Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:11][CH:7]([C:8](=[O:10])[CH2:9]1)[CH:6]1[CH:2]2[CH2:3][CH2:4][CH2:5]1.[CH3:12][Mg]Cl.O>O1CCCC1>[CH3:12][C:8]1([OH:10])[CH2:9][CH:1]2[CH2:11][CH:7]1[CH:6]1[CH:2]2[CH2:3][CH2:4][CH2:5]1
Reactant: C[Mg]Cl
Reactant: O=C1CC2CC1C1CCCC21
Solvent: O
Solvent: C1CCOC1
Product: CC1(O)CC2CC1C1CCCC21

Procedure:
Tricyclo[5.2.1.02, 6]decan-8-one (15.0 g) in tetrahydrofuran (THF, 50 ml) is slowly added into CH3MgCl (9.7 g) in THF and the reaction mixture is stirred completely. Tetrahydrofuran (THF, 100 ml) with 5% of water is added into the reaction mixture. Then 100 ml of water is added to the reaction mixture. The reaction mixture is extracted by ether. The organic extract is concentrated in vacuo to yield 8-methyl-tricyclo[5.2.1.02,6]decan-8-ol (formula (X)) as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[C:19]([CH2:20][NH:21][CH2:22][CH3:23])=[CH:18][C:17]([CH3:24])=[CH:16][N:15]=2)[CH:7]=1)[CH3:2].FC(F)(F)C([O-])=O.[C:33](Cl)(=[O:42])[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[C:19]([CH2:20][N:21]([CH2:22][CH3:23])[C:33](=[O:42])[CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:18][C:17]([CH3:24])=[CH:16][N:15]=2)[CH:7]=1)[CH3:2]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CCNCc1cc(C)cnc1-c1cc(CC(=O)OCC)ccc1OC
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ncc(C)cc2CN(CC)C(=O)CCc2ccccc2)c1

Procedure:
[3-(3-Ethylaminomethyl-5-methyl-pyridin-2-yl)-4-methoxy-phenyl]-acetic acid ethyl ester, trifluoroacetate (0.36 mmol) was reacted with hydrocinnamoyl chloride (0.06 mL, 0.44 mmol) and triethylamine (0.15 mL, 1.09 mmol) in CH2Cl2 to give the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:22][C@@H:21]([CH3:23])[N:11]2[C:12]3[CH:13]=[C:14]([CH3:20])[C:15]([Br:19])=[CH:16][C:17]=3[CH:18]=[C:10]2[CH2:9]1)=O)(C)(C)C.[ClH:24]>C(OCC)(=O)C>[ClH:24].[Br:19][C:15]1[C:14]([CH3:20])=[CH:13][C:12]2[N:11]3[C@H:21]([CH3:23])[CH2:22][NH:8][CH2:9][C:10]3=[CH:18][C:17]=2[CH:16]=1
Reactant: Cc1cc2c(cc1Br)cc1n2[C@H](C)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1Br)cc1n2[C@H](C)CNC1

Procedure:
A solution of 0.12 g (R)-8-bromo-4,7-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester in 3 ml of a 2M solution of hydrochloric acid in ethyl acetate was stirred at room temperature under argon for 2 h. The precipitate was collected by filtration and dried to constant weight to yield the title compound (0.065 g) as off-white crystals. m.p.: 241° C. (dec.); ISP-MS: M+H=279.1; 1HNMR: (250 MHz, DMSO-d6, δ [ppm]) 1.50 (d, J=6.5 Hz, 3H); 2.45 (s, 3H); 3.48-3.74 (m, 2H); 4.36-4.58 (m, 2H); 4.74-4.89 (m, 1H); 6.35 (s, 1H); 7.54 (s, 1H); 7.78(s, 1H)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:27]=1>>[CH:20]1([CH2:19][CH2:18][CH2:17][C@@H:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH:1][S:32]([C:28]3[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=3)(=[O:34])=[O:33])[N:7]=2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNS(=O)(=O)c2cccnc2)no1

