Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH2:6][O:7][Si:8]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10])[C:3]([OH:5])=O.CCN=C=NCCCN(C)C.Cl.[CH3:31][NH:32][O:33][CH3:34].CCOC(C)=O>ClCCl.CN(C1C=CN=CC=1)C>[CH3:34][O:33][N:32]([CH3:31])[C:3](=[O:5])[C:2]([CH3:1])([CH3:18])[CH2:6][O:7][Si:8]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)[Si](OCC(C)(C)C(=O)O)(C(C)C)C(C)C
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CON(C)C(=O)C(C)(C)CO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of 2,2-dimethyl-3-triisopropylsilanyloxy-propionic acid in anhydrous dichloromethane (13 ml) was slowly treated with EDCI (1.03 g, 5.38 mmol) followed by N,O -dimethylhydroxylamine hydrochloride (525 mg, 5.4 mmol), DMAP (55 mg, 0.045 mmol), and TEA (0.75 ml, 5.38 mmol). After stirring overnight at room temperature the reaction mixture was partitioned between DCM/water. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a greenish oil. Silica gel chromatography using 10-60% EtOAc in hexanes as eluant provided 1.13 mg (79%) of N-methoxy-2,2,N-trimethyl-3-triisopropylsilanyloxy-propionamide as a colorless oil. M+H=318.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].C(OC(=O)[NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33](N)=[CH:32][CH:31]=1)(C)(C)C.FC(F)(F)C(O)=O.ClCCl>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][NH2:28])=[CH:31][CH:32]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: ClCCl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2ccc(CN)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
To a stirred solution of 100 mg (0.348 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (6 ml), (4-aminobenzyl)carbamic acid tert-butyl ester (Gallo-Rodriguez, C et al J. Med. Chem. 1994, 37(5), 636-46) (1.16 mg, 0.52 mmol) was added portionwise. The resulting mixture was stirred at room temperature for 1 h. The precipitate thus formed was collected by filtration and washed with diethylether. Then it was solved in dichloromethane (1 mL) and trifluoroacetic acid (0.23 mL, 3.03 mmol) was added dropwise. The final mixture was stirred at room temperature for 20 minutes. Some more dichloromethane was added and this solution was washed with saturated K2CO3 solution until pH 6. The organic layer was dried and solvent removed to yield 70 mg (54% yield) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[CH:13][C:5]=1[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Nc1ccccn1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1Nc1ccccn1
Reaction time: 1.67 h
Yield: 84.6 %

