Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[CH:23]1(Br)[CH2:27][CH2:26][CH2:25][CH2:24]1.[Na+].[I-]>CN(C=O)C.O>[CH:23]1([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=3)[CH2:6][CH2:5]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: BrC1CCCC1
Reactant: COC(=O)c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(N2CCN(C3CCCC3)CC2)nc1
Reaction time: 4 h
Yield: 59.9 %

Procedure:
To a solution of 2.21 g of methyl 6-piperazinylnicotinate (compound 6), 3.18 g of sodium carbonate and 1.64 g of cyclopentyl bromide in 50 ml of DMF was added a catalytic amount of NaI. The mixture was heated to 120°-130° C. and stirred for 4 hours. The resulting mixture was poured into 150 ml of water and extracted with ethyl acetate. The extract was washed twice with water, and once with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate and concentrated. Purification of the concentrate by column chromatography (silica gel; ethyl acetate) afforded 1.73 g of methyl 6-(4 -cyclopentyl-1-piperazinyl)nicotinate (yield 60%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[ClH:20].[CH3:21]O>>[ClH:20].[CH3:21][O:10][C:9](=[O:11])[CH:8]([NH:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C(O)C(NCc1ccccc1)c1ccc(F)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)C(NCc1ccccc1)c1ccc(F)cc1
Reaction time: 3 h
Yield: 84 %

Procedure:
4-Fluoro-α-[(phenylmethyl)amino]benzeneacetic acid (12.2 kg, 47.1 moles) was slurried in methanol (37 L), then hydrogen chloride gas was passed over the mixture. The resulting slurry was stirred at 35°-45° C. for 3 hours, then concentrated to 30°-35 L by distillation. Methyl-t-butyl ether (20 L) was added and the batch was seeded with 4-Fluoro-α-[(phenylmethyl)amino]benzeneacetic acid methyl ester hydrochloride. Upon development of the seed-bed, methyl-t-butyl ether (20 L) was added. The slurry was aged for 1 hour, then filtered. The filter cake was washed with methyl-t-butyl ether:methanol (95:5, 8.0 L), then dried under vacuum at 30° C. to give 12.2 kg (84% yield) of 4-fluoro-α-[(phenylmethyl)amino]-benzeneacetic acid methyl ester hydrochloride.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14](B2OC(C)(C)C(C)(C)O2)=[CH:13][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:33]1[C:34]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[N:35][N:36]([CH3:38])[CH:37]=1>CN(C)C=O.O>[C:1]([NH:4][CH:5]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:33]2[C:34]([NH:39][C:40]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:46])=[N:35][N:36]([CH3:38])[CH:37]=2)=[CH:15][CH:16]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)C(Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)NC(C)=O
Reactant: Cn1cc(Br)c(NC(=O)OC(C)(C)C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Cc1ccc(-c2cn(C)nc2NC(=O)OC(C)(C)C)cc1)NC(C)=O
Temperature: 85 °C
Reaction time: 8 h

Procedure:
1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (353 mg, 0.43 mmol) was added to a degassed, ambient temperature solution of methyl 2-(acetylamino)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (1.5 g, 4.3 mmol), potassium carbonate (2.39 g, 17.3 mmol) and tert-butyl (4-bromo-1-methyl-1H-pyrazol-3-yl)carbamate (1.19 g, 4.3 mmol) in wet N,N-dimethylformamide (40 mL). After stirring at 85° C. overnight, the reaction mixture was cooled, diluted with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% acetone/methylene chloride afforded methyl 2-(acetylamino)-3-(4-{3-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrazol-4-yl}phenyl)propanoate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: C1CNCCN1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: COc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 89.9 %