Procedure:
Method same as Preparation 14 using tert-butyl(3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (200 mg, 057 mmol) and 3-pyridinesulphonylchloride (EP911333) (134 mg, 0.63 mmol) as starting materials.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[C:10]([CH3:14])[C:11]([OH:13])=[O:12].[CH:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17](O)[CH:16]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CC=CN=1)C.ClCCl>[N+:21]([C:20]1[CH:15]=[CH:16][C:17]([O:12][C:11](=[O:13])[C:10]([CH3:14])=[CH:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[NH2:1])=[CH:18][CH:19]=1)([O-:23])=[O:22]
Reactant: CC(=Cc1ccc(Cl)cc1N)C(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CC(=Cc1ccc(Cl)cc1N)C(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
Into 20 ml of dichloromethane, 0.81 g (3.8 mmol) of (E) 3-(2-amino-4-chlorophenyl)-2-methyl-2-propenoic acid and 1.0 g of p-nitrophenol (manufactured by Wako Pure Chemical Industries, Ltd.) were dissolved; and 40 mg of dimethylaminopyridine (manufactured by Wako Pure Chemical Industries, Ltd.) were added thereto. Further, while the mixture was stirred under cooling with ice, 1.0 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC-HCl) (manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto in portions. The mixture was returned to room temperature and then was stirred for 20 hours. After the end point of this reaction was verified by TLC, the reaction liquid was concentrated under a reduced pressure and then was dissolved in 100 ml of ethyl acetate. This solution was washed several times with a 5% aqueous sodium hydrogencarbon ate solution and then with a saturated aqueous sodium chloride solution, and was dried with magnesium sulfate anhydride. Thereafter, the solvent was evaporated, whereby a crude product was obtained. This product was recrystallized from ethanol, whereby 1.2 g of the aimed compound were obtained as a crystal (yield: 91%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:22]O>[Pd]>[NH2:12][C:9]1[CH:10]=[CH:11][C:2]([O:1][CH3:22])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: CO
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1O
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1cc(N)ccc1OC

Procedure:
The hydrogenation of methyl 2-hydroxy-5-nitrobenzoate (700 mg, 3.3 mmol) using 10% Pd—C (100 mg) and Na2SO4 (100 mg) in MeOH at 50 psi gave methyl 5-amino-2-methoxybenzoate (600 mg).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[S:11][C:10]([N:12]=CN(C)C)=[N:9][C:8]=1[CH3:17])=O.[N+]([O-])(O)=O.[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH2:36])=[NH:35])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>CC#N>[NH2:12][C:10]1[S:11][C:7]([C:5]2[CH:4]=[CH:3][N:36]=[C:34]([NH:33][C:30]3[CH:29]=[CH:28][C:27]([S:24]([CH3:23])(=[O:25])=[O:26])=[CH:32][CH:31]=3)[N:35]=2)=[C:8]([CH3:17])[N:9]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)N)cc1
Reactant: Cc1nc(N=CN(C)C)sc1C(=O)C=CN(C)C
Solvent: CC#N
Solvent: O=[N+]([O-])O
Product: Cc1nc(N)sc1-c1ccnc(Nc2ccc(S(C)(=O)=O)cc2)n1

Procedure:
By condensation of N′-[5-(3-dimethylamino-acryloyl)-4-methyl-thiazol-2-yl]-N,N-dimethyl-formamidine and N-(4-methanesulfonyl-phenyl)-guanidine nitrate. Yellow solid. Anal. RP-HPLC: tR=13.2 min (0-60% MeCN, purity>97%). 1H-NMR (DMSO-d6) δ: 1.98 (s, 3H, CH3), 2.54 (s, 3H, CH3), 7.06 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.80 (m, 2H, Ph-H), 8.00 (m, 2H, Ph-H), 8.45 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 10.05 (sbr, 2H, NH2). MS (ESI+) m/z 362.38 [M+H]+ (C15H15N5O2S2 requires 361.44).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]=[C:6]=[O:7].C[O:9][C:10]([C:12]1([CH3:33])[CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:25])[CH:21]=3)[NH:16][C:15]=2[CH:14]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[NH:13]1)=O>>[Cl:25][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]1[CH:14]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=3)[N:13]3[C:6](=[O:7])[N:5]([CH2:4][CH2:3][CH2:2][Cl:1])[C:10](=[O:9])[C:12]3([CH3:33])[CH2:24][C:23]2=1
Reactant: O=C=NCCCCl
Reactant: COC(=O)C1(C)Cc2c([nH]c3ccc(Cl)cc23)C(c2cccc(O)c2)N1
Product: CC12Cc3c([nH]c4ccc(Cl)cc34)C(c3cccc(O)c3)N1C(=O)N(CCCCl)C2=O

