Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]3[C:12](=[O:13])[CH2:11][CH:10]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:9][C:7]3=[N:8][C:4]=2[CH:3]=1.[Cl:22]C1C=CC2N=C3CC(C4C=CC=CC=4)CC(=O)N3C=2C=1.[NH3:43]>O1CCOCC1.O.CC(C)=O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[N:43]=[C:7]([CH2:9][CH:10]([C:14]3[CH:19]=[CH:18][C:17]([Cl:22])=[CH:16][CH:15]=3)[CH2:11][C:12]([NH2:6])=[O:13])[NH:8][C:4]=2[CH:3]=1
Reactant: N
Reactant: O=C1CC(c2ccccc2)Cc2nc3cc(Cl)ccc3n21
Reactant: O=C1CC(c2ccccc2)Cc2nc3ccc(Cl)cc3n21
Solvent: CC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)CC(Cc1nc2ccc(Cl)cc2[nH]1)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
A 1:1-mixture of 7-chloro-3-phenyl-3,4-dihydropyrido[1,2-a]-benzimidazol-1(2H)-one and 8-chloro-3-phenyl-3,4-dihydropyrido[1,2-a]benzimidazol-1(2H)-one (222 mg)—see example 1.27.1—was dissolved in 1,4-dioxane (3 ml) at reflux temperature. A 25% solution of ammonia in water (2 ml) was added to give a light red solution. Refluxing was continued for 1 h. All volatiles were removed at the water aspirator to leave a light red oil, which was dissolved in acetone (3 ml). Soon precipitation occurs and the solid is isolated by suction filtration and washed with acetone. After drying in vacuo 4-(5-chloro-2-benzimidazolyl)-3-(4-chlorophenyl)-butyramide (120 mg) is obtained as colourless solid.
Reaction SMILES: O.NN.[N+:4]([C:7]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[C:19]([O:26][CH3:27])=[CH:18][C:8]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][OH:17])=[O:10])([O-])=O.[H][H]>CO.[Ni]>[NH2:4][C:7]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[C:19]([O:26][CH3:27])=[CH:18][C:8]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][OH:17])=[O:10]
Reactant: [H][H]
Reactant: COc1cc(C(=O)N2CCCC2CO)c([N+](=O)[O-])c(OC)c1OC
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)N2CCCC2CO)c(N)c(OC)c1OC
Reaction time: 2 h
Yield: 78.3 %

Procedure:
Hydrazine hydrate (1.33 mL, 41.5 mmol) was added dropwise to a solution of 116 (2.83 g, 8.3 mmol) in methanol (142 mL) gently refluxing over Raney nickel (500 mg, slurry). The resulting vigorous evolution of hydrogen gas subsided after approximately 10 minutes and the reaction was deemed to be complete by TLC after 2 h. The reaction mixture was filtered through celite and the solvent evaporated. Distilled water (100 mL) was added to the residue, and the aqueous mixture was extracted with EtOAc (3×100 mL) and the combined organic phase washed with H2O (3×100 mL) and brine (3×100 mL) and dried over anhydrous MgSO4. Evaporation of the solvent afforded the product (2.18 g, 6.5 mmol) as a brown oil: 1H NMR (270 MHz, CDCl3) δ 1.6-2.0 (m, 3H), 2.1-2.2 (m, 1H), 3.4-3.7 (m, 4H), 3.8 (s, 3H), 3.8-3.9 (2×s, 6H), 4.4 (br s, 1H), 4.7-4.3 (br s, 1H), 6.6 (s, 1H); 13C NMR (67.8 MHz, CDCl3) δ 144.7, 144.5, 141.6, 134.6, 107.1, 66.9, 61.0, 60.9, 60.5, 56.8, 50.9, 28.6, 24.9, 21.1, 14.2.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:10]([CH2:24][CH2:25][CH3:26])[CH:11]1[CH2:20][C:19]2[C:14](=[C:15]([O:21][CH3:22])[CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=O)[CH2:8][CH3:9].C(OCC)(=O)C.CO>C1COCC1>[CH3:22][O:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[NH:13][CH2:12][CH:11]([N:10]([CH2:7][CH2:8][CH3:9])[CH2:24][CH2:25][CH3:26])[CH2:20]2
Reactant: CCCN(CCC)C1Cc2cccc(OC)c2NC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCCN(CCC)C1CNc2c(cccc2OC)C1
Temperature: 50 °C
Yield: 98.3 %

Procedure:
Lithium aluminum hydride (1.08 g, 27.7 mmol) was added to a stirred solution of 3-(dipropylamino)-3,4-dihydro-8-methoxy-2(1H)quinolinone (1.05 g, 3.8 mmol) in THF (50 mL) and the solution was heated to 50° C. for 1 hour. After cooling, ethyl acetate followed by methanol were added to destroy excess hydride, and the solvent was evaporated. The residue was partitioned between ethyl acetate and water. Evaporation of the ethyl acetate gave 0.98 g of 1,2,3,4-tetrahydro-8-methoxy-N,N-dipropyl-3-quinolinamine as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][CH2:8][NH2:9])[N:6]=1.[C:10](O)(=O)C.C=O>CO>[NH2:1][C:2]1[S:3][C:4]2[CH2:10][NH:9][CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: CC(=O)O
Reactant: NCCc1csc(N)n1
Agent: C=O
Solvent: CO
Product: Nc1nc2c(s1)CNCC2
Yield: 91 %

Procedure:
A solution of 2-amino-4-(2-aminoethyl)thiazole (1.57 g, 11.0 mmol) in methanol (120 ml) was treated with acetic acid (0.15 ml, 2.6 mmol) and formaldehyde (0.89 ml of a 37% aqueous solution, 11 mmol). After ten minutes, the reaction mixture was concentrated in vacuo and subjected to column chromatography (eluant: 95:4:1 chloroform:methanol:concentrated ammonium hydroxide). The product was obtained as a white solid, m.p. 169°-173° (1.547 g, 10.0 mmol, 91% yield).
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6](=O)[CH2:5][CH2:4][N:3]3[CH2:2]1.[N-:14]=[N+]=[N-].[Na+].[OH-:18].[Na+]>>[CH2:4]1[N:3]2[C:12]3[CH:7]([CH2:8][C:9](=[O:18])[CH2:10][C:11]=3[CH:1]=[CH:2]2)[NH:14][CH2:6][CH2:5]1.[CH2:4]1[N:3]2[C:12]3[CH:7]([CH2:8][CH2:9][C:10](=[O:18])[C:11]=3[CH:1]=[CH:2]2)[CH2:6][NH:14][CH2:5]1
Reactant: [OH-]
Reactant: O=C1CCN2CCc3cccc1c32
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: O=C1CCC2CNCCn3ccc1c32
Product: O=C1Cc2ccn3c2C(C1)NCCC3
Temperature: 90 °C
Yield: 68 %
Yield: 18 %

Procedure:
Add 1,2,5,6-tetrahydropyrrolo[3,2,1-ij]quinolin-6-one (15.49 g, 89.43 mmol) to polyphosphoric acid (512 g) at 67-70° C. and stir vigorously. Add three portions of sodium azide (2.43 g (37.4 mmol), 2.42 g (37.2 mmol) and 2.42 g (37.2 mmol)) at 20 minute intervals then heat to 90° C. and stir for 3.5 hours. Pour into ice (511.6 g). Add, with cooling, 50% aqueous sodium hydroxide (500 mL) 40 minutes. Extract with chloroform (3×500 mL). Wash the combined organic phases with water (500 mL) and saturated aqueous sodium chloride (500 mL). Dry over sodium sulfate and concentrate under reduced pressure. Subject the residue to chromatography (pre-packed silica gel), eluting with a gradient 98:2-97:3-96:4 chloroform/methanol to provide 1,2,4,5-tetrahydro-7H-[1,4]diazepino[3,2,1-hi]indol-6-one (2.95 g, 18%) and 1,2,4,5-tetrahydro-6H-[1,4]diazepino[6,7,1-hi]indol-7-one (11.51 g, 68%) as beige solids.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:28][CH:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]2=[O:34])[CH:5]=[CH:6][C:7]=1[C:8]([CH2:10][O:11][CH:12]1[CH2:17][O:16][C:15]2=[N:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][N:14]2[CH2:13]1)=C.C[OH:36]>O=[Os](=O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:28][CH:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]2=[O:34])[CH:5]=[CH:6][C:7]=1[C:8](=[O:36])[CH2:10][O:11][CH:12]1[CH2:17][O:16][C:15]2=[N:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][N:14]2[CH2:13]1
Reactant: C=C(COC1COc2nc([N+](=O)[O-])cn2C1)c1ccc(N2CC(CNC(C)=O)OC2=O)cc1F
Reactant: CO
Agent: O=[Os](=O)(=O)=O
