Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][C:12]=1[CH2:27][CH2:28][CH3:29])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:30][O:31][CH2:32]Cl.O>O1CCCC1>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:26][CH2:30][O:31][CH3:32])([C:18]([F:19])([F:20])[F:21])[C:22]([F:23])([F:24])[F:25])=[CH:13][C:12]=1[CH2:27][CH2:28][CH3:29])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COCCl
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1OCc1ccccc1
Reaction time: 8 h
Yield: 90.6 %

Procedure:
Sodium hydride (purity: 50%) (38.9 mg, 0.81 mmol) was added to a mixed solution of 2-(4-benzyloxy-3-propylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (264.0 mg, 0.67 mmol) in tetrahydrofuran (5 mL) under ice-cooling. Then, chloromethyl methyl ether (65.0 mg, 0.81 mmol) was added, followed by stirring overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel preparative thin-layer chromatography (hexane:ethyl acetate=10:1) to obtain 264.9 mg of the title compound (yield: 90%) as a pale yellow oil.
Reaction SMILES: C1([NH:7][C:8]([C:10]2[C:11](=[O:23])[N:12]([CH3:22])[C:13]3[C:18]([C:19]=2O)=[CH:17][C:16]([CH3:21])=[CH:15][CH:14]=3)=O)CCCCC1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:21])[CH:17]=2)[N:12]([CH3:22])[C:11](=[O:23])[C:10]=1[C:8]#[N:7]
Reactant: Cc1ccc2c(c1)c(O)c(C(=O)NC1CCCCC1)c(=O)n2C
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(c1)c(Cl)c(C#N)c(=O)n2C
Yield: 54 %

Procedure:
A solution of Compound 20 (3 g, 9.5 mmol) in 30 mL neat phosphorus oxychloride was heated at 100° C. for 3 h. The solvent was evaporated under reduced pressure. The residue was suspended in ice water and neutralized by solid sodium bicarbonate. The solids formed were filtered, washed by water, and purified by flash chromatography eluting with 1% methanol in dichloromethane to yield 1.2 g (54%) of yellow solids. M.P. 241° C. 1H NMR (DMSO-d6): δ 2.44 (s, 3H), 3.64 (s, 3H), 7.62 (d, J=8.7 Hz, 1H), 7.73 (dd, J=1.5, 8.7 Hz, 1H), 7.85 (d, J=1.5 Hz, 1H). EIMS m/z 255 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]>C(Cl)Cl>[NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: Cc1ccnc(Cl)c1N
Solvent: ClCCl
Product: Nc1c(-c2ccccc2)ccnc1Cl

Procedure:
adjusting the pH of the aqueous phase to between 3.5 and 5 by the addition of a base, and isolating the 3-amino-2-chloro-4-methyl-pyridine so produced by extraction into methylene chloride, followed by evaporation of the methylene chloride.
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].Cl.[OH-].[Na+]>CO>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3]
Reactant: CN(C)C(=N)N=C(N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)C(=N)NC(=N)N
Yield: 78.9 %