Procedure:
The title compound is prepared analogously to the procedure described for example 22, using chloro propyl isocyanate and (1RS,3SR)-6-chloro-1-(3-hydroxy-phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-betacarboline-3-carboxylic acid methyl ester. MS: m/z (MH+)=457.9
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](O)=[N:6][CH:7]=1.P(Br)(Br)([Br:12])=O>CN(C=O)C>[Br:12][C:5]1[C:4]([F:9])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1
Reactant: O=P(Br)(Br)Br
Reactant: Oc1ncc(Cl)cc1F
Solvent: CN(C)C=O
Product: Fc1cc(Cl)cnc1Br
Temperature: 130 °C
Yield: 73984.3 %

Procedure:
To solid 5-chloro-3-fluoro-2-hydroxypyridine (75 g, 0.51 mmol) was added melted POBr3 (150 g, 0.52 mmol). DMF (2 mL) was then added by pipet, and the mixture was heated at 130° C. for 1 h. The excess POBr3 was quenched by the careful addition of water to the reaction mixture at 0° C., and the resulting mixture was dissolved in a 2:1 mixture of EtOAc:water. The organic layer was washed three times with water and once with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting yellow oil was passed through a plug of silica gel (10% Et2O:90% hexanes) to provide the title compound as a white solid (79.4 g, 74%). The product was characterized by 1H NMR.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)[N:5]2[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=[C:4]2[CH:3]=1.[CH:22]([NH:25][C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)=[O:27])([CH3:24])[CH3:23]>>[CH:22]([NH:25][C:26](=[O:27])[C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=3)[N:5]3[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=[C:4]3[CH:3]=2)[CH:33]=1)([CH3:24])[CH3:23]
Reactant: Cc1cc(Nc2nc(Cl)cc3nc(C(F)(F)F)cn23)n[nH]1
Reactant: CC(C)NC(=O)c1cccc(B(O)O)c1
Product: Cc1cc(Nc2nc(-c3cccc(C(=O)NC(C)C)c3)cc3nc(C(F)(F)F)cn23)n[nH]1

