Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:5]=1.C([O-])(O)=O.[Na+].Cl[S:24]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]=[CH:34][C:35]([OH:37])=[O:36])=[CH:29][CH:28]=1)(=[O:26])=[O:25].Cl>O1CCOCC1.O>[F:17][C:3]([F:2])([F:16])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([S:24]([C:27]3[CH:28]=[CH:29][C:30](/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36])=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)/C=C/c1ccc(S(=O)(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)cc1
Yield: 82.7 %

Procedure:
To a suspension of 1-(α,α,α-trifluoro-m-tolyl)piperazine hydrochloride (0.43 g, 1.62 mmol) in dioxane (5 mL) a solution of NaHCO3 (0.27 g, 3.24 mmol) in water (4 mL) and a solution of 3-(4-chlorosulfonyl-phenyl)-acrylic acid (8) (0.40 g, 1.62 mmol) were added and the resultant mixture was stirred at ambient temperature for 20 hours. The reaction mixture was poured into water (50 mL) and the pH of the medium was brought to ˜4 with 2 N HCl. The precipitated solid was filtered, washed with water, and dried in vacuum to give the title compound (0.59 g, 82%). 1H NMR (DMSO-d6, HMDSO), δ: 2.96-3.67 (8H, m, overlapped with a signal of water); 6.74 (1H, d, J=16.3 Hz); 7.01-7.57 (4H, m); 7.67 (1H, d, J=16.3 Hz); 7.82 (2H, d, J=8.4 Hz); 8.00 (2H, d, J=8.4 Hz); 12.71 (1H, br s).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1.C(=O)(O)[O-].[Na+]>C(O)C>[N+:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:15]#[N:16])=[C:2]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1)([O-:14])=[O:13]
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: Cc1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1
Yield: 73.7 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-3-quinolinecarbonitrile, 200 ml ethanol, and 2.75 ml (25.7 mmol) 3-toluidine was heated to reflux for 4.5 hours. Cooled and added a saturated sodium bicarbonate until pH was basic. Stripped solvents and azeotroped with ethanol. Slurried with hexane, collected, and air dried. Washed with water and dried in vacuo. Boiled in ethyl acetate, stirred with Darco and filtered. Stripped solvent and dried in vacuo to give 4.82 g of yellow-orange solid: mass spectrum (electrospray m/e): M+H=305.2.
Reaction SMILES: C([O:8][C:9]1[C:14]([O:15][CH3:16])=[C:13]([CH3:17])[N:12]=[C:11]([CH3:18])[C:10]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])C1C=CC=CC=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl.CCO.[Pd]>[CH2:19]([C:10]1[C:9](=[O:8])[C:14]([O:15][CH3:16])=[C:13]([CH3:17])[N:12]([OH:34])[C:11]=1[CH3:18])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCCc1c(C)nc(C)c(OC)c1OCc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCCc1c(C)n(O)c(C)c(OC)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 20 (19 mg, 0.66 mmol) and mCPBA (125 mg, 0.72 mmol) in anhydrous CH2Cl2 (2 mL) was stirred at 0° C. for 1 hr under argon atmosphere, the solution was washed with aqueous NaHCO3 dried over anhydrous MgSO4 and concentrated under diminished pressure to afford a crude residue. The residue was dissolved in EtOH, Pd/C was added and after applying an H2 atmosphere (1 bar), the solution was stirred at room temp for 30 min, After filtration through celite, which was thoroughly washed with EtOH, the filtrate was concentrated under diminished pressure and purified by chromatography on a silica gel column. Elution with 20:1 ethyl acetate/methanol gave 3-heptyl-1-hydroxy-5-methoxy-2,6-dimethylpyridin-4(1H)-one (CPD-5) as a light yellow oil; yield 9 mg (61%); silica gel TLC Rf 0.25 (3:1 ethyl acetate/methanol); 1H NMR (CDCl3) δ 0.84-0.89 (m, 3H), 1.24-1.35 (m, 10H), 2.45 (s, 3H), 2.50 (s, 3H) 2.63-2.67 (m, 2H) and 3.74 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:30])[NH:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])=[CH:16][CH:15]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:30])[NH:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:18][CH:19]=1
Reactant: CCOC(=O)CCNC(=O)Nc1ccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(NC(=O)NCCC(=O)O)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of ethyl 3-(3-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)ureido)propanoate (150 mg, 0.33 mmol, 1.00 equiv) in methanol (10 mL), water (2 mL) and sodium hydroxide (80 mg, 2.00 mmol). The resulting solution was stirred for 2 h at 25° C. and the resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 7-8 with hydrogen chloride. The resulting solution was extracted with chloroform (3×10 ml) and the organic layers combined and dried over sodium sulfate. This resulted in 31.5 mg (22%) of 3-(3-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)ureido)propanoic acid as a white solid. 1H-NMR (300 MHz, DMSO, ppm): δ 8.56 (1H, s), 7.45 (1H, s), 7.29-7.32 (2H, d, J=8.1 Hz), 7.04-7.07 (2H, d, J=8.4 Hz), 6.79 (1H, s), 6.21 (1H, s), 4.16 (1H, m), 3.56-3.58 (2H, d, J=5.4 Hz), 3.27-3.29 (2H, d, J=6 Hz), 2.82-2.87 (1H, m), 2.59 (2H, s), 2.38-2.40 (4H, m). MS (ES, m/z): 422 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13](OS(C(F)(F)F)(=O)=O)[C:12]=1[N+:25]([O-:27])=[O:26].[CH:28]1([C@@H:31]([NH2:34])[CH2:32][CH3:33])[CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:34][C@H:31]([CH:28]2[CH2:30][CH2:29]2)[CH2:32][CH3:33])[C:12]=1[N+:25]([O-:27])=[O:26]
Reactant: CC[C@H](N)C1CC1
Reactant: COc1cc(Cl)c(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])cc1F
Product: CC[C@H](Nc1nccc(-c2cc(F)c(OC)cc2Cl)c1[N+](=O)[O-])C1CC1
Yield: 11.3 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-5-fluoro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl ester (0.3 g, 0.70 mmol) and (S)-1-cyclopropyl-propylamine (0.28 g, 2.09 mmol) were treated substantially as described in Part C of Example 19a to produce 30 mg (12%) of crude (S)-[4-(2-chloro-5-fluoro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[C:10](Cl)([Cl:12])=[O:11]>>[Cl:12][C:10]([O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=1)=[O:11]
Reactant: O=C(Cl)Cl
Reactant: OCc1cccc(Cl)c1
Product: O=C(Cl)OCc1cccc(Cl)c1