Procedure:
To 5-fluoro-2-nitrophenyl methyl ether (Example 22, step A) (0.8 g, 4.67 mmol) in 10 mL of dioxane was added, piperazine (1.2 g, 14 mmol). The mixture was heated to 120° C. for 2 h. The mixture was purified by flash chromatography to give the title compound of step A (1 g, 4.2 mmol, 90%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.85 (d, J=9.34 Hz, 1H), 6.55 (d, J=2.56 Hz, 1H), 6.52 (s, 1H), 6.46 (d, J=2.56 Hz, 1H), 3.87 (s, 3H), 3.25-3.33 (m, 4H), 2.73-2.79 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH:21](=O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(O)(=O)C.[BH4-].[Na+]>CN(C=O)C>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: CCCCCCC=O
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCCCCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 18 h
Yield: 41.1 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and heptanal (3.4 mL, 24 mmol) and acetic acid (2 mL) in DMF (20 mL) was heated until all solid was dissolved. To the mixture was added sodium borohydride (605 mg, 16 mmol) and kept at room temperature for 18 h. To the mixture was added sodium borohydride (150 mg, 3.9 mmol) and kept at room temperature for 1 d. The mixture was extracted with ethyl acetate (200 mL) and water (100 mL). The organic layer was washed with water (100 mL), The solvent was removed in vacuo to give an oil. The oil was purified by column chromatography (Silca Gel, 33% EtOAc:CH2Cl2) to give 2-(2,6-Dioxo-piperidin-3-yl)-4-heptylamino-isoindole-1,3-dione as a yellow solid (610 mg, 41% yield): mp, 107–109° C.; 1H NMR (DMSO-d6) δ 0.82–0.87 (m, 3H, CH3), 1.24–1.29 (m, 8H, 4 CH2), 2.00–2.04 (m, 1H, CHH), 2.43–2.62 (m, 2H, CH2), 2.82–2.96 (m, 1H, CHH), 3.23–3.31 (m, 2H, CH2), 5.06 (dd, J=5.3, 12.4 Hz, 1H, NCH), 6.51 (t, J=5.9 Hz, 1H, NH), 7.01 (d, J=7.0 Hz, 1H, Ar), 7.07 (d, J=8.6 Hz, 1H, Ar), 7.57 (dd, J=7.4, 8.4 Hz, 1H, Ar), 11.10 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.91, 22.03, 22.17, 26.28, 28.42, 28.69, 30.98, 31.22, 34.84, 48.55, 109.03, 110.36, 117.13, 132.18, 136.24, 146.43, 167.29, 168.96, 170.05, 172.77; Anal Calcd for C20H25N3O4: C, 64.67; H, 6.78; N, 11.31. Found: C, 64.62; H, 6.76; N, 11.13.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[C:6]([CH:10]3[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([C:21]([F:24])([F:23])[F:22])[NH:13][C:12]([CH:25](OCC)[O:26]CC)=[C:11]3[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:7][CH:8]=[CH:9][C:2]=12.Cl.C(OCC)(=O)C.CC(O)C>O1CCCC1>[N:1]1[O:5][N:4]=[C:3]2[C:6]([CH:10]3[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([C:21]([F:24])([F:23])[F:22])[NH:13][C:12]([CH:25]=[O:26])=[C:11]3[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC(C(F)(F)F)=C(C(=O)OCC)C1c1cccc2nonc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C=O)NC(C(F)(F)F)=C(C(=O)OCC)C1c1cccc2nonc12
Yield: 7.1 %

Procedure:
To a solution of diethyl 4-(4-benzofurazanyl)-2-(diethoxymethyl)-1,4-dihydro-6-(trifluoromethyl)-3,5-pyridinedicarboxylate (7.6 g, 14.5 mmoles) in tetrahydrofuran (100 ml) was added 25% aqueous hydrochloric acid solution (100 ml) and the resulting solution heated at reflux. After 1.5 hours the cooled solution was poured into ethyl acetate (200 ml). The organic phase was separated and washed with water, saturated aqueous sodium bicarbonate solution, brine and dried (MgSO4). Evaporation of the solvent left an oil (7.5 g) which was purified by chromatography on silica (300 g) using ether-petroleum ether (60°-80°) as eluent. The major component was obtained as an oil which gave a solid on trituration with 2-propanol. Recrystallisation from 2-propanol gave the title compound (0.45 g) as yellow crystals mp 94°-5°.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:16][O:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[CH3:16][O:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Reactant: COCCCc1ccccc1B(O)O
Product: COCCCc1ccccc1-c1cc(C(F)(F)F)c(C(=O)OC)cn1