Procedure:
A mixture of 2-nitro-N-(2-pyridyl)-4-trifluoromethylaniline (1.00 g, 3.5 mmol), 5% palladium on carbon (0.23 g) and methanol (50 ml) was stirred under a hydrogen atmosphere for 100 min. The mixture was filtered through a pad of celite and the filtrate was concentrated to dryness to give 0.75 g (85%) of the titled compound as yellow brown solids. 1H-NMR (CDCl3) δ: 8.19 (1H, ddd, J=5.1, 1.8, 0.7 Hz), 7.49 (1H, ddd, J=8.3, 7.0, 1.8 Hz), 7.35 (1H, d, J=7.7 Hz), 7.05-7.01 (2H, m), 6.76 (1H, ddd, J=7.0, 5.1, 1.1 Hz), 6.55 (1H, ddd, J=8.3, 1.1, 0.7 Hz), 6.31 (1H, br.s), 3.98 (2H, br.s).
Reaction SMILES: Cl.[H-].[Na+].[CH3:4][N:5]1[CH2:18][CH2:17][C:8]2[NH:9][C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][C:15]=3[C:7]=2[CH2:6]1.Cl[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22]>CCCCCC.C1COCC1>[CH3:4][N:5]1[CH2:18][CH2:17][C:8]2[N:9]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][C:15]=3[C:7]=2[CH2:6]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: O=C(CCl)N1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCCCC2)CCN(C)C1
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetic acid (1.5 g, 5.8 mmol) was taken in dichloromethane (15 mL) and was cooled to 0° C. using an ice-bath; oxalyl chloride (0.61 mL, 6.9 mmol) was added drop-wise, catalytic amount (2 drop) of dimethyl formamide was added to the reaction mixture. After the addition, reaction mixture was stirred for 1 h at room temperature. Excess oxalyl chloride was distilled away under reduced pressure. To this residue, solution of Piperidine (0.68 mL, 6.9 mmol) in 4 mL DCM and DMAP (0.71 g, 5.8 mmol) was added under nitrogen at room temperature and reaction mass was stirred for 0.5 h at room temperature. The reaction mixture was quenched by ice water and extracted with Dichloromethane and purified by column chromatography to gives 0.8 g of desired compound as free base. The free base was converted into HCl salt by treatment with ethanolic HCl. Sodium hydride (0.8 g, 20 mmol) washed with hexane for removal of oil and dried under vacuum. Then sodium hydride was taken in THF. To this solution 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2 g, 10 mmol) in THF was added drop wise at 0° C. Then reaction mixture stirred for 0.5 h. The solution of 2-chloro-1-(piperidin-1-yl)ethanone (1.9 g, 12 mmol) in THF was added drop wise in react ion mixture. Then reaction mixture stirred at RT for 2 h. Reaction monitored by TLC. After completion of reaction, reaction mixture quench with ice-water. THF was evaporated and aqueous layer was extracted with ethyl acetate. Organic layer was dried over anhydrous sodium sulphate. The crude compound was washed with hexane and diethyl ether for removal of color impurities then recrystallized by using methanol to give 1 g of desired compound then it was stirred with ethanolic HCl to give HCl salt of 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(piperidin-1-yl)ethanone.
Reaction SMILES: [C:1]([C@@H:3]([NH:5][C:6](=[O:12])OC(C)(C)C)[CH3:4])#[N:2].[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=1)[CH2:24][O:25][C:26]1[CH:34]=[CH:33][C:29](C(O)=O)=[CH:28][CH:27]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=1)[CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([C:6]([NH:5][C@H:3]([C:1]#[N:2])[CH3:4])=[O:12])=[CH:33][CH:34]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C[C@@H](C#N)NC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(OCc2cccc(OCc3ccccc3)c2)cc1
Product: C[C@@H](C#N)NC(=O)c1ccc(OCc2cccc(OCc3ccccc3)c2)cc1
Yield: 51.1 %

Procedure:
General procedures D and E were used to deprotect 0.45 mmols of (S)-tert-butyl 1-cyanoethylcarbamate and couple to 0.45 mmols of the acid 36. After purification by flash chromatography, 0.23 mmols of the title product was recovered. 1H NMR (500 MHz, CDCl3) δ 7.78-7.72 (m, 2H), 7.47-7.42 (m, 2H), 7.41-7.37 (m, 2H), 7.36-7.29 (m, 2H), 7.06 (s, 1H), 7.02 (s, 1H), 7.01-6.98 (m, 2H), 6.95 (dd, J=2.5, 8.2, 1H), 6.46 (s, 1H), 5.15 (dd, J=7.6, 14.9, 1H), 5.09 (s, 2H), 5.07 (s, 2H), 1.65 (d, J=7.2, 3H). 13C NMR (75 MHz, CDCl3) δ 191.04, 163.88, 159.36, 137.82, 136.98, 132.24, 130.09, 128.86, 128.29, 127.74, 120.05, 115.39, 114.79, 114.14, 70.25.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].ClCCl.C(N(CC)CC)C>N1C=CC=CC=1>[F:1][C:2]([F:8])([F:7])[S:3]([O:6][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4])(=[O:5])=[O:4]
Reactant: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F