Product: CC(=O)NCC1CN(c2ccc(C(=O)COC3COc4nc([N+](=O)[O-])cn4C3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-(3-{3-Fluoro-4-[1-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)-vinyl]-phenyl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide (48 mg) was dissolved in 1.5 mL methanol, followed by addition of NaIO4 (54 mg) and OsO4 (0.02 mL, 2.5% in water). The solution was stirred at room temperature for 4 hours and then Celite (500 mg) was added. The resulting mixture was stirred for 30 min before it was filtered and washed with EtOAc. The organic layer was dried over Na2SO4 and purified with preparative TLC (CH2Cl2/MeOH, v/v, 10/1). The titled compound was obtained as yellow solid (8 mg). ESI MS m/z 478 (M+H). 1H NMR (400 MHz, MeCN-d3) 8.06 (t, J=8.4 Hz, 1H), 7.74 (s, 1H), 7.69 (dd, J=14.0, 2.0 Hz, 1H), 7.52 (dd, J=8.8, 2.4 Hz, 1H), 6.84 (b, 1H), 4.95-5.00 (m, 2H), 4.83-4.92 (m, 1H), 4.78 (dt, J=12.0, 2.8 Hz, 1H), 4.53 (d, J=12.8 Hz, 1H), 4.41 (dt, J=12.8, 2.0 Hz, 1H), 4.30-4.35 (m, 1H), 4.29 (dd, J=12.8, 3.2 Hz, 1H), 4.21 (t, J=9.2 Hz, 1H), 3.89 (dd, J=9.2, 6.4 Hz, 1H), 3.58-3.68 (m, 2H), 3.39 (d, J=5.2 Hz, 1H), 1.98 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2Cl.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[CH:17]2>>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[CH:17]2
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: Nc1ccc2[nH]ccc2c1
Product: Ic1ccc2ncnc(Nc3ccc4[nH]ccc4c3)c2c1

Procedure:
JP-A-10-152477 describes a process for preparing a 4-arylaminoquinazoline compound from a quinazolin-4-one, which comprises the steps of chlorinating 4-iodoquinazolin-4-one using an excessive amount of oxalyl chloride to produce 6-iodo-4-chloroquinazoline (intermediate compound), concentrating the reaction product under reducing pressure to isolate the resulting product; reacting the 6-iodo-4-chloroquinazoline with 5-aminoindole to give 6-iodo-4 (5-indolylamino)quinazoline. Unfortunately, the yield is not high. Further, it should be noted that the intermediate compound, i.e., 4-chloroquinazoline compound, shows no satisfactory stability in the presence of water and no satisfactory resistance to heat. Accordingly, the compound should be handled carefully.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C@@H:14]([NH:18][C:19]([C:21]2([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22]2)=[O:20])[CH2:13][CH2:12]3)O1.Br[C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[C:35]([F:40])[C:34]=1[C:41]1[N:45]=[C:44]([CH3:46])[O:43][N:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.O.[Pd](Cl)Cl>[Cl:39][C:37]1[CH:36]=[C:35]([F:40])[C:34]([C:41]2[N:45]=[C:44]([CH3:46])[O:43][N:42]=2)=[C:33]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C@@H:14]([NH:18][C:19]([C:21]2([NH:24][C:25](=[O:30])[C:26]([F:28])([F:29])[F:27])[CH2:23][CH2:22]2)=[O:20])[CH2:13][CH2:12]3)[CH:38]=1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2Br)no1
Reactant: CC1(C)OB(c2ccc3c(c2)CC[C@@H]3NC(=O)C2(NC(=O)C(F)(F)F)CC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(NC(=O)C(F)(F)F)CC2)no1
Temperature: 80 °C
Yield: 54.3 %

Procedure:
1-(2,2,2-Trifluoro-acetylamino)-cyclopropanecarboxylic acid[(S)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yl]-amide (intermediate A-2) (0.145 g, 331 μmol) and 3-(2-bromo-4-chloro-6-fluoro-phenyl)-5-methyl-[1,2,4]oxadiazole (intermediate B-2) (106 mg, 364 μmol) were dissolved in DMSO (5.00 ml), then sodium carbonate (87.7 mg, 827 μmol), dissolved in water (0.63 ml) was added, followed by (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) (12.1 mg, 16.5 μmol, eq: 0.05). This mixture was heated up to 80° C. for 2 hours, then poured into H2O (50 ml) and extracted with CH2Cl2 (2×25 mL). The organic layers were dried over MgSO4, filtered and concentrated in vacuo to give a crude product (0.213 g) which was purified by flash chromatography (silica gel, 20 g, 10% to 50% EtOAc in heptane) to yield the title compound (0.094 g, 54%) as light yellow solid. MS: 523.1 (MH+, 1Cl).
