Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([CH:8]2[C:14](=[O:15])[CH:13]3[CH2:16][CH:10]([CH2:11][CH2:12]3)[C:9]2=[O:17])=[O:7])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.[CH3:23]O>S(=O)(=O)(O)O>[CH3:23][O:17][CH:9]1[CH:8]([C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][C:4]=2[N+:20]([O-:22])=[O:21])[C:14](=[O:15])[CH:13]2[CH2:16][CH:10]1[CH2:11][CH2:12]2
Reactant: O=C(c1ccc(Cl)cc1[N+](=O)[O-])C1C(=O)C2CCC(C2)C1=O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC1C2CCC(C2)C(=O)C1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
A solution of 3-(4-chloro-2-nitrobenzoyl)-bicyclo[3,2,1]-octane-2,4-dione (2.54 mmol) and 2 drops of conc. sulfuric acid in 20 ml of methanol is heated under reflux for 48 hours. The reaction mixture is concentrated and the residue is taken up in ether. The ethereal solution is washed with aqueous sodium bicarbonate and with brine, dried and evaporated to dryness to give 2-methoxy-3-(4-chloro-2-nitrobenzoyl)bicyclo-[3,2,1]-octane-4-one.
Reaction SMILES: C(N(CC)CC[N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14](C=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])C.FC1C(F)=CC=CC=1C1C(F)=CC=C2C=1CC(=O)N2.N1CCCCC1>C(O)C>[CH3:16][C:15]1[C:8]2[C:7](=[O:19])[NH:6][CH2:12][CH2:11][CH2:10][C:9]=2[NH:13][CH:14]=1
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Agent: O=C1Cc2c(ccc(F)c2-c2cccc(F)c2F)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c[nH]c2c1C(=O)NCCC2
Temperature: 25 °C
Yield: 56 %

Procedure:
5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j (73 mg, 0.25 mmol) and 4-(2,3-difluoro-phenyl)-5-fluoro-1,3-dihydro-indol-2-one 74 g (60 mg, 0.23 mmol) were dissolved in 2 ml of ethanol, and added with 35 μl of piperidine to the solution at room temperature. Upon completion of the addition, the mixture was heated to reflux for 2 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (3 ml×2) and dried to obtain the title compound (Z)-5-(2-(diethylamino)ethyl)-2-(4-(2,3-difluorophenyl)-5-fluoro-2-oxoindolin-3-ylidene)methyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 74 (23 mg, yield 19%) as an orange solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[N:12]([CH3:28])[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=2)=[N:14][C:15]=1[Br:16])=O.CCOC(C)=O.Cl>C1COCC1.O>[Br:16][C:15]1[N:14]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=2)[N:12]([CH3:28])[C:11]=1[CH2:9][OH:8]
Reactant: COC(=O)c1c(Br)nc(-c2cccc(OC(F)(F)F)c2)n1C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(Br)c1CO
Temperature: -70 °C
Yield: 98.5 %