Procedure:
Prepared according to the procedure described in EXAMPLE 1, step 1 using commercially available methyl 6-chloro-4-(trifluoromethyl)nicotinate and [2-(3-methoxypropyl)phenyl]boronic acid from EXAMPLE 3, step 1 as starting materials. Purification by column chromatography on silica gel, eluting with Hex/EtOAc 10% afforded the desired compound as a colorless oil.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Cl[C:6]1[C:11]([C:12]#[N:13])=[C:10]([Cl:14])[N:9]=[C:8]([NH:15][CH2:16][CH3:17])[N:7]=1.[CH:18](N)(C)[CH3:19]>>[Cl:14][C:10]1[C:11]([C:12]#[N:13])=[C:6]([NH:4][CH:1]2[CH2:3][CH2:2]2)[N:7]=[C:8]([NH:15][CH:16]([CH3:17])[CH2:18][CH3:19])[N:9]=1
Reactant: CCNc1nc(Cl)c(C#N)c(Cl)n1
Reactant: NC1CC1
Reactant: CC(C)N
Product: CCC(C)Nc1nc(Cl)c(C#N)c(NC2CC2)n1

Procedure:
4-Chloro-6-cyclopropylamino-2-(1-methylpropylamino)-5-pyrimidinecarbonitrile was prepared by the method of Example XVII, substituting 4,6-dichloro-2-(1-methylpropylamino)-5-pyrimidinecarbonitrile and cyclopropylamine for 4,6-dichloro-2-ethylamino-5-pyrimidinecarbonitrile and isopropylamine. The reaction product was recrystallized from methylcyclohexane to give 4-chloro-6-cyclopropylamino-2-(1-methylpropylamino)-5-pyrimidinecarbonitrile; mp, 112°-114°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.CC(O)(C(C)(O)C)C.Br[C:29]1[S:33][C:32]([C:34]2([OH:38])[CH2:37][CH2:36][CH2:35]2)=[N:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:29]2[S:33][C:32]([C:34]3([OH:38])[CH2:37][CH2:36][CH2:35]3)=[N:31][CH:30]=2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: OC1(c2ncc(Br)s2)CCC1
Reactant: CC1(C)OB(c2cc(Cl)cc([N+](=O)[O-])c2)OC1(C)C
Agent: CC(C)(O)C(C)(C)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(Cl)cc(-c2cnc(C3(O)CCC3)s2)c1
Yield: 54.8 %

Procedure:
The product of Step 1 (1.6 g, 3.98 mmol), Intermediate 1 (839 mg, 3.58 mmol), PdCl2 (dppf)-dichloromethane adduct (163 mg, 0.199 mmol), sodium carbonate (2M in water) (5.97 mL, 11.95 mmol), and DMF (39.8 mL) were heated at 100° C. for 2 hours under nitrogen. The reaction mixture was diluted with ethyl acetate and water, the solids were filtered and the organic fraction was washed with water, brine and dried over Na2SO4. Filtration and solvent evaporation gave a residue which was further purified by column chromatography on silica gel, eluting with ethyl acetate/hexane with a gradient 30-50% to afford 1-[5-(3-chloro-5-nitrophenyl)-1,3-thiazol-2-yl]cyclobutanol (610 mg, 49.3%).
Reaction SMILES: Cl.[CH3:2][C:3]1[S:7][C:6]([CH:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21](O)[CH2:20]2.N1(O)C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C@@H:21]([O:10][C:9](=[O:11])[CH:8]([C:6]1[S:7][C:3]([CH3:2])=[CH:4][CH:5]=1)[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:20]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: Cc1ccc(C(Nc2ccccc2)C(=O)O)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cc1ccc(C(Nc2ccccc2)C(=O)O[C@H]2CN3CCC2CC3)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.8 %