Procedure:
Prepared according to the procedure described in Example 56, Step 1, using the following starting materials: 3-chlorobenzyl alcohol and phosgene (20% in toluene).
Reaction SMILES: [Cl:1]C1C=CC(N)=CC=1[N+]([O-])=O.C(Cl)(Cl)Cl.ClC1C=CC(N[S:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])(=[O:26])=[O:25])=CC=1[N+]([O-])=O>N1C=CC=CC=1>[CH2:27]([S:24]([Cl:1])(=[O:26])=[O:25])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Nc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCS(=O)(=O)Cl

Procedure:
Hexadecanesulfonylchloride, which was prepared by the method as described in J. M. Sprague, et al., J. Amer. Chem. Soc., Vol. 59, page 1837 (1937), was reacted with 2-chloro-5-aminonitrobenzene in a chloroform solution in the presence of pyridine to prepare 2-chloro-5-hexadecanesulfonamidonitrobenzene.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[Br-:12].[K+].BrBr>O>[Br:12][C:8]1[CH:9]=[C:2]([F:1])[C:3]([O:10][CH3:11])=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: [Br-]
Reactant: COc1cc(C=O)ccc1F
Agent: BrBr
Agent: [K+]
Solvent: O
Product: COc1cc(C=O)c(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
A solution of 4-fluoro-3-methoxybenzaldehyde (4.3 g, 28 mmol), potassium bromide (16.6 g, 140 mmol), bromine (3.6 mL, 70 mmol), and water (45 mL) were stirred at room temperature for 24 hours. More bromine (1.4 mL, 28 mmol) was added and the reaction was stirred at room temperature overnight. The product precipitated out of solution and was collected via filtration and dried under reduced pressure to give 2-bromo-4-fluoro-5-methoxybenzaldehyde (6.01 g, 92%).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[NH:9][CH2:10][CH2:11][N:12]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=1.I[CH3:31]>CN(C=O)C>[CH3:31][N:9]([C:4]1[N:5]=[CH:6][CH:7]=[CH:8][N:3]=1)[CH2:10][CH2:11][N:12]([CH2:25][C:26]([F:27])([F:28])[F:29])[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:23])([F:22])[F:24])[CH:14]=1
Reactant: CI
Reactant: N#Cc1ccc(N(CCNc2ncccn2)CC(F)(F)F)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1)c1ncccn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 68.1 %