Procedure:
A solution of 5.62 ml (5.6 mmol) of lithium aluminium hydride (1 molar in THF) was slowly added to a solution of 3.55 g (9.4 mmol) of 5-bromo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazole-4-carboxylic acid methyl ester in 100 ml of THF cooled down to −70° C. The reaction mixture was warmed up to 0° C. and after 30 min cooled down to −50° C. and hydrolyzed with i) EtOAc, ii) H2O and iii) HCl (1N); after warming up to RT, it was extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (n-heptane/EtOAc 9:1 to 1:1) to give 3.25 g (99%) of the title compound as colorless solid. MS: 351.0 (MH+, 1Br).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([S:12](=[O:27])(=[O:26])[N:13]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=2)[CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].C(OCCCC)=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.Cl>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([S:12](=[O:26])(=[O:27])[N:13]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][CH3:25])=[CH:22][CH:23]=2)[CH2:14][CH:15]([CH3:16])[CH3:17])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(Br)c(C(=O)OC)c2)cc1
Agent: [Pd+2]
Agent: C=COCCCC
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(Br)c(C(=O)O)c2)cc1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a suspension of methyl 2-bromo-5-(N-(4-ethylphenyl)-N-isobutylsulfamoyl)benzoate (300 mg, 0.660 mmol), palladium(II) acetate (14.82 mg, 0.066 mmol), 1-(vinyloxy)butane (BVE) (0.427 mL, 3.30 mmol) and triphenylphosphine (34.6 mg, 0.132 mmol) in acetonitrile (1 mL) in air, at room temperature, was added triethylamine (0.110 mL, 0.792 mmol). The reaction vessel was sealed and heated by microwaves to 150° C. for 1 hour then the solvent was evaporated in vacuo and the residue redissolved in tetrahydrofuran (THF) (1.0 mL) and treated with HCl (2N, 1 mL, 3.29 mmol). The mixture was stirred vigorously for 1 hour then stood overnight. Analysis showed hydrolysed starting material was present. The crude was purified by MDAP (Method F) to isolate the hydrolysed starting material as the product, 84.8 mg. LCMS (M+1) 440/442, RT 1.25 mins.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][O:12][CH:11]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[CH3:32][O:31][C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH2:15][CH:11]2[O:12][CH2:13][CH2:14][NH:9][CH2:10]2)[CH:30]=[CH:29][CH:28]=1
Reactant: COc1cccc(CCc2ccccc2OCC2CN(C(=O)OC(C)(C)C)CCO2)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc(CCc2ccccc2OCC2CNCCO2)c1
Reaction time: 16 h
Yield: 52 %

Procedure:
2 ml of a 4N solution of hydrogen chloride in dioxane were added to a solution of 0.99 g of 4-t-butoxycarbonyl-2-{2-[2-(3-methoxyphenyl)ethyl]phenoxymethyl}morpholine [prepared as described in step (a) above] in 2 ml of dioxane, and the mixture was allowed to stand at room temperature for 16 hours, after which it was concentrated by distillation under reduced pressure. The resulting residue was dissolved in ethyl acetate, and the solution was allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo, to give 0.42 g (yield 52%) of the title compound as colorless crystals, melting at 110°-112° C.
Reaction SMILES: [NH2:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:34][CH3:35])[CH:3]=1.[CH:36](=O)[CH3:37].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[CH2:36][CH3:37])[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:34][CH3:35])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccc(Cl)c(Cl)c2)CC1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc(Cl)c(Cl)c1

Procedure:
4-Amino-5-chloro-N-((1-(5-(3,4-dichlorobenzylamino)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide (2.0 g) as starting compound, acetaldehyde (0.27 ml) and sodium cyanoborohydride (0.3 g) were reacted and treated in the same manner as in Example 136 to give 0.82 g of 4-amino-5-chloro-N-((1-(5-(N-(3,4-dichlorobenzyl)-N-ethylamino)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13]([CH3:15])=O.[C:16]([O:20][CH3:21])(=[O:19])[NH:17][NH2:18]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13](=[N:18][NH:17][C:16]([O:20][CH3:21])=[O:19])[CH3:15]
Reactant: COC(=O)NN
Reactant: CC(=O)c1nc(-c2ccccc2)[nH]c1C
Solvent: Cc1ccccc1
Product: COC(=O)NN=C(C)c1nc(-c2ccccc2)[nH]c1C