Procedure:
Title compound was synthesized from 7-chloro-N-(5-methyl-1H-pyrazol-3-yl)-2-(trifluoromethyl)imidazo[1,2-c]pyrimidin-5-amine and 3-(isopropylcarbamoyl)phenyl boronic acid using the procedure described in Example 278. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (d, J=6.57 Hz, 6H) 2.32 (s, 3H) 4.15 (td, J=13.45, 6.69 Hz, 2H) 6.74 (s, 1H) 7.60 (t, J=7.71 Hz, 1H) 7.78 (s, 1H) 7.90 (d, J=7.83 Hz, 1H) 8.27 (d, J=8.08 Hz, 1H) 8.38 (d, J=7.58 Hz, 1H) 8.57 (s, 1H) 9.03 (s, 1H) 10.55 (s, 1H); ESI-MS: m/z calc'd for C21H20F3N7O 443.43; found 444.3 (M+H)+.
Reaction SMILES: [S:1]1CS[C:2]1=[C:5]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[C:6]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12])=O.O.[NH2:23][NH2:24]>C(O)C>[SH:1][C:2]1[NH:24][N:23]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])[C:5]=1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1
Reactant: NN
Reactant: N#Cc1cccc(C(=O)C(=C2SCS2)c2ccncc2)c1
Solvent: CCO
Solvent: O
Product: N#Cc1cccc(-c2n[nH]c(S)c2-c2ccncc2)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
3-(2-[1,3]Dithietan-2-ylidene-2-pyridin-4-yl-acetyl)-benzonitrile (5 g, 16.1 mmol) was suspended in absolute ethanol (50 mL) and heated to 60° C. Hydrazine monohydrate (3.13 mL, 64.4 mmol, 4 eq) was added dropwise and the mixture was stirred at 60° C. for 2 hours. The suspension was concentrated to about ¼ of the original volume, diluted with THF (50 mL) and stirred for 5 minutes. The yellow solid was filtered, washed with THF and dried at 50° C. for 1 hours. The crude product (4.59 g) was used in the following step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+].[C:22]1(=[O:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CCCCCC>[C:16]([CH:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)[C:22]1([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)#[N:17]
Reactant: O=C1CCCCC1
Reactant: N#CCc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCCC
Product: N#CC(c1ccc(OCc2ccccc2)cc1)C1(O)CCCCC1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
p-Benzyloxyphenyl acetonitrile (100 g) and methanol (300 ml) was charged into flask Subsequently the reaction mixture was cooled to 0-5° C. and 10% aqueous solution of sodium hydroxide (180 g) and PEG-400 (10 ml) were added. The reaction mixture was then stirred for 30 min. and cyclohexanone (64 g) was added dropwise at 0-5° C. Subsequently, the reaction mass temperature was raised to 25-27° C. and stirred for 15 hours. After completion of the reaction hexane (600 ml) was added, the reaction mixture filtered, washed with hexane (100 ml) followed by DM water to obtain 120 g (83.9%) of the 1-[cyano(p-benzyloxyphenyl)methyl]cyclohexanol.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.CCN(CC)CC.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:21]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](OC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a solution of (3S)-pyrrolidin-3-ol (0.87 g, 10.0 mmol) in THF (20 mL) was slowly added a solution of di-tert-butyl dicarbonate (2.18 g, 10.0 mmol) in THF (10 mL) at room temperature. After addition was completed, the reaction mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (0-2.5% methanol in dichloromethane) to give intermediate tert-Butyl(3S)-3-hydroxypyrrolidine-1-carboxylate. To a solution of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (900 mg, 4.8 mmol) in CH2Cl2 (6 mL) was added Et3N (699 mg, 6.91 mmol) followed by benzoyl chloride (809 mg, 5.76 mmol) at 0° C. After addition was completed, the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between CH2Cl2 and H2O. The organic layer was successively washed with aqueous NaHCO3 and water, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-1% methanol in dichloromethane) to give the subtitled compound (642 mg).
Reaction SMILES: CO[C:3](=[O:23])[CH2:4][N:5]1[CH2:9][C:8]([OH:10])=[C:7]([C:11]2[CH2:15][N:14]([CH2:16][C:17]([O:19]C)=O)[C:13](=[O:21])[CH:12]=2)[C:6]1=[O:22].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[OH:10][C:8]1[CH2:9][N:5]([CH2:4][C:3]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[C:6](=[O:22])[C:7]=1[C:11]1[CH2:15][N:14]([CH2:16][C:17]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:19])[C:13](=[O:21])[CH:12]=1
Reactant: C1COCCN1
Reactant: COC(=O)CN1CC(C2=C(O)CN(CC(=O)OC)C2=O)=CC1=O
Product: O=C1C=C(C2=C(O)CN(CC(=O)N3CCOCC3)C2=O)CN1CC(=O)N1CCOCC1

Procedure:
Analogously to the procedure described in Example 2, from 4.8 g (0.015 mol) of 1,1',5,5'-tetrahydro-4-hydroxy-2,2'-dioxo-[3,4'-bi-2H-pyrrole]-1,1'-diacetic acid dimethyl ester and 25 ml of morpholine there is obtained 1,1',5,5'-tetrahydro-4-hydroxy-2,2'-dioxo-[3,4'-bi-2H-pyrrole]-1,1'-diacetic acid dimorpholide in the form of pale yellow crystals having a melting point of 250° (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[C:14](Cl)=[O:15].O.[NH3:18].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[C:14]([NH2:18])=[O:15]
Reactant: COc1cc2nccc(Cl)c2cc1C(=O)Cl
Reactant: N
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2nccc(Cl)c2cc1C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7-Methoxy-4-chloroquinoline-6-carbonyl chloride (2.7 g) was dissolved in tetrahydrofuran (150 ml), and the solution was cooled to 0° C. After adding 30% ammonia water (5 ml), the mixture was stirred at room temperature for 30 minutes. Water was added, extraction was performed 3 times with ethyl acetate, and then the organic layers were combined, washed with water and saturated brine, dried over sodium sulfate and dried under reduced pressure to obtain the title compound (1.35 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][N:11]3[CH:18]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][CH2:28][F:29].O>C(Cl)(Cl)Cl>[F:29][CH2:28][CH2:27][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][N:11]3[CH:18]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc2nc(-c3ccc(O)cc3)cn2c1
Reactant: FCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc2nc(-c3ccc(OCCCF)cc3)cn2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63 %