Procedure:
2 kg (1 equivalent) of metformin hydrochloride and 483 g (1 equivalent) of sodium hydroxide were stirred in 10 L of methanol for 2 hours at room temperature, and then remaining solid was filtered and the filtrate was concentrated under reduced pressure. Then 15 L of acetone was added to the resulting solid and stirred. Insoluble material was filtered, and the filtrate was concentrated under reduced pressure to obtain 1,230 g of metformin free base. The metformin free base was dissolved in 33 L of acetone, 2.8 L (4 equivalents) of acetic acid was added, and then the mixture was stirred for 2 hours at room temperature. The resulting crystal was filtered, and re-crystallized in water and acetone to obtain 1,089 g of metformin acetate (yield: 47.7%).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[O:7][C:8]3[C:9](=[C:11]([C:17]([OH:19])=[O:18])[CH:12]=[CH:13][C:14]=3[O:15][CH3:16])[CH:10]=2)=[O:5])[CH2:3][CH2:2]1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)([O-:22])=[O:21].Cl.CN(C)CCCN=C=NCC.O>ClCCl.CN(C)C1C=CN=CC=1>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([O:18][C:17]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:8]3[O:7][C:6]([C:4]([CH:1]4[CH2:2][CH2:3]4)=[O:5])=[CH:10][C:9]=23)=[O:19])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: COc1ccc(C(=O)O)c2cc(C(=O)C3CC3)oc12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc(C(=O)C3CC3)oc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
To a stirred suspension of 2-cyclopropanecarbonyl-7-methoxybenzofuran-4-carboxylic acid (0.50 g) in dichloromethane (30 ml) under an atmosphere of nitrogen was added 4-nitrophenol (0.29 g), 4-dimethylaminopyridine (20 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.41 g). The reaction mixture was stirred at room temperature for 18 h. Water (30 ml) was added and the mixture extracted with dichloromethane (150 ml). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with 40% ethyl acetate in hexane afforded the title compound as a pale yellow solid (0.59 g).
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[N:8]=[C:9]3[C:17](=[N:18][C:6]2=[N:5][N:4]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:10]3=O)[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[N:7]2[N:8]=[C:9]3[C:17](=[N:18][C:6]2=[N:5][N:4]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:10]3=[N:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCc1nnc2nc3c(nn12)C(=O)c1ccccc1-3
Solvent: Cc1ccccc1
Product: CCc1nnc2nc3c(nn12)C(=Nc1ccccc1)c1ccccc1-3
Temperature: 130 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
To a suspension of 1g/A (200 mg, 0.79 mmol) and molecular sieves in toluene (4 ml), aniline (72 μl, 0.79 mmol) was added. The mixture was stirred at 130° C. for 4 h, then the solvent was evaporated and he crude purified by flash chromatography (CH2Cl2/EtOAc/MeOH 80:18:2), affording 11 (231 mg, 90%) as orange solid in diastereoisomeric ratio 1:1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[I:15]Cl.O>C(O)(=O)C>[OH:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[I:15]
Reactant: ClI
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(I)c(O)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 91075.4 %

Procedure:
To a solution of methyl 4-hydroxy-3-nitrobenzoate (2.0 g) in acetic acid (15 mL) was added iodine monochloride (1.65 mg) in acetic acid, and the mixture was stirred at 100° C. for 1.5 h. After cooling to room temperature, the mixture was poured into water (200 mL), and stirred for 30 min. The mixture was filtered and washed with water and hexanes. The yellow powder was collected by filtration and dried in vacuum oven overnight to give 2.99 g of the title compound: 1H NMR (300 MHz, CDCl3) δ 11.68, 8.81, 8.72, 3.96.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)(=[O:7])[CH3:6]>O>[C:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:1]([O-:4])=[O:2])=[C:11]([Cl:15])[CH:10]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Nc1cccc(Cl)c1
Reactant: O=[N+]([O-])O
Solvent: O
Product: CC(=O)Nc1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 0 °C

Procedure:
To fuming nitric acid (120 mL) at -50° C. was added N-acetyl-3-chloroaniline (30 g) over a period of 45 minutes. The reaction was kept between -50° C. and -30° C. using a dry ice/acetone bath. The reaction mixture was stirred for an additional hour and then poured into 1500 mL of crushed ice and water. The precipitate was filtered and slurried with 1 liter of slightly alkaline water (ammonium hydroxide) twice. The precipitate was then dried and recrystallized from toluene to yield (3.6 g) of N-acetyl-3-chloro-4-nitroaniline; m.p. 134°-136° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:10][C:11]([O:13]CC)=[O:12])=[CH:5][CH:4]=1.[OH-].[Na+].[CH2:26](O)C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[C:10]([CH3:26])[C:11]([OH:13])=[O:12])=[CH:7][CH:8]=1
Reactant: CCO
Reactant: CCOC(=O)C=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(=C(C)C(=O)O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 6.019 g of ethyl 3,3-bis(4-methoxyphenyl)acrylate (prepared as described in Preparation 107), 120 ml of ethanol and 80 ml of a 10% w/v aqueous solution of sodium hydroxide was stirred for 14 hours at room temperature. At the end of this time, the reaction mixture was heated on an oil bath at 100° C. for 4 hours, and then ethanol was distilled off. The residue was diluted with ice-water and washed with ethyl acetate. Concentrated hydrochloric acid was dropped onto the aqueous phase on an ice bath, to adjust the pH to a value of 2. The aqueous phase was extracted twice with methylene chloride. The combined methylene chloride extracts were washed with water, dried over anhydrous sodium sulfate and condensed by evaporation under reduced pressure, to afford 5.117 g of the title compound as white crystals, melting at 134°-135° C. (after recrystallisation from a mixture of methylene chloride and hexane).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[C:3]=1[F:11].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[CH:7]=[N:8][C:4]=2[C:3]=1[F:11]
Reactant: C1=COCCC1
Reactant: Fc1c(Br)ccc2[nH]cnc12
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: C1CCOC1
Product: Fc1c(Br)ccc2c1ncn2C1CCCCO1
Yield: 78.3 %

