Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:22]([Sn](CCCC)(CCCC)C#CC)[CH2:23][CH2:24]C>O1CCOCC1.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:22]([C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1)#[C:23][CH3:24]
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1nccnc1C1CN(c2ccc3ccccc3n2)C1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Product: CC#Cc1nccnc1C1CN(c2ccc3ccccc3n2)C1
Temperature: 100 °C
Yield: 63.2 %

Procedure:
A mixture of 2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (0.200 g, 0.674 mmol), tributyl(prop-1-yn-1-yl)stannane (0.266 g, 0.809 mmol), and bis(tri-t-butylphosphine) palladium (o) (0.017 g, 0.034 mmol) in p-dioxane (4 mL) was heated at 100° C. in 16 h. The reaction mixture was cooled, concentrated, and purified by ISCO (0-60% EtOAc/Hexanes) to give the title compound (128 mg, 68%).
Reaction SMILES: [CH3:1][CH:2]([NH:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[CH:14][N:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl:20]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:20][C:17]1[C:12]([NH:11][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:1])=[N:13][CH:14]=[N:15][C:16]=1[O:18][CH3:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCCCCCCC(C)Nc1cc(OC)ncn1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCC(C)Nc1ncnc(OC)c1Cl
Yield: 84.5 %

Procedure:
4.0 g (0.015 mol) of 4-(2-decylamino)-6-methoxypyrimidine were refluxed for 1 hour together with 2.2 g (0.016 mol) of N-chlorosuccinimide in 25 ml of chloroform. After cooling, the mixture was extracted by stirring with 2N sodium hydroxide solution, and the organic phase was dried and concentrated. 3.8 g (84.3% of theory) of 5-chloro-4-(2-decylamino)-6-methoxypyrimidine were obtained in the form of a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:10][N:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][N:12]3[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:5]=[CH:4][N:3]=1.[CH:34]1([NH2:37])[CH2:36][CH2:35]1>C(Cl)(Cl)Cl.O>[CH:34]1([NH:37][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[N:10][N:11]4[C:16]=3[CH2:15][CH2:14][CH2:13][N:12]4[C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH:5]=[CH:4][N:3]=2)[CH2:36][CH2:35]1
Reactant: O=C(OCc1ccccc1)N1CCCc2c(-c3ccnc(Cl)n3)c(-c3ccc(F)cc3)nn21
Reactant: NC1CC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)N1CCCc2c(-c3ccnc(NC4CC4)n3)c(-c3ccc(F)cc3)nn21
Reaction time: 0.08 h