Procedure:
Methyl 5-methyl-2-phenyl-4-imidazolyl ketone (4.5 gm., 0.023 mole) is refluxed with methyl carbazate (2.4 gm., 0.023 mole) in toluene (112 ml.) for 5 hours. The toluene is removed, and the solid washed with water (3×50 ml.). The solid is recrystallized from methanol to yield the product (1.28 gm., 20.9%), m.p. 201°-201.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:15]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:14](=[O:23])[O:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[CH2:1]([O:8][C:9]([NH:11][CH:15]([C:14]([O:13][CH3:12])=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCCCC1C(=O)OCN1C(=O)OCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(CCCCC(=O)O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
A solution of 0.20 g (0.62 mmol) of the resultant compound of Example 187 in methanol was treated with sodium methoxide and stirred at ambient temperature for 2 h. The solvent was removed in vacuo, and the residue was acidified with IN HCl, extracted with chloroform, and concentrated to give 159 mg of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:37]([F:40])([F:39])[F:38])[N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][CH:16]([NH:27]C(OC(C)(C)C)=O)[CH2:17][C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=3[F:26])[C@H:10]([CH3:36])[C:9]=12)=[O:4].[ClH:41]>C(OCC)(=O)C>[ClH:41].[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:37]([F:40])([F:38])[F:39])[N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][CH:16]([NH2:27])[CH2:17][C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=3[F:26])[C@H:10]([CH3:36])[C:9]=12)=[O:4]
Reactant: COC(=O)c1nc(C(F)(F)F)n2c1[C@@H](C)N(C(=O)CC(Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C(F)(F)F)n2c1[C@@H](C)N(C(=O)CC(N)Cc1cc(F)c(F)cc1F)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-8-methyl-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester 39d (0.23 g, 0.4 mmol) was added into the reaction flask. A solution of 2.3 N hydrochloric acid in 5 mL of ethyl acetate was then added to the flask. The reaction mixture was stirred at room temperature for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-8-methyl-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester hydrochloride 39 (0.205 g, yield 100%) as a white solid.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C:7](=[CH:9][CH:10]=O)[CH3:8])[CH3:3].[CH3:12][C:13]([CH3:15])=[O:14]>>[CH3:3][C:2]([CH3:1])=[CH:4][CH2:5][CH2:6]/[C:7](/[CH3:8])=[CH:9]/[CH:10]=[CH:12]/[C:13]([CH3:15])=[O:14]
Reactant: CC(C)=O
Reactant: CC(C)=CCCC(C)=CC=O
Product: CC(=O)/C=C/C=C(\C)CCC=C(C)C

Procedure:
WO 2003/047747 and WO 2003/047748 (publ. Jun. 12, 2003) describe metal oxide catalysts based on γ-aluminum oxide, their use during the aldol condensation of citral and acetone to give pseudoionone, and also special columns for carrying out the reaction by reactive distillation. The metal oxides are oxides of the elements with the atomic numbers 39 (Y) and 57 (La)-71 (Lu), with yttrium oxide and praseodymium oxide being emphasized as being preferred. When using a catalyst of 5% Pr on γ-Al2O3, in the 24 hour operation, pseudoionone was obtained with a yield of 66.7% and a selectivity of 97.3% based on citral. The concentration of the active components based on the total weight of the supported catalyst is in the range of 5 to 12% by weight, preferably 7.5 to 10% by weight. Whereas, as a result of extensive screening investigations, γ-Al2O3 has proven to be a particularly suitable support material, which relates to the activity of the catalyst, it is emphasized that both the geometry of the catalyst support and also the maintenance of the aforementioned concentrations are of decisive importance for obtaining good space-time yields.
Reaction SMILES: [O:1]1[C:3]2([CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]2)[CH2:2]1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C1COCC1>[N:14]1([CH2:2][C:3]2([OH:1])[CH2:4][NH:5][CH2:6]2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CC2(CO2)C1
Solvent: C1CCOC1
Product: OC1(CN2CCOCC2)CNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.1 %

Procedure:
1,1-Dimethylethyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (51 mg, 0.28 mmol) was taken into THF (1 mL) followed by addition of morpholine (123 μL, 1.4 mmol) and the mixture was stirred for one hour at room temperature. The solution was then concentrated and the residue partitioned with ethyl acetate and water. The organic layer was washed once with water then brine and the organic layer dried over anhydrous sodium sulfate. Filtration and concentration gave a colorless oil that was purified by silica gel flash chromatography using ethyl acetate to 10% methanol in dichloromethane as eluents. The combined pure fractions were concentrated and the residue treated with neat TFA (1 mL) for 5 minutes then concentrated. The residue was taken into methanol (2 mL) and basified to pH>10 by addition of Biorad AG-1X hydroxide form resin. Filtration and concentration afforded 3-(morpholin-4-ylmethyl)azetidin-3-ol (11.6 mg, 24% yield) as a colorless oil. 1H NMR (400 MHz, CD3OD): 3.69-3.66 (m, 4H), 3.55 (d, 2H), 3.49 (d, 2H), 2.66 (s, 2H), 2.57-2.55 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([Cl:26])[CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[Cl-].[NH4+]>[Fe].O>[C:1]([O:5][C:6](=[O:27])[NH:7][CH:8]1[CH2:9][CH2:10][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([Cl:26])[CH:18]=2)(=[O:16])=[O:15])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])c(Cl)c2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(N)c(Cl)c2)CC1
Temperature: 80 °C
Yield: 26.9 %