Procedure:
242 mg (corresponding to 1.0 mmol) of 2-(4′-hydroxyphenyl)-6-methoxyimidazo[1,2-a]pyridine that was sufficiently dried to remove moisture was dissolved in 10 L of N,N-dimethylformamide, and 418 mg (corresponding to 3.0 mmol) of potassium carbonate was added thereto. The mixture was supplemented with 140 μL (corresponding to 1.5 mmol) of 1-bromo-3-fluoropropane, and then was stirred at room temperature for 18 hours. After the completion of the reaction, the reaction solution was poured into water and extracted three times with chloroform. The combined chloroform layer was washed once with water and once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by recycle preparative HPLC (HPLC apparatus: LC-908 (under trade name: manufactured by Japan Analytical Industry Co., Ltd.); column: two JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), to obtain 189 mg (corresponding to 0.63 mmol) of 2-[4′-(3″-fluoropropoxy)phenyl]-6-methoxyimidazo[1,2-a]pyridine (hereinafter referred to as Compound 1) (FIG. 2, Step 6).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:13]#[N:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH2:15]([S:18](Cl)(=[O:20])=[O:19])[CH2:16][CH3:17].[OH-].[Na+]>C(Cl)Cl.CCN(C(C)C)C(C)C>[CH2:15]([S:18]([N:10]1[CH2:9][CH2:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)([C:13]#[N:14])[CH2:12][CH2:11]1)(=[O:20])=[O:19])[CH2:16][CH3:17]
Reactant: N#CC1(c2ccccn2)CCNCC1
Reactant: CCCS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CCC(C#N)(c2ccccn2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Pyridin-2-ylpiperidine-4-carbonitrile (1-2) (3.55 g, 19 mmole) was dissolved in DCM-DIEA (v/v 5:1, 60 mL) at 0° C. To this solution was added n-PrSO2Cl (2.98, 21 mmole). The reaction mixture was then stirred for 1 h at 0° C. After this time, LCMS indicated that the reaction was completion. 2N NaOH (40 mL) was added and the reaction mixture was stirred 1 h at 0° C. The reaction mixture solution was then extracted with EtOAc (4×200 mL). The combined EtOAc extracts were washed with brine, dried over MgSO4, filtered, concentrated to afford the desired product 1-(propylsulfonyl)-4-pyridin-2-ylpiperidine4-carbonitrile (I-4A) as a yellow-brown solid. Analytical LCMS: single peak (214 nm), 2.642 min. This product was used in next step reaction without further purification.
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=1.Cl.[CH:22]1([C:25]2[C:26]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[N:27][CH:28]=[C:29]([CH3:31])[CH:30]=2)[CH2:24][CH2:23]1>>[CH:22]1([C:25]2[C:26]([N:32]3[CH2:37][CH2:36][N:35]([C:11]([C:10]4[CH:14]=[CH:15][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:20])=[CH:8][C:9]=4[S:16]([CH3:19])(=[O:18])=[O:17])=[O:13])[CH2:34][CH2:33]3)=[N:27][CH:28]=[C:29]([CH3:31])[CH:30]=2)[CH2:23][CH2:24]1
Reactant: Cc1cnc(N2CCNCC2)c(C2CC2)c1
Reactant: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C2CC2)c1
Yield: 69.5 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylbenzoic acid (319 mg) described in Preparation Example 22 and 1-(3-cyclopropyl-5-methylpyridin-2-yl)piperazine hydrochloride (254 mg) described in Preparation Example 85 and by the reaction and treatment in the same manner as in Example 86, the title compound (360 mg) was obtained.
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([NH:9][NH2:10])[CH3:8].[F:11][C:12]([F:20])([F:19])[C:13](=O)[CH2:14][C:15](=O)[CH3:16].ClCCl>C(O)C>[CH2:7]([N:9]1[C:15]([CH3:16])=[CH:14][C:13]([C:12]([F:20])([F:19])[F:11])=[N:10]1)[CH3:8]
Reactant: CCNN
Reactant: CC(=O)CC(=O)C(F)(F)F
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: CCO
Product: CCn1nc(C(F)(F)F)cc1C