Procedure:
A solution of the phenylmethyl 3-(2-chloro-4-pyrimidinyl)-2-(4-fluorophenyl)-5,6-dihydropyrazolo[1,5-b]pyridazine-7(4H)-carboxylate (i.e. the product of Step C) (464 mg, 1.0 mmol) and cyclopropylamine (1.3 mL, 18.5 mmol) in chloroform (3 mL) was heated at 120° C. in a sealed tube under microwave irradiation for 1 h and then at 160° C. for 5 minutes. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by medium pressure liquid chromatography using 20-100% ethyl acetate in hexanes as eluant to give 240 mg of the title compound as a solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[C:10](Br)[C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(O)(O)[C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1.[F-].[Cs+]>O1CCOCC1.C(Cl)Cl>[CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C1C=C(Br)C(=O)N1Cc1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(C2=CC(=O)N(Cc3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of bromomaleic anhydride (1 g, 5.7 mmol) and benzyl amine (0.7 mL, 6.8 mmol) in acetic acid (15 mL) was warmed to 50° C. and stirred overnight. The reaction was then cooled to room temperature, diluted with CH2Cl2 (50 mL) and washed with NaHCO3 (3×25 mL) and brine (25 mL). The organic layer was then dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified using gradient flash chromatography (0-100% ethyl acetate in pet ether) to provide 1-benzyl-3-bromo-1H-pyrrole-2,5-dione (18). 1H NMR (400 MHz, CDCl3) δ 4.71 (s, 2H), 6.87 (s, 2H), 7.26-7.37 (m, 5H). A stirred solution of 1-benzyl-3-bromo-1H-pyrrole-2,5-dione (0.26 g, 1.0 mmol) and p-tolylboronic acid (0.16 g, 1.2 mmol) in dioxane (10 mL) was degassed with a stream of nitrogen for 10 minutes before being treated with CsF (0.39 g, 2.6 mmol) and C12Pd(dppf).CH2Cl2 (0.05 g, 0.06 mmol). The reaction was stirred at room temperature for 1 h then warmed to 40° C. for 1 h. The mixture was then cooled, diluted with CH2Cl2 (30 mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure and purified using gradient flash chromatography (0-10% ethyl acetate in pet ether) to provide the title compound 15.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=O.[C:14]1([C:20]2([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Na+].Cl>C1(C)C=CC=CC=1.O1CCCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[C:11]([N:23]1[CH2:22][CH2:21][C:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([O:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=2)[CH2:25][CH2:24]1)=[O:13]
Reactant: FC(F)(F)c1ccc(OC2(c3ccccc3)CCNCC2)cc1
Reactant: O=C(O)C1CCc2ccccc2O1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(C1CCc2ccccc2O1)N1CCC(Oc2ccc(C(F)(F)F)cc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.89 g (5.5 mmol) of 1,1-carbonyldiimidazole and 11 ml of dry tetrahydrofuran is added dropwise to a solution of 0.89 g (5.0 mmol) of 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid and 5.5 ml of dry tetrahydrofuran at 20°-25° C. in the course of 1 hour. The reaction solution is then stirred at room temperature for a further 2 hours. A solution of 1.93 g (6.0 mmol) of 4-phenyl-4-(4-trifluoromethyl-phenoxy)-piperidine is then added dropwise at 25° C. in the course of 1 hour. After 18 hours at room temperature, the reaction solution is stirred into a mixture of 220 ml of 5% strength sodium chloride solution, 13 ml of 1 molar hydrochloric acid and 110 ml of toluene for working up. The aqueous phase is extracted once more with 55 ml of toluene. The combined organic phases are then washed with 55 ml each of 0.1 molar hydrochloric acid, followed by 1% strength sodium bicarbonate solution and then water. The organic phase is dried with sodium sulphate and concentrated to dryness.
Reaction SMILES: [CH2:1]([C:8]1S(=O)(=O)[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:22](#[N:27])/[CH:23]=[CH:24]/[C:25]#[N:26]>C(Cl)(Cl)Cl>[CH2:13]([C:10]1[CH:11]=[CH:12][C:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[C:24]([C:25]#[N:26])[C:23]=1[C:22]#[N:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: N#C/C=C/C#N
Reactant: CCCCCCCC1=CC=C(CCCCCCC)S1(=O)=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCc1ccc(CCCCCCC)c(C#N)c1C#N
Yield: 0 %

Procedure:
In a typical experiment 2,5-diheptylthiophene 1,1-dioxide (2 g, 6.4×10 mole) and fumaronitrile (0.5 g, 6.4×10 mole) in chloroform (5 ml) were heated in a sealed tube to 180° for 18 H. The contents of the tube were evaporated to dryness and chromatographed over silica (toluene as eluent) to afford 3,6-diheptylphthalonitrile (0.98 g, 47%) as a yellow solid. The material was recrystallised from ethanol to afford a colourless solid, mp 44°-46° C. 1H-nmr (CDCl3) shows S 7.52 (s, 2H); 2.85 (t, 4H); 1.0-1.9 (m, 20H); 0.90 (t, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[N:10]=[N:11][C:12]([Cl:16])=[C:13](Cl)[N:14]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:8][C:9]1[N:10]=[N:11][C:12]([Cl:16])=[C:13]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:14]=1
Reactant: Nc1ccccc1
Reactant: Clc1nnc(Cl)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1nnc(Cl)c(Nc2ccccc2)n1

Procedure:
To a solution of Aniline (205 mg, 2.2 mmol) and 3,5,6-trichloro-1,2,4-triazine (2.7 mmol) in CH2Cl2, is added triethylamine (3 mmol). The reaction mixture is stirred at room temperature until formation of the desired product. Solvent is removed under reduced pressure. The residue can be purified by silica gel flash chromatography.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.C(=O)([O-])[O-].[K+].[K+].[Cl:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:15]=1[OH:27].O>CN(C)C=O>[Cl:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:15]=1[O:27][CH2:5][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: BrCCCCBr
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.5 %

