Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([C:27]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28])[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=2[O:25][CH3:26])[CH2:14][CH2:13]1)#[N:2].NC1C=CC=CC=1N(C(C1CCCCC1)=O)CCN1CCN([C:51]2C=CC=C[C:52]=2[O:57]C)CC1>>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([C:27]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28])[CH2:10][CH2:11][N:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:52](=[O:57])[CH3:51])=[CH:20][C:19]=2[O:25][CH3:26])[CH2:16][CH2:17]1)#[N:2]
Reactant: COc1ccccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2N)CC1
Reactant: COc1cc(N)ccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2C#N)CC1
Product: COc1cc(NC(C)=O)ccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2C#N)CC1
Temperature: 22.5 °C
Reaction time: 17 h

Procedure:
The title compound was synthesized according to the procedure reported in example 28 but substituting the compound of example 79 for the compound of example 27 and stirring at 20-25° C. for 17 h. The usual work-up afforded the title compound. Yield: 49%.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.[CH3:21][S:22][CH2:23][CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:24][CH2:23][S:22][CH3:21])=[CH:16][CH:15]=1
Reactant: CSCCO
Reactant: Oc1ccc(Br)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
Diethyl azodicarboxylate (13.4 g) was added over a period of 20 minutes to a stirred solution of 4-bromophenol (12 g), 2-methylthioethanol (6.4 g) and triphenylphospine (18.2 g) in tetrahydrofuran (250 ml) at -5° C. under an atmosphere of argon. The mixture was stirred at ambient temperature for 1 hour and the solvent was then removed by evaporation. The residue was partitioned between dichloromethane (150 ml) and water (150 ml). The aqueous phase was separated and extracted with dichloromethane (150 ml). The dichloromethane extracts were combined, washed with water (2×100 ml), dried (MgSO4) and evaporated. The residue was dissolved in a boiling mixture of toluene (50 ml) and n-heptane (50 ml). The solution was chilled and the precipitated triphenylphosphine oxide removed by filtration. The filtrate was evaporated and purified by medium pressure chromatography on silica gel using a 1:1 (v/v) mixture of toluene/n-heptane as eluent to give 1-(4-bromophenoxy)-2-methylthioethane as an oil (10.2 g); NMR(CDCl3): 2.2(3H,s), 2.88(2H,t), 4.12(2H,t), 6.77(2H,d) and 7.37(2H,d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([NH:18][S:19]([C:22]2[N:23]=[CH:24][N:25]([CH3:27])[CH:26]=2)(=[O:21])=[O:20])[CH:15]=[C:14]2[C:9]=1[CH2:10][N:11](CC1C=CC(OC)=CC=1)[C:12](=[O:36])[N:13]2[C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:35]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([NH:18][S:19]([C:22]2[N:23]=[CH:24][N:25]([CH3:27])[CH:26]=2)(=[O:21])=[O:20])[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:36])[N:13]2[C:28]1[C:29]([Cl:35])=[CH:30][CH:31]=[CH:32][C:33]=1[Cl:34]
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(NS(=O)(=O)c4cn(C)cn4)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cnc(S(=O)(=O)Nc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)c1

