mesh, 15-35% ethyl acetate in hexane) gave 4-fluoro-2-(4-methanesulfonyl-phenylethynyl)-benzaldehyde (3.32 g, 79%). MS (ESI+) cald. for C16H11FO3S [(M+H)+] 302, obsd. 302.
Reaction SMILES: C([NH:4][CH2:5][C:6]1[S:7][C:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:10]=1)(=O)C.[ClH:27].[OH-].[Na+]>O>[ClH:27].[NH2:4][CH2:5][C:6]1[S:7][C:8]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[N:10]=1
Reactant: COc1ccc(-c2nc(CNC(C)=O)sc2-c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(-c2nc(CN)sc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-acetylaminomethyl-4,5-bis(4-methoxyphenyl)thiazole (1.00 g) and concentrated hydrochloric acid (7 ml) was refluxed for 2 hours and 40 minutes. After allowing to cool to ambient temperature, the mixture was poured into water, and the resulting solution was neutralized by addition of 4N sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogencarbonate solution, water, and brine, and dried over magnesium sulfate and treated with activated charcoal. After filtration, the filtrate was evaporated in vacuo to give 2-aminomethyl-4,5-bis(4-methoxyphenyl)thiazole hydrochloride. And this compound was dissolved in dichloromethane (10 ml) and triethylamine (0.33 ml). To the above reaction mixture was added a solution of nicotinoyl chloride hydrochloride (0.58 g) and dichloromethane (5 ml) at ambient temperature, and was stirred at ambient temperature for 3 hours and refluxed for one and a half hour. After allowing to cool to ambient temperature, the mixture was poured into water, and the resulting solution was neutralized by addition of 4N sodium hydroxide, and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogencarbonate, water, and brine, and dried over magnesium sulfate and treated with activated charcoal. After filtration, the filtrate was evaporated in vacuo, and the resulting residue was dissolved in diethyl ether, and added methanol solution of hydrogen chloride. The resulting precipitate was collected by filtration and washed with ethanol and diethyl ether to give 4,5-bis(4-methoxyphenyl)-2-(nicotinoylaminomethyl)-thiazole hydrochloride (0.63 g).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:18]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][C:9]2[C:10](=[O:16])[C:11]([S:14][CH3:15])=[CH:12][O:13][C:8]=2[CH:7]=1)(=[O:4])=[O:3].ClC1C=CC=C(C(OO)=[O:34])C=1>>[CH3:15][S:14]([C:11]1[C:10](=[O:16])[C:9]2[CH:17]=[C:18]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[O:13][CH:12]=1)=[O:34]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1coc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c1=O
Product: CS(=O)c1coc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c1=O

Procedure:
7-Methylsulfonylamino-3-methylthio-6-phenoxy-4H-1-benzopyran-4-one was reacted with m-chloroperbenzoic acid in equimolar amounts to obtain 3-methylsulfinyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one [Compound No. 5].
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH:3]=[CH:2]1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:40](=[NH:42])[NH2:41])[CH:36]=2)[CH:31]=1)(=O)=O.C(OCC)C>N1C=CC=CC=1>[CH:1]1([CH2:6][C:7]([O:9][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([C:40](=[NH:41])[NH2:42])[CH:36]=3)[CH:31]=2)=[O:8])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=C(O)CC1C=CCC1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: N=C(N)c1ccc2cc(OC(=O)CC3C=CCC3)ccc2c1
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
To a solution of 2.2 g of 2-cyclopentene-1-acetic acid in 50 ml of anhydrous pyridine, while being cooled in ice and stirred, was added 4.4 g of DCC. After 30 minutes, 5.0 g of 6-amidino-2-naphthol methanesulfonate was added to the mixture and stirred for 24 hours at room temperature. The precipitate formed by the addition of ethyl ether was collected by filtration, admixed with dimethylformamide, and filtered to remove the insolubles. Ethyl ether was added to the filtrate and the precipitate which was formed was collected by filtration and recrystallized from a dimethyl formamide-ethyl ether mixture to yield 2.1 g of a white powder of 6-amidino-2-naphthyl 2-cyclopenteneacetate methanesulfonate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:10]=1[CH:11]=O)=[O:5])[CH3:2].[CH:27]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:10]=1[CH2:11][NH:32][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:5])[CH3:2]
Reactant: NC1CCCC1
Reactant: CCOC(=O)c1nc(-c2ccc(Cl)cc2)n(-c2ccccc2F)c1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2)n(-c2ccccc2F)c1CNC1CCCC1
Yield: 57 %

Procedure:
A solution of 2-(4-chloro-phenyl)-1-(2-fluoro-phenyl)-5-formyl-1H-imidazole-4-carboxylic acid ethyl ester I-5e-2 (1000 mg, 2.68 mmol), cyclopentylamine (251 mg, 2.95 mmol), NaBH(OAc)3 (796 mg, 3.76 mmol) in dichloroethane was stirred for 17 h at room temperature. The reaction was concentrated in vacuo and the residue was diluted with CHCl3. The organic solution was washed with sat'd aq. NaHCO3 and sat'd aq. NaCl, dried, and concentrated under vacuum. The crude residue was purified on SiO2-gel (Flash 40s) using a solvent gradient of 30% EtOAc/hexanes to 80% EtOAc/hexanes to give the desired product (I-5f) as a yellow oil (680 mg, 57%): +APCI MS (M+1) 442.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=1>CO.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:3][C:2]=2[F:1])=[N:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc([N+](=O)[O-])cn2)c(F)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(N)cn2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a suspension of tert-butyl {3-fluoro-4-[(5-nitropyridin-2-yl)oxy]phenyl}carbamate (15 g, 42.9 mmol) in methanol (300 mL) was added 5 wt % palladium/carbon (3.0 g), and the mixture was stirred at room temperature for 8 hr under a hydrogen atmosphere. After nitrogen substitution, insoluble material was collected by filtration and washed with methanol. The solvent of the filtrate was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure to give the title compound (12.3 g, 90%).
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[C:14]([OH:16])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:17]([N:19]1[CH:23]=[C:22]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[CH:21]=[N:20]1)[CH3:18]>>[CH2:17]([N:19]1[CH:23]=[C:22]([CH2:24][N:25]([C:26]2[CH:27]=[CH:28][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:30][CH:31]=2)[C:14]([CH:11]2[C:12]3[C:7](=[CH:6][CH:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:13]=3)[CH2:8][CH2:9][CH2:10]2)=[O:16])[CH:21]=[N:20]1)[CH3:18]
Reactant: CC(C)c1ccc2c(c1)C(C(=O)O)CCC2
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Product: CCn1cc(CN(C(=O)C2CCCc3ccc(C(C)C)cc32)c2ccc(C(C)C)cc2)cn1
Yield: 68.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-isopropyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.33 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-7-isopropyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.46 g) was obtained.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[NH2:28][CH2:29][CH2:30][CH2:31][CH2:32][OH:33]>>[OH:33][CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:23]([C:22]1[CH:26]=[CH:27][C:19]([C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:12][CH2:13]2)=[O:18])=[CH:20][CH:21]=1)=[O:25]
Reactant: NCCCCO
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCCCO)cc2)CC1
Yield: 84 %

Procedure:
By the same procedure as described in the example 1, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid and using 4-amino-1-butanol. Then, the product was recrystallized using ethyl acetate and isopropyl ether to give the desired compound.