Procedure:
To a solution of (5-methyl-thiophen-2-yl)-phenylamino-acetic acid hydrochloride (I268) (220 mg, 0.77 mmol), (R)-quinuclidin-3-ol (338 mg, 2.66 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (180 mg, 1.33 mmol) in dry THF (15 mL), is added PS-DCC (1.0 g, 1.330 mmol) and the mixture is shaken at RT for 15 hours. Then (R)-quinuclidin-3-ol (49.3 mg, 0.39 mmol) and PS-DCC (291 mg, 0.39 mmol) are added again and the reaction is shaken at RT for other 3 hours. The resin is filtered off and washed several time with EtOAc. The solvent is concentrated and washed with aq. NaHCO3, water and brine. The organic phase is dried over Na2SO4 and evaporated to obtain the title compound as a brown oil (175 mg, 63% yield).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[I:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CS(O)(=O)=O.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1>C(Cl)Cl.C1COCC1>[Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][O:24]1)[N:13]=[C:12]2[I:18])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C1=COCCC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]nc(I)c2c1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)c(I)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Cool a solution of 5-(tert-butyldimethylsilyloxy)-3-iodo-1H-indazole (387.00 g, 1.08 mol) in DCM (2.50 L) and THF (1.00 L) to 10° C. in a 10 L jacketed reactor vessel. To the resulting mixture add methanesulfonic acid (14.0 mL, 216.02 mmol), followed by 3,4-dihydro-2H-pyran (296 mL, 3.24 mol) over 0.5 hours, observing a slight exotherm. Stir the mixture at RT for 3 hours. Cool the reaction to 10° C. and quench with saturated aqueous sodium bicarbonate (2 L). Dilute the mixture with water (2 L) and extract the aqueous layer with DCM (2 L). Wash the combined organic extracts with water (2 L) and brine. Dry the organic mixture over anhydrous sodium sulfate, filter and concentrate in vacuo. Elute the residue through a silica gel pad with eluent (0 to 10% EA/hexanes) to give the title compound. Yield: 150 g (31%). MS (ES) m/z 459 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)=[N:9][N:10]=2)[CH:7]=1.C=O.[CH3:19]C(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([CH3:19])[CH2:12]3)=[N:9][N:10]=2)[CH:7]=1
Reactant: Fc1ccc2nnc([C@H]3CCCNC3)n2c1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC[C@H](c2nnc3ccc(F)cn23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a yellow solution of Intermediate 88c (220 mg, 1.00 mmol), formaldehyde (37% in water, 0.811 mL, 10.0 mmol) and AcOH (0.057 mL, 1.00 mmol) in DCM-MeOH (5:1, 12 mL) was added NaBH(OAc)3 (424 mg, 2.00 mmol) (CARE: gas evolution) and the solution stirred at RT for 2 h. The solution was concentrated in vacuo to 5 mL volume, then applied to an SCX-2 cartridge (10 g) and washed with MeOH (50 mL). The product was eluted with 2M NH3 in MeOH (50 mL); concentration in vacuo gave the title compound as a pale yellow gum, that became a white solid on standing (234 mg, quant.). LCMS (Method 3): Rt 0.45 min, m/z 235 [MH+].
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:3]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[OH:31]>ClCCl.CCCCCC>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:4]2[CH:3]=[C:2]([O:31][C:25]3[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=3[F:23])[N:7]=[N:6][C:5]=2[C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[CH:17][CH:18]=1
Reactant: Oc1ccc(F)cc1F
Reactant: CSc1ccc(-c2nnc(Cl)cc2-c2ccc(Cl)cc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CSc1ccc(-c2nnc(Oc3ccc(F)cc3F)cc2-c2ccc(Cl)cc2)cc1