Procedure:
To a solution of 144 (24 g, 0.111 mol) in dry THF (720 mL) was added 3,4-dihydro-2H-pyran (28.1 g, 0.334 mol) and camphorsulfonic acid (2.6 g, 0.011 mol) then heated to reflux for 16 h. The resulting mixture was concentrated and the residue purified by SiO2 chromatography eluting with 20% EtOAc/petroleum ether to afford 26 g (78%) of 5-bromo-4-fluoro-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole (146) as pale yellow oil: 1H-NMR (400 MHz, RT, DMSO-d6): δ 1.57-1.63 (m, 2H), 1.70-1.74 (m, 1H), 1.91-2.04 (m, 2H), 2.15-2.19 (m, 1H), 3.73-3.77 (m, 1H), 3.96-4.03 (m, 1H), 5.68-5.71 (dd, 1H), 7.50-7.53 (d, 2H), and 8.51 (s, 1H); MS (ESI): m/z=301.0 [M+1]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32]1[CH:47]=[CH:46][C:35]([O:36][C:37]2[N:45]=[CH:44][CH:43]=[CH:42][C:38]=2[C:39]([OH:41])=O)=[CH:34][CH:33]=1.C(N(C(C)C)CC)(C)C.[CH2:57]([NH2:61])[CH:58]([CH3:60])[CH3:59]>CN(C=O)C>[CH2:57]([NH:61][C:39](=[O:41])[C:38]1[CH:42]=[CH:43][CH:44]=[N:45][C:37]=1[O:36][C:35]1[CH:34]=[CH:33][C:32]([NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)=[CH:47][CH:46]=1)[CH:58]([CH3:60])[CH3:59]
Reactant: O=C(O)c1cccnc1Oc1ccc(Nc2ccccn2)cc1
Reactant: CC(C)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CNC(=O)c1cccnc1Oc1ccc(Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
HATU (178 mg, 0.469 mmol) was added to a mixture of 2-(4-(pyridin-2-ylamino)phenoxy)nicotinic acid (131 mg, 0.426 mmol) and diisopropylethylamine (148 μL, 0.853 mmol) in DMF (1 mL) and the mixture was stirred at rt for 10 min. Isobutylamine (63.5 μL, 0.639 mmol) was added and the mixture was stirred at rt for 1 h. The mixture was purified by chromatography on silica gel to deliver N-isobutyl-2-(4-(pyridin-2-ylamino)phenoxy)nicotinamide as a white solid. MS (ESI, pos. ion) m/z: 363.1 (M+1). IC50 (uM) 0.09344.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:5]=[CH:4][C:3]=1[N:16]1[CH:20]=[CH:19][C:18]([C:21]([O:23]C)=[O:22])=[N:17]1.[Li+].[OH-]>CO>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:5]=[CH:4][C:3]=1[N:16]1[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[N:17]1
Reactant: COCCOCCOc1ccc(-n2ccc(C(=O)OC)n2)c(O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COCCOCCOc1ccc(-n2ccc(C(=O)O)n2)c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 1-(2-hydroxy-4-(2-(2-methoxyethoxy)ethoxy)phenyl)-1H-pyrazole-3-carboxylate 4 (70 mg, 0.208 mmol, 1.00 equiv) in methanol (10 mL), LiOH (50%, 6 mg, 0.250 mmol, 1.20 equiv) was added. The resulting solution was stirred overnight at room temperature. The solvent was concentrated under vacuum, the residue was applied onto a silica gel column and eluted with DCM/MeOH (3/1). This resulted in 60 mg (89%) of 1-(2-hydroxy-4-(2-(2-methoxyethoxy)ethoxy)-phenyl)-1H-pyrazole-3-carboxylic acid 5 as a green oil. 1H NMR (300 MHz, CDCl3, n=2): δ 8.00-8.10 (m, 1H), 7.35-7.60 (m, 1H), 6.85-7.00 (m, 1H), 6.30-6.70 (m, 2H), 4.10-4.15 (m, 2H), 3.70-3.85 (m, 2H), 3.45-3.70 (m, 4H), 3.43 (s, 3H). LC-MS: m/z=323 (MH)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=O)[CH2:2]1.Cl.[CH3:12][O:13][NH2:14].CC([O-])=O.[Na+].ClCCl>CO.O>[CH3:12][O:13][N:14]=[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][CH2:2]1
Reactant: O=C1COc2ccccc21
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CON=C1COc2ccccc21
Yield: 75 %