Reaction SMILES: [C:1]([NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH2:7]1)(=[O:4])[CH2:2][CH3:3].FC(F)(F)C(O)=O.[N+:25]([O-])([OH:27])=[O:26]>O.C(OCC)C>[C:1]([NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[C:12]=2[N+:25]([O-:27])=[O:26])[CH2:7]1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)NC1CCc2cc(OC)ccc2C1
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCC(=O)NC1CCc2c(ccc(OC)c2[N+](=O)[O-])C1
Reaction time: 8 h

Procedure:
12.2 g of 2-propanoylamino-6-methoxy-1,2,3,4-tetrahydronaphthalene are introduced into 100 ml of trifluoroacetic acid, and 3 ml of nitric acid (d=1.49) are added dropwise thereto. Stirring is continued for 8 hours and the mixture is then taken up in water and diethyl ether. To separate the nitro isomers, the mixture is subjected to chromatography under pressure, on a silica column, elution being carried out with an 8/2 methylene chloride/ethyl acetate mixture. 5 g of the isomer nitrated in the 7-position and 3.8 g of the isomer nitrated in the 5-position are finally collected.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6](Cl)[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:23][CH2:22]1>CC(O)C>[CH2:30]([O:29][C:27]([N:24]1[CH2:25][CH2:26][CH:21]([CH2:20][NH:19][C:6]2[C:7]([Cl:8])=[C:2]([Cl:1])[N:3]=[N:4][CH:5]=2)[CH2:22][CH2:23]1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Clc1cnnc(Cl)c1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCC(CNc2cnnc(Cl)c2Cl)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 3,4,5-trichloropyridazine (2.22 g, 12.08 mmol) and DIPEA (4.21 mL, 24.16 mmol) in IPA (25 mL) was added benzyl-4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1, 3.00 g, 12.08 mmol). The resulting reaction solution was stirred at rt for 5 h, then concentrated in vacuo. The residue was dissolved in CH2Cl2 (200 mL), washed with water (50 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (1-7 (10% NH4OH in MeOH)/99-93 CH2Cl2) to give 4-[(5,6-dichloro-pyridazin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester. M.S.(M+1):395.28
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:34][CH2:35][CH2:36][CH2:37][CH3:38])([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.[H][H]>CO.O.[C].[Pd]>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:34][CH2:35][CH2:36][CH2:37][CH3:38])([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26])[C:13]([OH:15])=[O:14]
Reactant: CCCCOP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CCCCOP(=O)(CCC(N)C(=O)O)Oc1ccccc1
Yield: 74.6 %

Procedure:
Next, 0.64 g (1.19 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-[butyl(phenyl)phosphono]butanoate was dissolved in 20 mL of a solvent mixture of methanol and water at 3:1 and mixed with 200 mg of 5% palladium-carbon and hydrogen gas was introduced for 75 minutes. The palladium-carbon was removed by Celite filtration and the filtrate was vacuum-concentrated. The residue was purified by medium pressure reversed-phase column chromatography ODS-S-50B. The column was eluted with a linear gradient of 30 to 60% methanol at a flow rate of 6 mL/min, and the fractions containing the compound eluted at 60% methanol were collected. The elution and purity of the compound were confirmed by TLC (BuOH/AcOH/H2O=5:2:2, ninhydrin coloration). After vacuum concentration, freeze drying was carried out to obtain 2-amino-4-[butyl(phenyl)phosphono]butanoic acid (0.28 g, yield 75%) as a colorless solid.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N=C=N.[NH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[NH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:16]
Reactant: NC1CCCCC1
Reactant: Nc1ccccc1C(=O)O
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1ccccc1C(=O)NC1CCCCC1
Temperature: 40 °C

Procedure:
To a dry reaction vial was added cyclohexylamine (40 uμmol, 1.0 eq) and PS-carbodiimide resin (72 μmol, 1.8 eq). The solution of 2-amino-benzoic acid (44 μmol, 1.1 eq), diisopropyl ethyl amine (10 μLl) and HOBt (44 μmol, 1.1 eq) in THF (500 μL) was added to the above vial. The reaction mixture was heated at 40° C. for 6 h on a shaker. The resin was removed by filtration and washed with 10% MeOH/CH2Cl2. The solvent was removed in vacuo and the residue was applied to solid phase extraction cartridge (basic silica, 200 mg) and eluted with 50% EtOAc/CH2Cl2. After removal of the solvents, the crude 2-amino-N-cyclohexyl-benzamide was obtained and used for the following reaction.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]=C)=[CH:19][CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])C.C[N+]1([O-])CC[O:30]CC1>O1CCOCC1.O.CCOC(C)=O.[Os](=O)(=O)(=O)=O>[CH:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:11]([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:3])=[O:25])=[CH:18][CH:19]=1)=[O:30]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc(CN(CCCCCCC(=O)OCC)S(C)(=O)=O)cc1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N(CCCCCCC(=O)O)Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A solution of ethyl-7-[(4-vinyl-benzyl)-methanesulfonyl-amino]-heptanoate (2.2 g, 6.0 mmol) in dioxane (45 mL) was added to a solution of N-methylmorpholine N-oxide (1.47 g, 12.5 mmol) in water (45 mL). Osmium tetroxide (4.6 mL, 2.5 wt % in 2-methyl-2-propanol) was added and the mixture was stirred at room temperature for 1 h. The reaction was quenched with 1N HCl (50 mL) and the aqueous solution was extracted with CH2Cl2. The organic layer was washed with water (1×) followed by brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in 35% aqueous THF (100 mL) and NaIO4 (1.41 g, 6.59 mmol) was added. The mixture was stirred at room temperature for 2 h and was diluted with EtOAc and water. The organic solution was washed with water (1×) followed by brine (1×), dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound (1.9 g) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 10.0 (s, 1H), 7.82–7.90 (d, 1H), 7.50–7.59 (d, 2H), 5.30 (s, 2H), 4.45 (s, 2H), 4.05–4.18 (m, 2H), 3.12–3.22 (m, 2H), 2.86 (s, 3H), 2.19–2.30 (m, 2H), 1.42–1.62 (m, 6H), 1.18–1.30 (m, 3H); MS 387 (M+18).
Reaction SMILES: C[O:2][C@H:3](C1C=CC=CC=1)[C:4](O)=O.[F:13][C:14]1[C:19]([O:20][CH2:21][CH2:22][OH:23])=[CH:18][C:17]([O:24][CH3:25])=[CH:16][C:15]=1[C@@H:26]([NH:39][C:40]1[CH:48]=[CH:47][C:43]([C:44]([NH2:46])=[NH:45])=[CH:42][CH:41]=1)[C:27]1[NH:31][C:30](=[O:32])[N:29]([C:33]2[N:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[N:28]=1.[N+](C1C=CC(O[C:59](=[O:65])[O:60][CH2:61][C:62]([CH3:64])=[CH2:63])=CC=1)([O-])=O.C(N(CC)CC)C.C(OC(=O)C)(=O)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[NH2:45][C:44](=[N:46][C:59]([O:60][CH2:61][C:62]([CH3:64])=[CH2:63])=[O:65])[C:43]1[CH:42]=[CH:41][C:40]([NH:39][C@@H:26]([C:27]2[NH:31][C:30](=[O:32])[N:29]([C:33]3[N:34]=[CH:35][CH:36]=[CH:37][N:38]=3)[N:28]=2)[C:15]2[C:14]([F:13])=[C:19]([CH:18]=[C:17]([O:24][CH3:25])[CH:16]=2)[O:20][CH2:21][CH2:22][O:23][C:3](=[O:2])[CH3:4])=[CH:48][CH:47]=1
Reactant: COc1cc(OCCO)c(F)c([C@@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Reactant: CO[C@@H](C(=O)O)c1ccccc1
Reactant: C=C(C)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(C)COC(=O)N=C(N)c1ccc(N[C@@H](c2nn(-c3ncccn3)c(=O)[nH]2)c2cc(OC)cc(OCCOC(C)=O)c2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-{[(R)-[2-fluoro-3-(2-hy droxy ethoxy)-5-methoxyphenyl] (5-oxo-1-pyrimidi n-2-yl-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]amino}benzamidine (R)-methoxyphenylacetate (0.5 g, 0.755 mmol), carbonic acid 2-methylallyl ester 4-nitrophenyl ester [CAS No. 218598-29-9] (179 mg, 0.755 mmol), and N,N-dimethylformamide (1.5 mL), triethylamine (0.532 mL, 3.78 mmol) was added, and the resulting mixture was stirred overnight at room temperature. To the reaction solution, 4-dimethylaminopyridine (2.78 mg, 0.0228 mmol) and acetic anhydride (0.157 mL, 1.66 