Procedure:
Step 2 is a step of conversion of hydroxyl to a trifluoromethanesulfonate (triflate). Compound (B3-c) may be obtained by reaction with trifluoromethanesulfonic anhydride in a solvent such as dichloromethane in the presence of a base such as triethylamine or pyridine, or by reaction with compound (B3-e) in the presence of triethylamine or dimethylaminopyridine.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@@H:9]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])[CH2:8][C@H:7]1[CH2:17][O:18][CH3:19])=[O:4].Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=2)[N:24]=[CH:23][N:22]=1.C(N(CC)CC)C>C(O)C>[CH:14]([N:12]([CH3:13])[C@@H:9]1[CH2:10][CH2:11][C@H:6]([NH:5][C:3](=[O:4])[CH2:2][NH:1][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:33])([F:34])[F:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)[C@H:7]([CH2:17][O:18][CH3:19])[CH2:8]1)([CH3:16])[CH3:15]
Reactant: COC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)CN
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)CNc1ncnc2ccc(C(F)(F)F)cc12
Temperature: 25 °C
Yield: 52.2 %

Procedure:
A solution of the bis-trifluoroacetic acid salt of 2-amino-N-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(methoxymethyl)cyclohexyl)acetamide (57 mg) in ethanol (4 mL) was treated with 4-chloro-6-(trifluoromethyl)quinazoline (40 mg) and triethylamine (0.08 mL). The mixture was heated at reflux overnight. The mixture was then cooled to rt and purified by reverse phase HPLC and lyopholization to provide the bis-trifluoroacetic acid salt of the title product as a white powder (42 mg). MS found: (M+H)+=468.4.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH3:11][S:12](O)(=[O:14])=[O:13].C(N(CC)CC)C.S(Cl)(Cl)=O>ClCCl>[CH3:11][S:12]([O:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:14])=[O:13]
Reactant: On1nnc2ccccc21
Reactant: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CS(=O)(=O)On1nnc2ccccc21
Reaction time: 8 h
Yield: 28.2 %

Procedure:
In dichloromethane (20 ml) are added 1-hydroxy-1,2,3-benzotriazole (2.70 g) and methanesulfonic acid (1.92 g) and thereto is added triethylamine (5.6 ml). To the solution is added dropwise thionyl chloride (1.43 ml) with stirring under ice-cooling during 15 minutes. The mixture is stirred at the same temperature for 1 hour and 10 minutes and at room temperature for 7 hours and 45 minutes, and then allowed to stand overnight. Dichloromethane is distilled off under a reduced pressure. To the residue are added water (30 ml) and ethyl acetate (100 ml). The ethyl acetate layer is washed with a saturated aqueous sodium hydrogen carbonate and water in order and dried over anhydrous sodium sulfate. After drying, the solvent is distilled off. To the residue is added petroleum ether and the mixture is filtered to give 1-methanesulfonyloxy-1,2,3-benzotriazole (1.2 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:30][CH:31]=[CH2:32])[C:9]([N:11]=[C:12](SC)[NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[N:23][C:22]([CH3:25])=[N:21]3)=[C:16]([O:26][CH3:27])[CH:15]=2)=O)=[CH:4][CH:3]=1.[CH2:33]([NH:36][NH2:37])[CH:34]=[CH2:35]>>[CH2:33]([N:36]1[C:9]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:30][CH:31]=[CH2:32])=[N:11][C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[N:23][C:22]([CH3:25])=[N:21]3)=[C:16]([O:26][CH3:27])[CH:15]=2)=[N:37]1)[CH:34]=[CH2:35]
Reactant: C=CCC(C(=O)N=C(Nc1ccc(-n2cnc(C)n2)c(OC)c1)SC)c1ccc(F)cc1
Reactant: C=CCNN
Product: C=CCC(c1ccc(F)cc1)c1nc(Nc2ccc(-n3cnc(C)n3)c(OC)c2)nn1CC=C

Procedure:
Methyl N′-2-(4-fluorophenyl)pent-4-enoyl-N-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)carbamimidothioate (0.62 g, 1.367 mmol) was reacted with allylhydrazine (70% solution in water, 0.55 mL, 5.47 mmol) using a procedure analogous to Step B of Example 1 to provide 1-allyl-5-(1-(4-fluorophenyl)but-3-enyl)-N-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine. The purified product was dissolved in 0.1% TFA/dichloromethane and reconcentrated to afford 1-allyl-5-(1-(4-fluorophenyl)but-3-enyl)-N-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine, TFA salt (446 mg, 0.692 mmol, 51% yield) as a clear solid residue. LC-MS (M+H)+=560.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH3:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([NH:15][CH:12]2[CH2:14][CH2:13]2)[CH3:9])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: NC1CC1
Reactant: CC(=O)c1cc(Cl)nc(Cl)c1
Product: CC(NC1CC1)c1cc(Cl)nc(Cl)c1