Procedure:
A solution of N-[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]-1-methyl-1H-imidazole-4-sulfonamide (114 mg, 0.17 mmol) in 1.5 mL of trifluoroacetic acid was stirred at rt overnight. The resulting reaction mixture was concentrated under reduced pressure, diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 followed by brine. The organic layer was dried with Na2SO4 and concentrated under reduced pressure. The crude solid was purified by preparatory thin-layer chromatography, eluting with 90:10 CH2Cl2-2M NH3 in methanol to yield N-[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]-1-methyl-1H-imidazole-4-sulfonamide. Mass spectrum (ESI) 562 (M+1). 1H NMR (500 MHz, DMSO-d6): δ 3.67 (s, 3H); 3.93 (½ ABq, J=14.9 Hz, 1H); 3.99 (½ ABq, J=14.9 Hz, 1H); 4.02 (s, 1H); 5.95 (d, J=2.1 Hz, 1H); 6.55 (d, J=1.9 Hz, 1H); 7.30 (m, 2H); 7.35 (s, 1H); 7.43 (m, 2H); 7.58 (m, 2H); 7.69 (s, 1H); 7.72 (d, J=8.2 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[CH3:6][C:7]([CH3:51])([CH2:49][CH3:50])[CH2:8][C:9]1[N:10]=[C:11]([CH2:33][CH:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)=[CH:38][CH:37]=2)[NH2:35])[N:12]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1.C(N(CC)CC)C>ClCCl>[CH3:6][C:7]([CH3:51])([CH2:49][CH3:50])[CH2:8][C:9]1[N:10]=[C:11]([CH2:33][CH:34]([NH:35][C:3](=[O:4])[O:2][CH3:1])[C:36]2[CH:37]=[CH:38][C:39]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)=[CH:40][CH:41]=2)[N:12]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:13]=1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(N)c2ccc(-c3ccc(F)cn3)cc2)n1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(NC(=O)OC)c2ccc(-c3ccc(F)cn3)cc2)n1
Reaction time: 2 h

Procedure:
Methylchoroformate (16 μL, 0.21 mmol) was added to a solution of 2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethanamine (64 mg, 0.11 μmol) and triethylamine (31 μL, 0.22 mmol) in dichloromethane (5 mL) at ambient temperature. After stirring for 2 hr, the reaction mixture concentrated in vacuo to afford methyl {2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethyl}carbamate which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.[C:22]([O:27][CH3:28])(=[O:26])[C:23]([CH3:25])=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([C:22]([O:27][CH3:28])=[O:26])[CH3:25])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: COC(=O)C(C)=O
Reactant: NNC1=Nc2ccc(F)cc2C(c2ccccc2Cl)=NC1
Product: COC(=O)C(C)=NNC1=Nc2ccc(F)cc2C(c2ccccc2Cl)=NC1

Procedure:
In the manner given in Example 1, 7-fluoro-2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be stirred with methyl pyruvate at room temperature to give 7-fluoro-2-[[1-(methoxycarbonyl)ethylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([F:23])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.[NH2:24][C@@H:25]([C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([Br:42])[CH:36]=1)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:24][C@@H:25]([C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([Br:42])[CH:36]=3)[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:20])=[C:16]([F:23])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: Nc1ncc(C2CCOCC2)nc1-c1ccc(C(=O)O)c(F)c1
Reactant: CC(C)(C)OC(=O)NC[C@@H](N)c1cc(F)cc(Br)c1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC[C@@H](NC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoic acid (35 mg, 0.110 mmol) in DMF (368 μl) was added (S)-tert-butyl (2-amino-2-(3-bromo-5-fluorophenyl)ethyl)carbamate (40.8 mg, 0.110 mmol), aza-HOBt (22.52 mg, 0.165 mmol). EDC (31.7 mg, 0.165 mmol), and DIEA (57.8 μl, 0.331 mmol). The reaction mixture was stirred at room temperature for 3 h, and then partitioned between EtOAc and water. The organic was washed by NaHCO3, water and brine, dried over Na2SO4 and concentrated. The crude (S)-tert-butyl (2-(4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzamido)-2-(3-bromo-5-fluorophenyl)ethyl)carbamate was used in next step reaction without further purification. LCMS (m/z): 632.1/634.1 (MH+), 0.97 min.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[Na].[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:12][N:13]=[N+:14]=[N-:15]>C(O)C>[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:12][N:13]1[C:1]([NH2:2])=[C:3]([C:4]([NH2:6])=[O:5])[N:15]=[N:14]1
Reactant: N#CCC(N)=O
Reactant: [N-]=[N+]=NCc1ccc(Cl)c(Cl)c1
Agent: [Na]
Solvent: CCO
Product: NC(=O)c1nnn(Cc2ccc(Cl)c(Cl)c2)c1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A stirred mixture of 3,4-dichlorobenzyl chloride (12.6 g, 64.5 mmol) and sodium azide (7.0 g, 0.11 mole) in absolute ethanol (70 ml) was refluxed for 4.75 hours, cooled and filtered to provide a solution of 3,4-dichlorobenzyl azide. Separately, 2-cyanoacetamide (5.5 g, 65 mmol) was added to a 35° C. solution of sodium (1.5 g, 65 mmol) in absolute ethanol (125 ml), and to the resulting suspension was added the above azide solution dropwise over 10 minutes. The combined mixtures were refluxed for 1 hour, kept 16 hours at ambient temperature and 1 hour at 5° C., and filtered. The crude product was dried under vacuum, dissolved in boiling ethanol (290 ml), filtered hot, and cooled to 0° C. The solid was collected by filtration and dried under vacuum to provide 12.4 g (67%) of 1-(3,4-dichlorobenzyl)-5-amino-1,2,3-triazole-4-carboxamide, m.p 221°-222° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:10]([O-])=O)=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[O:13]1CC[CH2:15][CH2:14]1.C(OC(=O)C)(=O)C>C(O)C.[Pd].C(OCC)(=O)C>[CH3:9][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:10][C:14](=[O:13])[CH3:15]
Reactant: C1CCOC1
Reactant: COc1cccc(C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: COc1cccc(C)c1NC(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87 %