Procedure:
NaH (60% in oil, 0.003 g, 0.075 mmol) was added to an ice-cold solution of 4-[[2-(pyrimidin-2-ylamino)ethyl](2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.020 g, 0.051 mmol) in DMF (3 mL), under N2. After stirring for 5 min, iodomethane (0.011 g, 0.078 mmol) was added and stirred for 30 min. The mixture was partitioned between Et2O and water. The organic phase was washed with water and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (5-50% EtOAc/hexanes gradient) and the product crystallized from CH2Cl2/hexanes to give the title compound as a white solid (0.014 g, 68% yield): MS (ES) m/z 404 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[S:8][C:4]=2[C:3]=1[CH:12]=[O:13].[CH3:14][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[CH3:14][O:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[S:8][C:4]=2[C:3]=1[CH:12]=[O:13]
Reactant: Cc1nc2ccc(O)c(C=O)c2s1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COc1ccc2nc(C)sc2c1C=O

Procedure:
6-Hydroxy-2-methyl-benzothiazole-7-carboxaldehyde (75 mg, 0.362 mmol) was taken up in 30% methanol in benzene (7 mL) and treated with (trimethylsilyl)diazomethane (2.0M solution in hexanes) (0.5 mL, 1.0 mmol) for 2 hours at room temperature. The mixture was evaporated, and the title compound was purified by flash chromatography eluting with 25-30% ethyl acetate in hexane.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH3:11])[N:5]=1)([CH3:3])=[CH2:2].[Cl:12]N1C(=O)CCC1=O.C1C=CC=CC=1>CCCCCC>[Cl:12][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH3:11])[N:5]=1)=[CH2:3]
Reactant: C=C(C)c1cccc(SC)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCCCCC
Solvent: c1ccccc1
Product: C=C(CCl)c1cccc(SC)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
A mixture of 14.5 g of 2-isopropenyl-6-methylthiopyridine, 12.9 g of N-chlorosuccinimide and 30 ml of benzene was stirred at 80° C. for 1 hour. After the reaction mixture was cooled to room temperature, n-hexane was added thereto to remove the insoluble matter through filtration. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with n-hexane then n-hexane - ethyl acetate 20:1) to obtain 4.3 g of the objective compound.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[CH3:30][O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>CCCCCC.C(OCC)(=O)C>[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([CH:7]2[C:6]3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]([CH3:29])=[C:2]([C:36]4[CH:35]=[CH:34][CH:33]=[C:32]([O:31][CH3:30])[CH:37]=4)[C:10]=3[O:9][CH2:8]2)=[CH:16][CH:15]=1)([CH3:18])[CH3:19]
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cccc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)c1
Yield: 64 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (3-methoxyphenyl)boronic acid, the title compound was synthesized in the same manner as in Example 101. Yield: 64%. Melting point: 209-210° C. (hexane-ethyl acetate).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[C:6]1([CH3:16])[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.Cl>C(Cl)Cl.[OH-].[Na+]>[CH2:1]([NH:5][S:12]([C:9]1[CH:10]=[CH:11][C:6]([CH3:16])=[CH:7][CH:8]=1)(=[O:14])=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCNS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Dissolve butylamine (10 mmol) in methylene chloride (50 mL) and 10% sodium hydroxide (50 mL). Cool to 0° C. Add excess p-toluenesulfonyl chloride with stirring. After 1 hour allow the reaction to warm to room temperature and stir for 2 days. Neutralize the reaction with 0.5N hydrochloric acid and extract the aqueous with methylene chloride (2×100 mL). Rinse the combined organic extracts with water (100 mL), brine (100 mL), dry over anhydrous sodium sulfate, filter and concentrate under vacuum to provide N-butyl-4-methyl-benzenesulfonamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH:11]=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].CO.[CH2:15](Cl)CCl>C(#N)C.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH:11]=[O:12])[CH:10]=1)[C:5]([O:7][CH3:15])=[O:6]
Reactant: ClCCCl
Reactant: O=Cc1cc(Br)cc(C(=O)O)c1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CC#N
Product: COC(=O)c1cc(Br)cc(C=O)c1
Temperature: -10 °C
Reaction time: 20 h