Procedure:
To a solution of benzofuran-3(2H)-one (9) (100 g, 0.745 mol) in methanol (700 mL) was added O-methyl hydroxylamine hydrochloride (68.5 g, 0.820 mol) and NaOAc (67.3 g, 0.820 mol) at ambient temperature followed by heating to reflux for 1-3 h. The progress of the reaction was monitored by the HPLC analysis. Upon completion of the reaction, the inorganics were filtered off, and methanol was recovered from the filtrate to provide residue. The residue was subjected to extractive work-up using dichloromethane (500 mL) and water (1 L) followed by recovery of the organic layer to obtain the product meeting the desired specifications. Yield—75-83%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11](C(=O)C(F)(F)F)[CH2:10][CH:9]1[CH2:20][N:21]([C@@H:29]([C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1)[CH3:30])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25]>C1COCC1.CO.[OH-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[CH2:20][N:21]([C@@H:29]([C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1)[CH3:30])[C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CN(C(=O)C(F)(F)F)CCC1c1ccccc1F)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
695 mg of tert-butyl {[4-(2-fluorophenyl)-1-(trifluoroacetyl)piperidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate was dissolved in 5 mL of THF-2 mL of methanol, and 1 mL of a 1 M aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and chloroform was added to the obtained residue, followed by drying over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 636 mg of a colorless foamy substance of tert-butyl {[4-(2-fluorophenyl)piperidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate as a crude product.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][C:8]1[CH2:12][S:11][C:10](=[O:13])[N:9]=1.[F:14][C:15]([F:36])([F:35])[C:16]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:17]=1[CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([CH:25]=O)[CH2:21][CH2:20]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:36][C:15]([F:14])([F:35])[C:16]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:17]=1[CH2:18][N:19]1[CH2:24][CH2:23][CH:22](/[CH:25]=[C:12]2/[C:8]([NH:7][CH2:6][C:2]3[O:1][CH:5]=[CH:4][N:3]=3)=[N:9][C:10](=[O:13])[S:11]/2)[CH2:21][CH2:20]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: O=C1N=C(NCc2ncco2)CS1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(NCc2ncco2)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 60 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a solution of 4-[(1,3-oxazol-2-ylmethyl)amino]-1,3-thiazol-2(5H)-one (357 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (676 mg) in 2-propanol (5 mL) was added piperidinium acetate (289 mg) at room temperature. The reaction mixture was stirred at 60° C. for 5 hr, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) and recrystallized from ethyl acetate/heptane to give the title compound (751 mg)
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH2:17](O)[CH3:18]>>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([O:6][CH2:17][CH3:18])=[O:5]
Reactant: CCO
Reactant: Cc1cc(Br)c(N)c(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(C)cc(Br)c1N
Yield: 64 %

Procedure:
Ethanol (10 mL) was added to 2-amino-3-bromo-5-methylbenzoic acid (1.00 g, 4.4 mmol). While the mixture was stirred, thionyl chloride (1.03 g, 8.7 mmol) was added at room temperature, followed by stirring at 80° C. overnight. The reaction solution was concentrated, and then diluted with water under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=0/10, 4/6) to obtain 715 mg of the title compound as a pale yellow solid (64%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11]N=N[C:8]=2[CH:12]=1)([O-:3])=[O:2].[C:13]1([N:19]=[C:20]=[S:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:20](=[N:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:21][C:8]=2[CH:12]=1)([O-:3])=[O:2]
Reactant: S=C=Nc1ccccc1
Reactant: O=[N+]([O-])c1ccc2snnc2c1
Product: O=[N+]([O-])c1ccc2sc(=Nc3ccccc3)sc2c1