Procedure:
To a solution of 3-methyl-2-nitroanisole (10.00 g, 59.8 mmol) in ethanol (60 mL)-tetrahydrofuran (60 mL) is added a 10% palladium on carbon (50% wet, 2.00 g), and the mixture is subjected to hydrogenation, and stirred at room temperature for 1.5 hour. After the reaction is completed, the reaction solution is filtered through celite, and the solvent is evaporated under reduced pressure. To a solution of the residue in ethyl acetate (110 ml) is added acetic anhydride (9.0 mL, 95.2 mmol), and the mixture is refluxed for 5 hours. The reaction solution is cooled with ice, and the precipitated solid is collected by filtration, and washed with hexane to give the title compound (9.28 g, yield: 87%).
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[H-].[Na+].Br[CH2:21][CH2:22][O:23]C1CCCCO1>CN(C)C=O>[C:1]([N:11]1[CH2:16][CH2:15][N:14]([CH2:21][CH2:22][OH:23])[C:13](=[O:17])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: BrCCOC1CCCCO1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1CCO
Reaction time: 20 h

Procedure:
To a solution of 1-carbobenzoxypiperazin-3-one (234 mg, 1.0 mmol) in dimethylformamide (10 ml) under nitrogen was added in one portion, 50% sodium hydride (48 mg, 1 mmol). After stirring at 20°-25° for 30 minutes until all of the sodium hydride had reacted, a solution of 2-(2-bromoethoxy)-tetrahydropyran (209 mg, 1 mmol) in dimethylformamide (2 ml) was added and the reaction mixture stirred at 20°-25° for 20 hours. Solvent was removed at 40°-45° and 0.1 mm and the residue chromatographed over silica gel. Elution with 2% isopropanol -98% methylene chloride gave the pure protected alcohol as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].CC(C)([O-])C.[Na+]>CO.C1C=CC=CC=1.C1C=CC=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:10])[CH3:9]
Reactant: CC(=O)c1ccccc1Cl
Agent: Cl[Ru]Cl
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: CC(O)c1ccccc1Cl
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Benzeneruthenium(II) chloride dimer (0.5 mg, 1 μmol, 0.25 mol %) and a chiral ligand (M=Ru, R=t-Bu, Ar=C6H5—, 2.6 μmol, 0.33 mol %) were dissolved in methanol (3 mL) under nitrogen atmosphere, and then heated and stirred for 2 h at 65° C. After the mixture was cooled to room temperature, o-chloroacetophenone (0.8 mmol), methanol (2 mL) and a solution of sodium t-butoxide in methanol (0.4 mL, 0.2 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 6 h under H2 (40 atm) at 50° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent:ethyl acetate/petroleum ether=1/5). Accordingly, pure 1-(o-chlorophenyl)ethanol was obtained and the ee value (ee=97%) was measured by GC analysis.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:20][CH2:21][CH2:22][OH:23])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]([C:26]1[CH:27]=[C:28](O)[CH:29]=[CH:30][CH:31]=1)#[N:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:20][CH2:21][CH2:22][O:23][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([C:24]#[N:25])[CH:31]=1)[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCO)C(=O)OCc1ccccc1
Reactant: N#Cc1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCCOc1cccc(C#N)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.77 g (21 mmol) of benzyl 2-(2R)-t-butoxycarbonylamino-5-hydroxypentanoate was dissolved in 105 ml of tetrahydrofuran. 2.74 g (23 mmol) of 3-cyanophenol, 6.6 g (25 mmol) of triphenylphosphine and 10 g (23 mmol) of diethyl azodicarboxylate (40% solution in toluene) were added to the solution, and they were stirred at room temperature for one hour. The solvent was distilled off, and the residue was treated with ethyl acetate as the extractant in an ordinary manner. The solvent was distilled off, and the residue was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([O:29][CH2:30][C@@H:31]3[CH2:34][CH2:33][N:32]3[C:35](OC(C)(C)C)=O)[CH:28]=2)[CH2:19][CH2:18]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].CCOCC>C1COCC1.O>[CH2:7]([O:14][CH2:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([O:29][CH2:30][C@@H:31]3[CH2:34][CH2:33][N:32]3[CH3:35])[CH:28]=2)[CH2:21][CH2:22]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(N2CCC(CCOCc3ccccc3)CC2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CN1CC[C@H]1COc1cncc(N2CCC(CCOCc3ccccc3)CC2)c1
Temperature: 25 °C
Yield: 102.2 %