Procedure:
A reaction vessel was charged with 22.67 g of 1,4-dibromobutane, 11.06 g of potassium carbonate and 200 ml of N,N-dimethylformamide, to which a solution of 20.16 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol dissolved in 80 ml of N,N-dimethylformamide was slowly added dropwise. After stirring at room temperature for 24 hours, the reaction mixture was poured into water and extracted twice with 300 ml of diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 21.77 g of 3,5-dichloro-4-(4-bromobutyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (yield, 74%), nD25.0 1.5666.
Reaction SMILES: Cl[CH2:2][CH:3]=O.[NH2:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]>C(O)C>[N:5]1[CH:2]=[CH:3][N:14]2[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]=12
Reactant: O=CCCl
Reactant: Nc1ncccc1C(=O)O
Solvent: CCO
Product: O=C(O)c1cccn2ccnc12

Procedure:
Chloroacetaldehyde (45% aqueous solution) (6.6 mL, 38 mmol) is added to the stirred solution of 2-aminonicotinic acid (5.0 g, 25 mmol) in ethanol (35 mL) and warmed at reflux for 14 hours. The reaction mixture is concentrated and the crude material is triturated with EtOH-Et2O to afford imidazo[1,2-a]pyridine-8-carboxylic acid. Mp: 296-299° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C@H:6]([N:13]1[C:17]([CH2:18][NH:19]C=O)=[CH:16][NH:15][C:14]1=[S:22])[CH2:7]2.[ClH:23].CS(C)=O>C(O)(C)C>[ClH:23].[NH2:19][CH2:18][C:17]1[N:13]([C@H:6]2[CH2:5][CH2:4][C:3]3[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=3[F:1])[CH2:7]2)[C:14](=[S:22])[NH:15][CH:16]=1
Reactant: O=CNCc1c[nH]c(=S)n1[C@H]1CCc2c(F)cc(F)cc2C1
Agent: Cl
Solvent: CC(C)O
Solvent: CS(C)=O
Product: NCc1c[nH]c(=S)n1[C@H]1CCc2c(F)cc(F)cc2C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 79.8 %

Procedure:
A mixture of (S)-N-[3-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-4-ylmethyl]formamide (19.1 g, 59.0 mmol), prepared as in Example 30, and 25 mL of concentrated hydrochloric acid (12.0M, 25 mL, 300 mmol) in 400 mL of isopropanol was heated to reflux over 12 minutes and stirred for 1 hour 40 minutes. The mixture was distilled removing 150 mL of isopropanol. The mixture was gradually cooled to room temperature and stirred for 3 hours 45 minutes. The material was isolated by filtration and the filter residue was washed with 75 mL of isopropanol. Drying in vacuo at 110° to 125° C. with a nitrogen bleed gave (S)-5-aminomethyl-1-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione hydrochloride (15.6 g, 47.1 mmol), m.p. 251.9° C. [α]D +10.2° C. (c=0.500, DMSO).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:6]2[O:10][CH2:9][C:8](=[O:11])[C:7]=2[CH:12]=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:36]=O)=[CH:28]1>CO.N1CCCCC1>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](/[CH:36]=[C:9]2\[O:10][C:6]3[C:5]([CH2:13][N:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]4)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][C:7]=3[C:8]\2=[O:11])=[CH:28]1
Reactant: COc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)c2c(c1)C(=O)CO2
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: COc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)c2c(c1)C(=O)/C(=C/c1c[nH]c3ccccc13)O2
Temperature: 50 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A solution of tert-butyl 4-((5-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl)piperazine-1-carboxylate (0.024 g, 0.066 mmol) in methanol (2.0 mL) was added with 1H-indole-3-carboxaldehyde (0.011 g, 0.073 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 50° C. for 2 hours. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (90:10)) to obtain tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-5-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.027 g, 84%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[NH2:9][OH:10].Cl.N1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]([CH:7]=[N:9][OH:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)s1
Reactant: NO
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(C=NO)s1
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
1.20 kg (9.51 moles) of 5-methyl-2-thiophenecarboxaldehyde and 727 g (10.46 moles) of NH2OH.HCl were placed in a reaction vessel and cooled to 10° C. Then, 0.85 L (10.46 moles) of pyridine was dropwise added thereto for 1 hour (an exothermic reaction: 10° C.→43° C). After 10 minutes, 7 L of benzene was added thereto and heated to remove the obtained water by Dean-Stark apparatus (initial internal temperature: 80° C.). After 165 mL of water was collected for 8 hours, (theoretical quantity: 171 mL), the product was cooled to obtain 5-methyl-2-thiophenecarboxaldehyde oxime. At this time, if stirring was stopped, two-phases were formed. After 0.85 L (10.46 moles) of pyridine was completely added at 15° C., 1.26 kg (12.36 moles) of Ac2O was dropwise added thereto for 25 minutes, with maintaining a temperature less than 15° C. The reaction mixture was stirred for 1 hour at room temperature, and completion of the acetylation reaction was confirmed by HPLC (2 phases).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].CO[CH2:7][Cl:8].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([S:17][CH3:18])[CH:11]=1.O>C(=S)=S>[Cl:8][CH2:7][C:15]1[C:10]([F:9])=[CH:11][C:12]([S:17][CH3:18])=[C:13]([CH3:16])[CH:14]=1
Reactant: COCCl
Reactant: CSc1cc(F)ccc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: S=C=S
Product: CSc1cc(F)c(CCl)cc1C
Reaction time: 0.5 h