Procedure:
[1-(3-Chloro-4-nitro-benzenesulfonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.44 g, 1.05 mmol) was suspended in a 5:1 mixture of ethanol and water (30 ml). To this solution was added iron powder (0.29 g, 5.24 mmol) followed by saturated ammonium chloride solution (3 ml) and the mixture was heated to 80° C. for three hours. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of celite, the celite was washed with ethanol (10 ml) and EtOAc (50 ml) and the solution was concentrated under vacuum. The resulting residue was suspended in water (10 ml) and the solid precipitate collected by filtration and dried under vacuum to give the title compound (0.11 g, 18% yield) as a white solid. Tr=2.12 min, m/z (ES+) (M+Na)+ 412.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:27][NH:28][CH3:29].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:28]([CH3:29])[CH3:27])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
To a solution of 6-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.28 mmol) and dimethylamine hydrochloride (23.1 mg, 0.28 mmol) in THF (10 mL) were added at 0° C., 1-hydroxybenzotriazole hydrate (43.3 mg, 0.28 mmol), N-ethyldiisopropylamine (170 μL, 0.97 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (54.2 mg, 0.28 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed by distillation. The remaining material was purified by chromatography (silica, ethyl acetate:heptane=4:6 to 1:0) to afford the title compound (66 mg, 61%) as a white solid. MS: m/e=446.3 [M+OAc]−.
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.O=C1CC(=O)N(C2C=CC(C(OCC)=O)=CC=2)C2C=CC3C(C=2N1)=CC=CC=3.[Cl:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[CH2:60][CH2:61][C:62](Cl)=[O:63].O=C1CC(=O)N(C2C=CC(C(O)=O)=CC=2)C2C=CC3C(C=2N1)=CC=CC=3>>[Cl:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[CH2:60][CH2:61][C:62]([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:63]
Reactant: O=C(Cl)CCc1ccccc1Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: CCOC(=O)c1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(C(=O)O)cc2)c2ccc3ccccc3c2N1
Product: O=C(CCc1ccccc1Cl)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 56 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3) (35 mg, 0.110 mmol), and 3-(2-chlorophenyl)propionic acid chloride (0.132 mmol), the title compound (30 mg, yield 56%) was obtained as white crystals in the same manner as that of Example 1, (4).
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:12]=2[N:13]=1)=[O:7])(=O)C.N>CO>[Cl:18][C:14]1[C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[CH2:5][OH:4])[S:10][C:11]=2[CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)OCC(=O)Nc1nc2c(Cl)cccc2s1
Agent: N
Solvent: CO
Product: O=C(CO)Nc1nc2c(Cl)cccc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
2-(Acetoxyacetylamino)-4-chlorobenzothiazole (2.8 g) prepared in Example 8 is dissolved in methanol (100 ml) and thereto is added 28% aqueous ammonia (10 ml) and the mixture is stirred at room temperature for 1 hour. The solvent is distilled off and the resulting solids are washed with water, dried and recrystallized from ethanol to give the title compound (1.9 g) having the following physical properties.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[Se:9](=[O:16])[CH2:8]1>C(Cl)(Cl)Cl>[Cl:3][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[Se:9](=[O:16])[CH2:8]1
Reactant: O=[Se]1CN(CO)c2ccccc21
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=[Se]1CN(CCl)c2ccccc21

Procedure:
0.55 cm3 of thionyl chloride (0.02 mol) is added dropwise and with stirring into a round-bottom flask containing 0.01 mol of 3-(hydroxymethyl)benzoselenazolinone dissolved in 100 cm3 of chloroform. The mixture is brought to reflux for 2 hours and the chloroform is then evaporated off under reduced pressure. The product is recrystallized in cyclohexane.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19](Br)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][Sn](C)(C)C>CN(C)C=O.[Cl-].[Na+].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>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([CH3:28])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reactant: C[Sn](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cncc2cccc(S(=O)(=O)N3CCC(NC(=O)OC(C)(C)C)C3)c12
Temperature: 120 °C