Procedure:
A solution of 5-nitro-1,2,3-benzothiadiazole (4.6 g) in 50 ml of phenylisothiocyanate is heated at 220° C under an inert atmosphere until the evolution of nitrogen ceases (approximately 3 hours). The excess phenylisothiocyanate is removed in vacuo and the resultant residue chromatographed on 1000 ml of silica gel eluting with methylene chloride/pentane (1:4). The fractions containing the desired product are combined and concentrated in vacuo. The resultant solid is recrystallized from cyclohexane to yield 2.1 g of the title compound, melting point 136°-138° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][Si](C(C)(C)C)(C)C)[CH2:10][C@H:9]1[CH:21]1[CH2:25][NH:24][C:23](=[O:26])[CH2:22]1)=O)(C)(C)C.[ClH:27].CO>CO>[ClH:27].[OH:13][C@H:11]1[CH2:12][NH:8][C@H:9]([CH:21]2[CH2:25][NH:24][C:23](=[O:26])[CH2:22]2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C1CNC(=O)C1
Agent: Cl
Solvent: CO
Product: O=C1CC([C@@H]2C[C@@H](O)CN2)CN1
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
(2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(2-pyrrolidon-4-yl)pyrrolidine diastereomer B (62.48 g, 163 mmol, compound of Reference Example 12) was dissolved in methanol (600 ml), and the solution was cooled to 0° C. Then, a 2.5N hydrochloric acid/methanol solution (230 ml, 570 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. The precipitate was collected by filtration and dried to obtain white powder (30.01 g, yield: 89.1%) of (2S,4R)-4-hydroxy-2-(2-pyrrolidon-4-yl)pyrrolidine hydrochloride. This white powder (10.53 g, 50 mmol) was dissolved in a solvent mixture of dioxane (50 ml) and water (50 ml), and the pH was adjusted to 8 with triethyl amine. Then, 4,6-dimethyl-2-(p-nitrobenzyloxycarbonylthio)pyrimidine (17.55 g, 55 mmol) was added thereto, and the mixture was reacted for 6 hours while maintaining the pH at a level of 8. The reaction solution was concentrated, and tetrahydrofuran (100 ml) was added thereto. Insoluble matters were filtered off, and the filtrate was concentrated. The residue was subjected to column chromatography (Wakogel™ C-300, chloroform-methanol 40:1) to obtain (2S,4R)-4-hydroxy-N-(p-nitrobenzyloxycarbonyl)-2-(2-pyrrolidon-4yl)pyrrolidine diastereomer B (17.48 g, yield: 98.2%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C@@H:17]([C:18]([O:20]CC)=[O:19])[CH:16]3[CH2:23][CH2:24][CH:13]2[CH2:14][CH2:15]3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CO.[OH-].[Na+].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C@@H:17]([C:18]([OH:20])=[O:19])[CH:16]3[CH2:23][CH2:24][CH:13]2[CH2:14][CH2:15]3)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)[C@H]1C2CCC(CC2)N1S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2C3CCC(CC3)[C@@H]2C(=O)O)cc1
Temperature: 65 °C
Reaction time: 12 h

Procedure:
To a solution of ethyl (3R)-2-[(4-methoxyphenyl)sulfonyl]-2-azabicyclo[2.2.2]octane-3-carboxylate (399 mg, 1.13 mmol) in tetrahydrofuran (7 ml)-methanol (4 ml) was added 1N sodium hydroxide (7 ml), and the mixture was stirred at 65° C. for 12 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, to give (3R)-2-[(4-methoxyphenyl)sulfonyl]-2-azabicyclo[2.2.2]octane-3-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:14][CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([NH2:13])[C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH3:11])[C:6]=2[CH:12]=1.[OH-].[Na+]>P(=O)(O)(O)O>[Br:1][C:2]1[C:3]2[CH2:14][CH2:15][CH:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:13][C:4]=2[C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH3:11])[C:6]=2[CH:12]=1
Reactant: Cc1nc2c(N)c(CC=Cc3ccccc3)c(Br)cc2n1C
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2c3c(c(Br)cc2n1C)CCC(c1ccccc1)N3
Temperature: 130 °C
Yield: 85.2 %

Procedure:
A suspension of 2.0 g (5.6 mmol) 6-bromo-1,2-dimethyl-5-(3-phenyl-allyl)-1H-benzimidazol-4-ylamine in 10 ml phosphoric acid (85%) was heated to 130° C. for 20 min. The solution was poured onto crushed ice and the pH adjusted to pH=9 by the addition of 6N sodium hydroxide solution. The mixture was extracted with dichloromethane/methanol (10:1), the organic phase was separated, dried over anhydrous magnesium sulphate and evaporated. The residue was purified by column chromatography on silica gel (toluene/dioxane/methanol=6:3.8:02). Crystallization from diisopropyl ether yielded 1.7 g (84%) of the title compound as a colourless solid. m.p. 206-210° C.