Procedure:
To a suspension of lithium aluminum hydride (45 mg, 1.2 mmol, 5.0 equiv.) in THF (1.5 mL) was added a solution of 3-[4-[2-(benzyloxy)ethyl]-1-piperidinyl]-5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]pyridine (115 mg, 0.24 mmol) in THF (0.5 mL). The mixture was refluxed for 1 h, then cooled to room temperature. To a flask containing 4-5 g of Na2SO4 was added with stirring 40-50 mL of Et2O followed by the cooled reaction mixture. Water was subsequently added dropwise to quench residual hydride. When no more gas was generated, the mixture was filtered, and the solid phase was washed with CH2Cl2/MeOH 4:1 (100-150 mL). Solvent removal furnished crude 3-[4-[2-(benzyloxy)ethyl]-1-piperidinyl]-5-[(1-methyl-2(S)-azetidinyl)methoxy]pyridine (97 mg, 100%), which was used in the following step without purification.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(O)(=O)C.Br>O>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)=[CH:16][N:17]=2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(-c2ncc(-c3ccc(OC)cc3)s2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)s2)cc1
Reaction time: 16 h
Yield: 74.9 %

Procedure:
Then, in a 300 ml-three-necked flask, 13.9 g (39.3 mM) of 2-(4-hexylphenyl)-5-(4-methoxyphenyl)thiazole, 76.5 ml of acetic acid and 69.5 ml of 47%-hydrobromic acid were placed, followed by heat-stirring for 16 hours at 100°-110° C. After the reaction, the reaction mixture was poured into cool water, followed by extraction with ethyl acetate. The organic layer was successively washed with water, 5%-sodium hydrogencarbonate aqueous solution and water, followed by distilling-off of the solvent under reduced pressure. The residue was dissolved in a mixture solvent of ethanol/chloroform=1/1, followed by decolorization with activated carbon and distilling-off of the solvent under reduced pressure. The resultant residue was recrystallized two times from toluene to obtain 10.0 g of 2-(4-hexylphenyl)-5-(4-hydroxyphenyl)thiazole (Yield: 75.8%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:25][CH:24]=1)[C:3]([N:5]([CH2:14][CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[N:8]=1)=[O:4].[CH2:34]([NH:41][C:42]([NH:44][N:45]([CH2:50][CH:51]=[CH2:52])[CH2:46][C:47](O)=[O:48])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[CH2:34]([NH:41][C:42]([NH:44][N:45]([CH2:50][CH:51]=[CH2:52])[CH2:46][C:47]([NH:1][C@@H:2]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[CH:27][CH:28]=1)[C:3]([N:5]([CH2:14][CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[N:8]=1)=[O:4])=[O:48])=[O:43])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: C=CCN(CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(CN(Cc1cccc(F)n1)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C=CCN(CC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc(F)n1)CC(OCC)OCC)NC(=O)NCc1ccccc1
Yield: 90.4 %