Procedure:
A solution of Intermediate 1 (228 mg) obtained in Example 1, Step A and tetramethyltin (0.69 ml, Tokyo Kasei Kogyo) in N,N-dimethylformamide (4 ml) is added with tetrakis(triphenylphosphine)palladium(0) (29 mg, Kanto Chemicals), and the mixture is stirred at 120° C. with heating for 12 hours. The reaction mixture is cooled to room temperature, then added with saturated brine (5 ml), and extracted 3 times with ethyl acetate (5 ml for each time). The combined organic layer is washed with saturated brine (10 ml), and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, and then the residue is purified by silica gel chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (176 mg (predictive yield)).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[OH:5][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:21])=[N:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:9]1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>C(#N)C>[C:1]([CH2:2][CH2:3][O:5][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:21])=[N:15][CH2:16][C:17]([F:19])([F:18])[F:20])=[N:9]1)#[N:4]
Reactant: NC(=NCC(F)(F)F)Nc1ccn(CCO)n1
Reactant: C=CC#N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CC#N
Product: N#CCCOCCn1ccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
Acrylonitrile (0.8 g.) was added to a solution of 1-(2-hydroxyethyl)-3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazole (2.51 g.) in acetonitrile (10 ml.). Benzyltrimethylammonium hydroxide (40% w/v aqueous solution; 10 μl) was added. After stirring at room temperature for 1 hour, the solution was evaporated to dryness in vacuo, and the residue purified by medium pressure chromatography using triethylamine/EtOH/EtOAc 1:1:9 v/v/v as eluant to give 1-[2-(2-cyanoethoxy)ethyl]-3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazole (1.0 g.) having the following n.m.r. spectrum in d6DMSO: 7.6 (d, 1H); 5.8 (d, 1H); 4.2 (m, 2H); 4.1 (t, 2H); 3.8 (t, 2H); 3.6 (t, 2H); 2.7 (t, 2H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:12]=[C:11]([CH:13]=[CH2:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].Br[CH:18]([C:23]1[CH:28]=[C:27]([Cl:29])[C:26]([F:30])=[C:25]([Cl:31])[CH:24]=1)[C:19]([F:22])([F:21])[F:20].N1C=CC=CC=1C1C=CC=CN=1>CN1CCCC1.O.[Cu]Cl>[Cl:29][C:27]1[CH:28]=[C:23]([CH:18]([C:19]([F:22])([F:21])[F:20])/[CH:14]=[CH:13]/[C:11]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:3][C:2]([F:15])([F:16])[F:1])[CH:12]=2)[CH:24]=[C:25]([Cl:31])[C:26]=1[F:30]
Reactant: C=Cc1ccc(C(=O)O)c(OC(F)(F)F)c1
Reactant: Fc1c(Cl)cc(C(Br)C(F)(F)F)cc1Cl
Agent: Cl[Cu]
Agent: CN1CCCC1
Agent: c1ccc(-c2ccccn2)nc1
Solvent: O
Product: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(F)c(Cl)c2)C(F)(F)F)cc1OC(F)(F)F
Temperature: 150 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
To a stirred solution of 2-(trifluoromethoxy)-4-vinylbenzoic acid (0.356 g, 1.53 mmol) in 1N methyl pyrrolidine (5.0 mL) was added 1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichloro 4-fluorobenzene (1.0 g, 3.07 mmol), copper(I) chloride (CuCl; 0.03 g, 0.307 mmol) and 2,2 bipyridyl (0.095 g, 0.614 mmol). The reaction mixture was stirred at 150° C. for 1 h. After the reaction was complete by TLC, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to obtain the crude compound which was purified by flash column chromatography to afford the product as pale yellow gummy material (0.3 g, 21%): 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J=8.0 Hz, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.35 (s, 3H), 6.63 (d, J=16.0 Hz, 1H), 6.50 (dd, J=16.0, 8.0 Hz, 1H), 4.15 (m, 1H); ESIMS m/z 474.81 ([M−H]−).