Procedure:
6.2 g (27.1 mmol) of 3-bromo-5-formylbenzoic acid (J. Org. Chem., 2002, 67, 3548-3554) are dissolved in 110 ml of acetonitrile under argon. 330 mg (2.7 mmol) of 4-dimethylaminopyridine and 1.73 ml (54.2 mmol) of methanol are added thereto. The mixture is cooled to −10° C., and 6.23 g (32.5 mmol) of EDC are added. The mixture is slowly allowed to reach RT and is then stirred for 20 h. The solvent is then evaporated in vacuo, and the residue is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate (6:1)).
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[N:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[C:7]([CH3:23])=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>N1C=CC=CC=1>[CH2:39]([O:38][C:36]([NH:1][C:2]1[N:34]=[C:5]2[N:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[CH:25]=3)[C:7]([CH3:23])=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1)=[O:37])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc(N)nn2C1c1ccc(C#N)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc(NC(=O)OCc3ccccc3)nn2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, ethyl 2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (130 mg, 278 μmol) was dissolved in abs. pyridine (3.6 ml). At 0° C., benzyl chloroformate (379 mg, 2.2 mmol, 8 eq.) was added in four portions and the mixture was stirred for 12 h with warming to RT. Once HPLC analysis showed substantial conversion, the reaction mixture was concentrated under reduced pressure, and the residue was taken up in acetonitrile, acidified with 1 N hydrochloric acid and then purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (146.3 mg, 87% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18]C(C)C)[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.B(Cl)(Cl)Cl.CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc3ccc(OC(C)C)cc3s2)cc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(-c2cc3ccc(O)cc3s2)cc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
2-(4-Methoxyphenyl)-6-isopropoxybenzo[b]thiophene (1.0 g, 3.35 mmol) was dissolved in 10 mL of methylene chloride and warmed to 30° C. Boron trichloride (3.685 mL, 3.685 mmol 1M in methylene chloride) was slowly added to the stirring reaction solution. The reaction was allowed to proceed for one hour at ambient temperature. The reaction was quenched with the dropwise addition of methanol (0.536 g, 16.75 mmol). The reaction was stirred for two hours and a white precipitate formed. The solid was filtered off, was hed three times with 10 mL portions of methylene chloride and dried to yield the title compound as a white solid. EA calculated for C15H12O2S: C, 70.29; H, 4.72; S, 12.51. Found: C, 67.69; H, 4.65; S, 12.02. MS(FD): m/e=256 (M+).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11].Cl.C1C(=O)N([O:23][C:24]([O:26][CH2:27][CH:28]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]3[C:29]2=[CH:30][CH:31]=[CH:32][CH:33]=3)=O)C(=O)C1>C(=O)([O-])O.[Na+].COCCOC>[NH:8]([C:24]([O:26][CH2:27][CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]2[C:40]1=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:23])[C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: N[C@@H](CO)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: O=C(N[C@@H](CO)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
Under cooling on ice, sodium hydride (3.19 g, 133 mmol) was added to a solution of Boc-Ser (12.3 g, 53.9 mmol) in DMF (300 ml) and stirred at room temperature for 1.5 hours. Octane iodide (11.0 ml, 60.9 mmol) was added thereto and stirred at room temperature for 16 hours. After water (40 ml) was added dropwise to the reaction solution under cooling on ice, the solvent was evaporated under vacuum. The resulting residues were purified by applying them to silica gel column chromatography (gel; Art9385, Merck Co., Ltd, eluent; dichloromethane:methanol:acetic acid=120:10:1), to give 6.88 g Boc-Ser (C8H17) (yield, 36.2%) as pale yellow oily matter. Trifluoroacetic acid (120 ml) was added to this product, Boc-Ser (C8H17) (6.88 g, 21.7 mmol), under cooling on ice and stirred for 0.5 hour at room temperature. After the trifluoroacetic acid was evaporated, the resulting residues were dissolved in diethyl ether (120 ml), and 4N HCl-dioxane (22 ml) was added thereto and stirred for 1 hour under cooling on ice. The precipitated crystals were recovered by filtration to give 5.23 g H-Ser (C8H17) HCl (yield, 96.3%) as colorless crystals. After triethylamine (1.40 ml, 10 mmol) was added to a suspension (50 ml) of this product H-Ser (C8H17).HCl (2.54 g, 10.0 mmol) in 10% sodium hydrogen carbonate, a solution of Fmoc-Osu (5.00 g, 14.8 mmol) in 1,2-dimethoxyethane (20 ml) was added dropwise thereto over the period of 10 minutes and stirred at room temperature for 16 hours. The insolubles were filtered off, then dichloromethane was added to the filtrate, and the organic phase was separated and washed with 13% NaCl solution. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The resulting residues were purified by applying them to silica gel column chromatography (gel; BW-300, Fuji Silicia Co., Ltd, eluent; dichloromethane:methanol=93:7), to give 2.75 g Fmoc-Ser (C8H17) (yield: 62.6%) as colorless crystals. Rf=0.45 (CHCl3: MeOH=9:1, Silica gel 60F254, MERCK CO., Ltd). Fmoc-DSer(C8H17): Rf=0.45 (CHCl3: MeOH=9:1, Silica gel 60F254, MERCK Co., Ltd).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH3:15][N:16]=[C:17]=[O:18].C(N(CC)CC)C>C(Cl)Cl>[CH:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[O:6][C:5]=2[CH:13]=[CH:14][C:2]=1[O:1][C:17](=[O:18])[NH:16][CH3:15]
Reactant: Oc1ccc2oc3ccccc3c2c1
Reactant: CN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1ccc2oc3ccccc3c2c1
Yield: 84 %