Procedure:
To a mixed solution of (2S)-2-amino-3-(4-(tert-butoxy)phenyl)-N-(2,2-diethoxyethyl)-N-((6-fluoropyridin-2-yl)methyl)propanamide (881 mg, 1.91 mmol) described in Production Example 2-2 and DMF (10.0 mL) were added 2-(((benzylcarbamoyl)amino)(prop-2-en-1-yl)amino)acetic acid (503 mg, 1.91 mmol) described in International Publication No. 2009148192, triethylamine (532 μL, 3.82 mmol) and HATU (871 mg, 2.29 mmol) at room temperature. The resultant mixture was stirred at room temperature for 35 minutes. Water was added to the reaction mixture, and the resultant solution was extracted with ethyl acetate. An organic layer was washed with water and saturated brine, was then dried over anhydrous magnesium sulfate, and was then filtrated. The solvent was evaporated under a reduced pressure, the resultant residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1) to give the title compound (1.22 g, yield: 91%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24]=[C:25]=[O:26].O.N.C(OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:25]([NH:24][CH3:23])=[O:26])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN=C=O
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccccc2N)CC1
Agent: N
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)Nc1ccccc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
After dissolving 400 mg of 1-(tert-butoxycarbonyl)-4-(2-aminophenoxymethyl)piperidine in 10 ml of tetrahydrofuran, 458 mg of methyl isocyanate was added and the mixture was stirred overnight at room temperature. Ammonia water was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then filtered with NH silica gel. The solvent was distilled off under reduced pressure to obtain the title compound (469 mg, 99% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[C:19]([C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1)#[CH:20].[I-]>CN(C)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.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:20]#[C:19][C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Reactant: C#Cc1cncnc1
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)c1ccc(C#Cc2cncnc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.5 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (719 mg, 2.01 mmol) and triethylamine (3 mL, 0.015 mmol) in N,N-dimethylformamide (3 mL) was treated with 5-ethynyl-pyrimidine (230 mg, 2.21 mmol). The resulting reaction mixture was degassed with argon for 10 min and then treated with cooper iodide (92 mg, 0.48 mmol) and bis(triphenylphosphine)palladium (II) chloride (169 mg, 0.24 mmol). The reaction was stirred at 25° C. for 18 h and then heated at 67° C. for 2 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-pyrimidin-5-ylethynyl-phenyl)-propionic acid methyl ester (440 mg, 66%) as an orange oil: EI-HRMS m/e calcd for C21H22N2O2 (M+) 334.1681, found 334.1681.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[N:8]=[C:7]([CH:9]([CH3:23])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([F:22])[CH:11]=2)[O:6][N:5]=1.[C:24]([O-:27])(=[S:26])[CH3:25].[K+]>CN(C=O)C>[C:24]([S:26][CH2:2][CH2:3][C:4]1[N:8]=[C:7]([CH:9]([CH3:23])[C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([F:22])[CH:11]=2)[O:6][N:5]=1)(=[O:27])[CH3:25]
Reactant: CC([O-])=S
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CCCl)no1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SCCc1noc(C(C)c2ccc(-c3ccccc3)c(F)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of 2.44 g of 3-(2-chloroethyl)-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole in 40 ml of DMF was added 1.69 g of potassium thioacetate. After stirring at room temperature overnight, the reaction mixture was poured into ice-water. The resultant mixture was extracted with benzene and the organic phase was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed over silica gel using benzene to yield 2.62 g of 3-(2-acetylthioethyl)-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole as a light brown oil. It was crystallized from diisopropyl ether to give colorless needles, m.p. 56°-57° C.