Procedure:
To a suspension of aluminum chloride (29 g) in carbon disulfide (300 ml) is added chloromethyl methyl ether (17 ml), and the mixture is stirred for 30 minutes. To the mixture is added 4-fluoro-2-methylthiotoluene (17.2 g), and the mixture is stirred at room temperature for 2 hours. To the reaction mixture is added water, and the mixture is extracted with diethyl ether. The extract is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5-chloromethyl-4-fluoro-2methylthiotoluene (21 g).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24](I)=[CH:23][C:22]=2[F:28])=[N:16]1.[Cl:29][C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=1[C:40]#[CH:41].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:41]#[C:40][C:31]3[CH:32]=[CH:33][C:34]([C:36]([F:37])([F:38])[F:39])=[CH:35][C:30]=3[Cl:29])=[CH:23][C:22]=2[F:28])=[N:16]1
Reactant: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(I)cc3F)[nH]c2=O)c1)C1CC1
Reactant: C#Cc1ccc(C(F)(F)F)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(C#Cc4ccc(C(F)(F)F)cc4Cl)cc3F)[nH]c2=O)c1)C1CC1
Yield: 43.5 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 by using N-(4-chloro-3-(3-(2-fluoro-4-iodophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzyl)cyclopropanecarboxamide (Intermediate-48, 0.060 g, 0.117 mmol), 2-chloro-1-ethynyl-4-(trifluoromethyl)benzene (Intermediate-25, 0.037 g, 0.175 mmol), TBAF (0.073 g, 0.234 mmol), bis(triphenylphosphine)palladium(II) chloride (catalytic) and DMSO (1.0 mL) at 80° C. to afford 0.030 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.66-0.69 (m, 4H), 1.60 (m, 1H), 4.33 (d, J=6.0 Hz, 2H), 7.40 (d, J=8.4 Hz, 1H), 7.48 (s, 1H), 7.62-7.64 (m, 2H), 7.73 (d, J=11.4 Hz, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.92-7.97 (m, 2H), 8.09 (s, 1H), 8.69 (m, 1H), 12.00 (br s, 1H); MS (m/z): 589.14 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:14]=2[CH3:22])[S:11][CH:12]=1.[CH:23](OCC)=[O:24].Cl>C(O)=O.C(OCC)(=O)C>[CH3:22][C:14]1[CH:15]=[CH:16][C:17]([NH:19][CH:23]=[O:24])=[CH:18][C:13]=1[C:10]1[S:11][CH:12]=[C:8]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[CH3:1])[N:9]=1
Reactant: Cc1ccncc1-c1csc(-c2cc([N+](=O)[O-])ccc2C)n1
Reactant: CCOC=O
Agent: Cl
Solvent: O=CO
Solvent: CCOC(C)=O
Product: Cc1ccncc1-c1csc(-c2cc(NC=O)ccc2C)n1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
4-Methyl-3-[2-(2-methyl-5-nitrophenyl)-1,3-thiazol-4-yl]pyridine (98 mg) and reduced iron (170 mg) were suspended in a mixture of formic acid (3 ml)-ethyl formate (3 ml). 1N Hydrochloric acid (0.2 ml) was added and the mixture was stirred at 80° C. for 12 hrs. The reaction mixture was diluted with ethyl acetate and the insoluble material was filtered off. The organic layer was neutralized with saturated aqueous sodium hydrogen carbonate. The organic layer was separated and concentrated by drying. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1–0:1) for purification. Recrystallization from ethyl acetate gave the title compound (15 mg) as pale-yellow columnar crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31].C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[F:25][C:26]([F:36])([F:37])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:31]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3cccc(C(F)(F)F)c3)cc2)c2ccc3ccccc3c2N1
Yield: 12.9 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (30 mg, 0.095 mmol) obtained in Example 1, (3), and 3-(trifluoromethyl)benzoyl chloride (17 μL, 0.114 mmol), the title compound (6 mg, yield 13%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:13])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(Cl)c1
Product: O=C(Cl)c1cccc(Cl)c1
Yield: 90 %