mmol) were added, and the resulting mixture was stirred at room temperature for 1 hour and 20 minutes. A buffer of pH 6 was added to the reaction solution, and the resulting mixture was extracted four times with a mixture of ethyl acetate and tetrahydrofuran (ethyl acetate:tetrahydrofuran=1:1). All the organic layers were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then filtered. The filtrate obtained was concentrated under reduced pressure, after which acetone (3 mL) was added to the residue obtained, and the resulting mixture was stirred at room temperature for 3 days. The precipitated solid was filtered and washed with acetone (1.5 mL). The solid obtained was dried under air flow to obtain the captioned compound (246 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].C([N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])C.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1.C[C:24](C)=[O:25]>C(Cl)Cl>[C:12]1([CH3:22])[CH:13]=[CH:14][C:15]([S:18]([OH:21])(=[O:19])=[O:20])=[CH:16][CH:17]=1.[CH3:1][N:2]([CH3:4])[NH:3][C:24]([C:22]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH2:8][NH:7][CH2:10][CH2:11]1)=[O:25]
Reactant: CC(C)=O
Reactant: CCN(CC)CC
Reactant: CN(C)N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CN(C)NC(=O)C1(c2ccccc2)CCNCC1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
A solution of 7.15 g of the compound obtained in step B of PREPARATION 1.28 in 60 ml of DCM is cooled to 5° C., a solution of 1.44 g of 1,1-dimethylhydrazine and 4.04 g of triethylamine in 20 ml of DCM is added dropwise and the reaction mixture is left stirring overnight at RT. It is concentrated under vacuum, the residue is taken up with water, the product is extracted with AcOEt, the organic phase is washed with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated off under vacuum. The product obtained is dissolved in 100 ml of acetone, a solution of 3.59 g of p-toluenesulphonic acid in 10 ml of acetone is added rapidly and the mixture is concentrated under vacuum. The residue is taken up in an ether/DCM mixture and the precipitate formed is drained. 9.65 g of the expected product are obtained.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](/[CH:25]=[CH:26]/[C:27]2[N:41]=[C:30]3[CH:31]([CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH2:32][CH2:33][CH2:34][N:29]3[N:28]=2)[CH:16]=[CH:17][C:18]=1[N:19]1[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]1.O.C(OCC)(=O)C>C(Cl)Cl>[C:1]1([S:7]([N:38]2[CH2:39][CH2:40][CH:35]([CH:31]3[CH2:32][CH2:33][CH2:34][N:29]4[N:28]=[C:27](/[CH:26]=[CH:25]/[C:15]5[CH:16]=[CH:17][C:18]([N:19]6[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]6)=[C:13]([O:12][CH3:11])[CH:14]=5)[N:41]=[C:30]34)[CH2:36][CH2:37]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(/C=C/c2nc3n(n2)CCCC3C2CCNCC2)ccc1-n1cnc(C)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3C2CCN(S(=O)(=O)c3ccccc3)CC2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
TEA (20 μl) and benzenesulfonyl chloride (8 μl) were added to a solution of racemic 2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperidin-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine obtained in Examples 118 and 119 (20 mg) in methylene chloride (1 ml), and the reaction solution was stirred at room temperature for 40 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was sequentially washed with a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 24 mg of racemic 8-(1-benzenesulfonylpiperidin-4-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine. Then, the racemate was separated by CHIRALCEL™ OD-H manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethanol) to obtain the title optically active compound with a retention time of 24 minutes and positive optical rotation (7.3 mg; 100% ee) and the title optically active compound with a retention time of 29 minutes and negative optical rotation (7.4 mg; >98% ee).