Procedure:
1-(2,6-Dichloropyridin-4-yl)ethanone and cyclopropylamine were treated in the similar manner to Reference Example 6(6) to give N-[1-(2,6-dichloropyridin-4-yl)ethyl]-cyclopropylamine [Ex(297-1)] as a pale yellow oil.
Reaction SMILES: N1C=CC=CC=1.C(OC(=O)C)(=O)C.NCCCCCCC#N.[C:23]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]#[N:34])(=O)[CH3:24]>C1C=CC=CC=1>[CH2:23]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])[CH3:24]
Reactant: CC(=O)NCCCCCCC#N
Agent: N#CCCCCCCN
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCNCCCCCCCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The intermediate N-ethyl-1,7-heptanediamine was prepared in two steps as follows: To a stirred mixture kept in an ice bath and containing 7.2 g. of pyridine, 100 ml. of benzene and 9.2 g. of acetic anhydride was added dropwise over a period of a few minutes 10.0 g. of 7-aminoheptanonitrile. The ice bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was then evaporated to dryness and the residue taken up in a mixture of 60 ml. of water and 60 ml. of chloroform. The mixture was acidified with 6N hydrochloric acid and shaken well. The layers were separated and the aqueous layer was extracted with four 60 ml. portions of chloroform. The combined extracts were dried over anhydrous potassium carbonate and the solvent removed in vacuo to yield, as a viscous yellow liquid, 15.1 g. of 7-acetamidoheptanonitrile.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[N:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][CH:22]=3)[O:18][N:17]=2)[N:3]=1.[BH4-].[Na+].CCOC(C)=O.O>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]2[N:20]=[C:19]([C:21]3[N:26]=[CH:25][C:24]([CH:27]([OH:29])[CH3:28])=[CH:23][CH:22]=3)[O:18][N:17]=2)[N:3]=1
Reactant: CC(=O)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.7 %

Procedure:
1-[6-(3-{4-Amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)pyridin-3-yl]ethan-1-one (Intermediate 141, 0.934 g, 2.40 mmol) was suspended in THF (60 mL), sodium borohydride (0.227 g, 6.01 mmol) was added and the mixture stirred at room temperature for 2 h. EtOAc (50 mL) and water (100 mL) were added and the organic layer separated. The aqueous layer was neutralised using 1M aq. hydrochloric acid and extracted with EtOAc (3×30 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to afford the title compound as a pale yellow solid (1.0 g), which was used in the next step without further purification. Method C HPLC-MS: MH+ requires m/z=391 Found: m/z=391, Rt=1.18 min (84%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[CH2:25][C:26]#[N:27]>>[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1/[C:25](=[CH:12]/[C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:14][CH3:15])=[CH:6][CH:5]=2)/[C:26]#[N:27]
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Reactant: N#CCc1nc2ccccc2s1
Product: COc1ccc2nc(Cl)c(/C=C(\C#N)c3nc4ccccc4s3)cc2c1
Yield: 78.4 %

Procedure:
2-Chloro-6-methoxy-3-quinolinecarboxaldehyde (111 mg) was condensed with 2-benzothiazoleacetonitrile (87 mg) through Method B (production step 3), to thereby yield the target product (yield: 148 mg, 78%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[BrH:1].[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[NH:8])[N:6]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc(Br)cn1
Product: Br
Product: CCOC(=O)Cn1cc(Br)ccc1=N