Procedure:
In a similar manner as in Example 2, 6-chloro-4-(4-chlorophenyl)-3-[4-(methylthio)phenyl]pyridazine (230.0 mg, 0.662 mmol) and 2,4-difluorophenol were reacted as starting materials at 150° C. for 20 hours and post-treatment was then conducted, whereby the title compound was obtained as colorless plates (dichloromethane-hexane, 216.2 mg, 74.0%). Melting point: 163.2-164.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[CH:48]=[CH:47][O:46][N:45]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:32]([NH:43][C:44]2[CH:48]=[CH:47][O:46][N:45]=2)=[O:34])=[CH:18][C:17]=1[F:23]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: Nc1ccon1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccon4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 102.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (800 mg) was dissolved in chloroform (20 ml) and triethylamine (1.0 ml) to prepare a solution. A solution of triphosgene (378 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 3-aminoisoxazole (252 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Iced water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine and was then dried over anhydrous sodium sulfate. The dried organic layer was filtered and was then concentrated. Ether was added to the residue for crystallization. The crystal was collected by filtration. The collected crystal was purified by chromatography (chloroform:acetone=2:1). A 10% solution of hydrogen chloride in methanol was added to the purification product, followed by concentration. The resultant crystal was washed with ether to give 554 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.Cl.Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[CH2:22][N:23]1[CH2:27][CH2:26][C@@H:25]([NH2:28])[CH2:24]1.C([O-])([O-])=O.[K+].[K+].O>CN1CCN(C)C1=O>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[CH2:22][N:23]1[CH2:27][CH2:26][C@@H:25]([NH:28][C:2]2[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=2)[CH2:24]1
Reactant: CCOC(=O)/C=C/c1cnc(Cl)cn1
Reactant: COc1cccc(CN2CC[C@@H](N)C2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3cccc(OC)c3)C2)cn1
Temperature: 106 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
To a mixture of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (278 mg) in 1,3-dimethyl-2-imidazolidinone (2.78 mL) was added (3R)-1-(3-methoxybenzyl)-3-pyrrolidinamine dihydrochloride (547.5 mg) and K2CO3 (1.08 g), which was stirred at 106° C. for 3 hours. To the resultant was added H2O, which was extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(5-{[(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (367.5 mg) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[N:21][C:22](Cl)=[CH:23][C:24]=2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[CH:4][C:5]([F:17])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[N:21][C:22]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([F:32])[CH:38]=3)=[CH:23][C:24]=2[C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[CH:4][C:5]([F:17])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: Cn1nccc1-c1cc(Cl)ncc1Oc1cc(F)c(S(=O)(=O)Nc2nccs2)cc1Cl
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(-c2cccc(F)c2)ncc1Oc1cc(F)c(S(=O)(=O)Nc2nccs2)cc1Cl
Reaction time: 0.17 h
Yield: 35.7 %

Procedure:
10 mg (0.02 mmol) of 5-chloro-4-((6-chloro-4-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)oxy)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide was dissolved in 3 mL of N,N-dimethylformamide, and 4.2 mg (0.03 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 2.3 mg (10 mol %) of Pd(PPh3)4, 6.3 mg (0.6 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 4 mg (36% yield) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[N:11][CH2:12][C:6]2=[N:5][N:4]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25].[I-].[Na+]>>[CH2:24]([N:26]([CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[N:11][CH2:12][C:6]2=[N:5][N:4]=1)[CH2:27][CH3:28])[CH3:25]
Reactant: CCNCC
Reactant: ClCc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2
Agent: [I-]
Agent: [Na+]
Product: CCN(CC)Cc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, 1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine was reacted with diethylamine in the presence of sodium iodide to give 1-[(diethylamino)methyl]-6-(o-chlorophenyl)4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[C:21]([N:25]=[C:26]=[S:27])([O:23][CH3:24])=[O:22]>C(OCC)C>[C:21]([NH:25][C:26](=[S:27])[NH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])([O:23][CH3:24])=[O:22]
Reactant: COC(=O)N=C=S
Reactant: CCCCNc1ccc(C(=O)c2ccccc2)cc1N
Solvent: CCOCC
Product: CCCCNc1ccc(C(=O)c2ccccc2)cc1NC(=S)NC(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.2 %

Procedure:
To a solution of 3-amino-4-n-butylaminobenzophenone (2.38 g.) in diethyl ether (200 ml.) is added carbomethoxy isothiocyanate (1.4 g.). The reaction mixture is stirred at room temperature for three hours. The product is collected by filtration and dried to afford 0.2 g. of product, m.p. 160°-162° C., dec. The filtrate is allowed to stand overnight at room temperature and a second crop is collected amounting to 0.15 g., m.p. 162° C., dec. The total amount of 3-(3-carbomethoxythioureido)-4-n-butylaminobenzophenone obtained is 0.35 g. (10.2% yield).