Procedure:
A solution of 25.0 g (grams) (167 mmol) (millimoles) of ethylhydrazine oxalate in 50 mL (milliliters) of ethanol was added to a solution of 25.0 g (162 mmol) of 1,1,1-trifluoro-2,4-pentanedione in 200 mL of ethanol at ambient temperature with stirring. The mixture was heated to reflux with stirring for 18 hours and was then allowed to cool. The volatile components were removed by evaporation under reduced pressure and the residue obtained was taken up in 150 mL, of dichloromethane. The resulting solution was washed twice with 100 mL portions of water, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 19.1 g (66 percent of theory) of the title compound as an amber oil
Reaction SMILES: ClCCl.[CH3:4][N:5]=[C:6]=[S:7].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[N:16]2[CH2:19][C:18](=[CH:20][S:21]([CH2:24][C:25]3[CH:26]=[C:27]([N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[CH:28]=[CH:29][CH:30]=3)(=[O:23])=[O:22])[CH2:17]2)=[CH:11][CH:10]=1>O>[CH3:4][NH:5][C:6]([N:34]1[CH2:35][CH2:36][N:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][S:21]([CH:20]=[C:18]3[CH2:17][N:16]([CH:15]([C:12]4[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=4)[C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)[CH2:19]3)(=[O:22])=[O:23])[CH:26]=2)[CH2:32][CH2:33]1)=[S:7]
Reactant: CN=C=S
Reactant: O=S(=O)(C=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)Cc1cccc(N2CCNCC2)c1
Solvent: ClCCl
Solvent: O
Product: CNC(=S)N1CCN(c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1
Reaction time: 6 h
Yield: 99.1 %

Procedure:
2 cm3 of dichloromethane and then 11 mg of methyl isothiocyanate are successively added, at a temperature close to 20° C., to 54.25 mg of 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine. After stirring for 6 hours at a temperature close to 20° C., 0.05 cm3 of water is added to the reaction mixture. After stirring for 15 minutes at the same temperature, the reaction medium is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40° C. 61 mg of 4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carbothioic acid N-methylamide are thus obtained in the form of a beige lacquer [1H NMR spectrum (400 MHz, CDCl3), δ in ppm): 2.77 (s, 3H), 3.20 (d, J=5 Hz, 3H), 3.32 (t, J=5.5 Hz, 4H), 3.81 (mt, 2H), 4.00 (t, J=5.5 Hz, 4H), 4.33 (mt, 2H), 4.49 (s, 1H), 5.63 (broad q, J=5 Hz, 1H), 6.80 (d, J=8 Hz, 1H), 6.85 (dd, J=8 and 2.5 Hz, 1H), 6.94 (broad s, 1H), from 7.20 to 7.30 (mt, 5H), 7.32 (d, J=8 Hz, 4H)].
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[N:10]1([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=3)[N:21]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:13]2[CH2:12][CH2:11][N:10]([C:16]3[CH:17]=[CH:18][C:19]4[N:20]([C:22]([C:25]([F:26])([F:27])[F:28])=[N:23][N:24]=4)[N:21]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cccc(Br)n4)CC3)nn12
Yield: 66 %

Procedure:
A mixture of 6-bromopyridine-2-carboxaldehyde and 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 5 to give 6-[4-[(6-bromopyridin-2-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine in 66% yield.