Procedure:
By carrying out the process as in Example 3.1 and using 5.0 g of 5-bromopyridin-2-ylamine and 9.6 ml of ethyl 2-bromoacetate, 9.56 g of compound are obtained.
Reaction SMILES: [F:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.C(Cl)(=O)C(Cl)=O.[CH3:39][NH:40][CH3:41]>C(Cl)Cl.C1COCC1>[CH3:39][N:40]([CH3:41])[C:6]([CH:4]1[CH2:5][C:2]([F:1])([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:13][CH:14]=2)[CH2:3]1)=[O:8]
Reactant: O=C(O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Reactant: CNC
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Reaction time: 1 h
Yield: 29 %

Procedure:
To a stirred solution of 3-fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid (Preparation 7, 0.085 g, 0.166 mmol) in DCM (4 mL) was added oxalyl chloride (0.025 g, 0.199 mmol) at 0° C. and stirred for 1 hour. After 1 hour, saturated solution of dimethyl amine in THF (4 mL) was added. Resulting reaction mixture was stirred at room temperature for 16 hours. After complete consumption of starting material, reaction mixture was concentrated in vacuo to afford crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 0.7% methanol in DCM to afford off white solid (0.026 g, 29%). 1H-NMR (400 MHz, CDCl3) δ: 2.72-2.78 (m, 2H), 2.87-2.92 (m, 1H), 2.94 (s, 3H), 2.98 (s, 3H), 2.99-3.09 (m, 2H), 3.68 (d, 1H, J=17.2 Hz), 4.08 (d, 1H, J=17.16 Hz), 7.54 (d, 2H, J=8.16 Hz), 7.64 (s, 2H), 7.70 (d, 2H, J=8.24 Hz); LC-MS (m/z): [M−H] 534.60.
Reaction SMILES: [F:1][C:2]1[C:15]([NH:16][C:17](OC)=[O:18])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[NH2:21]/[C:22](/[C:29]([F:32])([F:31])[F:30])=[CH:23]\[C:24]([O:26]CC)=O.[H-].[Na+].O>CN(C)C=O>[F:1][C:2]1[C:15]([N:16]2[C:24](=[O:26])[CH:23]=[C:22]([C:29]([F:30])([F:31])[F:32])[NH:21][C:17]2=[O:18])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: C#CCN1C(=O)COc2cc(F)c(NC(=O)OC)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN1C(=O)COc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21

Procedure:
A mixture of 7-fluoro-6-methoxycarbonylamino-4-propargyl-2H-1,4-benzoxazin-3(4H)-one (1.4 g) and ethyl 3-amino-4,4,4-trifluorocrotonate was dissolved in dimethylformamide (5 g), and sodium hydride (0.2 g) was added thereto. The resultant mixture was stirred for 30 minutes while cooling with ice and heated under reflux for 3 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by column chromatography to give 1-[7-fluoro-4-propargyl-2H-1,4-benzoxazin-3(4H)-on-6-yl]-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione (0.2 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][N:16]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:32])=O>O>[Cl:32][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cn1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a mixture of 2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine-5-methanol (12.2 g) and toluene (200 ml) was added thionyl chloride (5.39 g), and the mixture was stirred at room temperature for 1 hr. Iced water was added to the reaction mixture, and after neutralization with saturated aqueous sodium hydrogencarbonate, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to give crystals (11.7 g, yield 90%) of 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 86-87° C.
Reaction SMILES: CN(C)C=O.Cl.[CH3:7][C:8]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][C:9]=1[NH2:10].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>C(OCC)(=O)C.C(N(CC)CC)C>[CH3:7][C:8]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:11][C:9]=1[NH:10][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(Oc2ccccc2)cc1N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccccc2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5 mL of N,N-dimethylformamide containing 0.50 g of 2-methyl-5-phenoxyaniline hydrochloride, 0.91 mL of triethylamine and 0.27 mL of benzoyl chloride were added sequentially while ice-cooled sequentially and stirred at room temperature for 3 hours. Ethyl acetate and 1.0 mol/L hydrochloric acid were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 1.0 mol/L hydrochloric acid, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 0.42 g of N-(2-methyl-5-phenoxyphenyl)benzamide as white solid.