Procedure:
A solution of 3-chlorobenzoic acid (30 g, 191.61 mmol) in thionyl chloride (200 ml) was stirred overnight at 90° C. The resulting mixture was concentrated under vacuum to afford 3-chlorobenzoyl chloride as light yellow oil (30 g, 90%).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:6])[CH2:4]Cl.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([SH:15])[CH:12]=[CH:13][CH:14]=1.[OH-].[Na+]>CO.O.O>[Cl:1][CH2:2][C:3](=[O:6])[CH2:4][S:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH3:7])[CH:10]=1
Reactant: COc1cccc(S)c1
Reactant: O=C(CCl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(SCC(=O)CCl)c1
Temperature: 0 °C
Reaction time: 10 h

Procedure:
To a stirred solution of 1,3-dichloro-2-propanone (12.70 g, 0.1 mol) in methanol/water (100 ml, 1:3) at 0° C. is added a suspension of 3-methoxybenzenethiol (14.02 g, 0.1 mol) and sodium hydroxide (4.00 g, 0.10 g) in water (100 ml). The mixture is stirred at 0° C. for 7 h and at mom temperature for 10 h. The precipitated product is extracted with dichloromethane (100 ml), washed with water (80 ml), and dried with sodium sulfate. After removal of the solvent, we obtained the good product (oil, 18.70 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:7][C:6]2[CH:8]=[C:9]([N+:13]([O-])=O)[C:10]([NH2:12])=[CH:11][C:5]=2[CH:4]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:3]1[OH:22].[H][H]>C(O)C.[C].[Pd]>[CH3:1][C:2]1([CH3:23])[O:7][C:6]2[CH:8]=[C:9]([NH2:13])[C:10]([NH2:12])=[CH:11][C:5]=2[CH:4]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:3]1[OH:22]
Reactant: [H][H]
Reactant: CC1(C)Oc2cc([N+](=O)[O-])c(N)cc2C(N2CCCCC2)C1O
Agent: [Pd]
Solvent: CCO
Product: CC1(C)Oc2cc(N)c(N)cc2C(N2CCCCC2)C1O
Yield: 94.7 %

Procedure:
0.28 g (0.87 mmol) of 3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(1-piperidinyl)-6-amino-7-nitro-2H-benzo[b]pyran was dissolved in 44.8 g of ethanol and hydrogen gas was blown in in the presence of 0.20 g of 5% palladium-carbon, as a catalyst, at room temperature for 3 hours under one atmospheric pressure while stirring. The reaction liquid was filtered under suction to remove the catalyst therefrom, and the solvent was removed by distillation to obtain 0.24 g (yield: 95%) of 3,4-dihydro-2,2-dimethyl-3-hydroxy-4-(1-piperidinyl)-6,7-diamino-2H-benzo[b]pyran as a dark red oil. 0.12 g (0.86 mmol) of thionylaniline and 4 g of benzenewere added thereto and heated under reflux for 2.5 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate-ethanol=1:3) to obtain 60 mg (yield: 23%) of the intended compound as an yellow solid.
Reaction SMILES: ClCCl.[N:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[CH2:12][NH:13][C:14](=[O:26])[C:15]=3[CH:16]=[C:17]3[CH:25]=[CH:24][C:23]4[O:22][CH2:21][O:20][C:19]=4[C:18]=23)=[CH:6][CH:5]=1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1>O>[N:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[CH2:12][NH+:13]([O-:35])[C:14](=[O:26])[C:15]=3[CH:16]=[C:17]3[CH:25]=[CH:24][C:23]4[O:22][CH2:21][O:20][C:19]=4[C:18]=23)=[CH:6][CH:5]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1NCc2c1cc1ccc3c(c1c2-c1ccncc1)OCO3
Solvent: O
Solvent: ClCCl
Product: O=C1c2cc3ccc4c(c3c(-c3ccncc3)c2C[NH+]1[O-])OCO4
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.9 %

Procedure:
To a dichloromethane (100 ml) solution of 8,9-dihydro-10-(4-pyridyl)-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one (200 mg) was added MCPBA (350 mg) and stirred for 2 hours at room temperature. To the reaction mixture was added water. The organic layer was taken and washed with sodium hydrogencarbonate solution and water. The mixture was dried with magnesium sulfate and concentrated to give the entitled compound (84 mg).