Procedure:
A solution of 2-hydroxydibenzofuran (5.0 g, 27 mmol), methyl isocyanate (1.9 mL, 32 mmol) and triethylamine (3.0 mL, 22 mmol) in 75 mL of methylene chloride was stirred under nitrogen at room temperature overnight. During this time a solid formed. Additional methylene chloride was added and the solid dissolved. The reaction was then extracted with 1N HCl, dried (MgSO4) and the solvent removed under reduced pressure to give 5.47 g of a yellow solid. Recrystallization from isopropyl ether gave 3.43 g (52%) of the title compound as a light brown crystalline solid, mp 155°-156° C.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[CH:11]=[O:12])([CH3:3])[CH3:2].[C:13]1([CH2:19][CH2:20][CH2:21][Mg]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[C:11](=[O:12])[CH2:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1C=O
Reactant: Br[Mg]CCCc1ccccc1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1C(=O)CCCc1ccccc1

Procedure:
The title compound was prepared following the general procedure of Example 1 starting from (1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarbaldehyde and (3-phenylpropyl)magnesium bromide.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:17](I)[CH3:18]>CC(C)=O>[CH2:17]([C:3]1([C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[CH3:18]
Reactant: CCI
Reactant: COC(=O)C1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC1(C(=O)OC)CCCC1=O
Yield: 101.6 %

Procedure:
Under vigorously agitation, 14.8 g of methyl 2-oxocyclopentane carboxylate was added to 41.9 g of fine powdery anhydrous potassium carbonate, and after stirring for several minutes, to the mixture was added 100 ml of acetone. The reaction mixture was further stirred for 15 to 30 minutes at room temperature, then thereto was dropwise added 31.2 g of ethyl iodide. Upon the completion of the addition, the reaction mixture was heated for reflux for 2 hours. The solvent was removed under reduced pressure, and solid residue was washed with diethyl ether. The washing liquor was collected and washed with water. After removing the solvent, 18.0 g of pale yellow liquid was obtained, The liquid was distilled under reduced pressure, and 15.9 g of colorless liquid as a distillate cut of 122-124° C./25 mmHg was collected. Yield: 93.5%.