Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=2[O:19][CH3:20])[C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]=2[N:4]([CH3:25])[C:3]1=[O:26].[CH3:27][C:28]1[CH:29]=[C:30]([N:34]=[C:35]=[O:36])[CH:31]=[CH:32][CH:33]=1>>[CH3:25][N:4]1[C:5]2[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=2[C:7]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=2[O:19][CH3:20])=[N:8][CH:2]([NH:1][C:35]([NH:34][C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([CH3:27])[CH:29]=2)=[O:36])[C:3]1=[O:26]
Reactant: COc1cc(OC)c(C2=NC(N)C(=O)N(C)c3ccccc32)c(OC)c1
Reactant: Cc1cccc(N=C=O)c1
Product: COc1cc(OC)c(C2=NC(NC(=O)Nc3cccc(C)c3)C(=O)N(C)c3ccccc32)c(OC)c1
Yield: 94 %

Procedure:
By condensing 3-amino-1,3-dihydro-1-methyl-5-(2,4,6-trimethoxyphenyl)-1,4-benzodiazepin-2-one with 3-methylphenyl isocyanate, 1,3-dihydro-1-methyl-3-(3-methylphenylureido)-5-(2,4,6-trimethoxyphenyl)-1,4-benzodiazepin-2-one is obtained; m.p.=240° C., Yield=94%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:38])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:11]=2[NH:17][C:18](=[O:37])[C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[C:26]3=[O:36])=[CH:21][CH:20]=2)=[N:6][CH:7]=1.C(OO)(=[O:41])C.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:38])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:11]=2[NH:17][C:18](=[O:37])[C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][N+:33]([CH3:35])([CH3:34])[O-:41])[C:26]3=[O:36])=[CH:21][CH:20]=2)=[N:6][CH:7]=1
Reactant: CC(=O)OO
Reactant: CN(C)CCN1CCCC(c2ccc(C(=O)Nc3c(O)cccc3C(=O)Nc3ccc(Cl)cn3)cc2)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[N+](C)([O-])CCN1CCCC(c2ccc(C(=O)Nc3c(O)cccc3C(=O)Nc3ccc(Cl)cn3)cc2)C1=O

Procedure:
N-(5-chloropyridin-2-yl)-2-[(4-{1-[2-(dimethylamino)ethyl]-2-oxopiperidin-3-yl}benzoyl)amino]-3-hydroxybenzamide (300 mg) was dissolved in dimethylformamide (6 mL), and with cooling with ice, an aqueous 32% peracetic acid solution (135 μL) was added, followed by stirring with cooling with ice for 30 minutes. The reaction solution was put into an aqueous saturated sodium hydrogencarbonate solution (30 ml), followed by extraction with chloroform. The organic layer was dried with sodium sulfate and evaporated under reduced pressure to obtain N-(5-chloropyridin-2-yl)-2-[(4-{1-[2-(dimethylnitroryl)ethyl]-2-oxopiperidin-3-yl}benzoyl)amino]-3-hydroxybenzamide (210 mg). The resulting N-(5-chloropyridin-2-yl)-2-[(4-{1-[2-(dimethylnitroryl)ethyl]-2-oxopiperidin-3-yl}benzoyl)amino]-3-hydroxybenzamide (209 mg) was dissolved in dimethylformamide (3 mL), then at room temperature, water (3 ml), benzoic acid (46 mg) and an aqueous 1 M iron chloride solution (38 μL) were added, followed by stirring at room temperature for 2 hours. An aqueous saturated sodium hydrogencarbonate solution was added to the reaction mixture, followed by extraction with chloroform. The organic layer was evaporated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (chloroform:methanol=100:0 to 95:5). The purified product was dissolved in ethanol, and 4 M hydrochloric acid/ethyl acetate solution (1 mL) was added, followed by evaporation under reduced pressure. Ethyl acetate was added to the residue, followed by stirring at room temperature for 1 hour. The precipitate formed was collected by filtration and dried at 40° C. under reduced pressure to obtain N-(5-chloropyridin-2-yl)-3-hydroxy-2-[(4-{1-[2-(methylamino)ethyl]-2-oxopiperidin-3-yl}benzoyl)amino]benzamide hydrochloride (108 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH3:16])[C:6]=2[CH:17]=1.[OH:18][CH2:19][C:20]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:25])[CH2:21][CH:22]([CH3:24])[CH3:23]>CCOCC>[C:29]([O:28][C:27](=[O:33])[NH:26][C:20]([CH3:25])([CH2:21][CH:22]([CH3:23])[CH3:24])[CH2:19][O:18][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH3:16])[C:6]=2[CH:17]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)CC(C)(CO)NC(=O)OC(C)(C)C
Reactant: Cn1c(=O)c2cnccc2c2ccc(Cl)cc21
Solvent: CCOCC
Product: CC(C)CC(C)(COc1ccc2c3ccncc3c(=O)n(C)c2c1)NC(=O)OC(C)(C)C
Yield: 111.3 %

Procedure:
8-Chloro-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (0.15 g, 0.613 mmol), prepared as described in Example 2, Part C, and tert-butyl (1-hydroxy-2,4-dimethylpentan-2-yl)carbamate (0.284 g, 1.226 mmol) were subjected to ether synthesis as described in Example 2, Part D, to afford tert-butyl(2,4-dimethyl-1-((6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (0.3 g, 28% yield) as pale yellow solid. LC/MS (ESI) m/e 440.2 [(M+H)+, calcd for C25H34N3O4 440.2]; LC/MS retention time (method C): tR=2.67 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10]1(=O)[C:20]2=[C:21]3[C:16](=[CH:17][CH:18]=[CH:19]2)[CH:15]=[CH:14][CH:13]=[C:12]3[C:11]1=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[C:10]1[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:21]=3[C:12]([C:11]1=[N:9]2)=[CH:13][CH:14]=[CH:15]4
Reactant: Nc1ccc(Cl)cc1N
Reactant: O=C1C(=O)c2cccc3cccc1c23
Product: Clc1ccc2nc3c(nc2c1)-c1cccc2cccc-3c12
Yield: 90 %

Procedure:
When 0.05 mole each of 4-chloro-o-phenylenediamine and acenaphthenequinone were reacted by the method of Example 7(A), 13 g. (90 percent yield) of 9-chloroacenaphtho-[1,2-b]quinoxaline, mp = 224°-225° C., were obtained
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1([CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[CH2:8][C:7]2[C:9]([CH3:16])=[C:10]([NH2:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1.C(=O)([O-])[O-].[Na+].[Na+].[C:36](Cl)(=[O:38])[CH3:37]>O1CCCC1.O>[CH3:3][C:4]1([CH2:17][N:18]2[CH2:19][CH2:20][CH:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][CH2:23]2)[CH2:8][C:7]2[C:9]([CH3:16])=[C:10]([NH:15][C:36](=[O:38])[CH3:37])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(c3ccccc3)CC1)O2
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1c(C)c(C)c2c(c1C)CC(C)(CN1CCC(c3ccccc3)CC1)O2
Reaction time: 0.08 h
Yield: 90 %

Procedure:
To a suspension of 2,3-dihydro-2,4,6,7-tetramethyl-2-[(4-phenyl-1-piperidinyl)methyl]-5-benzofuranamine dihydrochloride (1.3 g) in tetrahydrofuran (10 mL) was added a solution of sodium carbonate (0.95 g) in water (5 mL) with ice-cooling and the mixture was stirred for 5 minutes. Then, 0.26 mL of acetyl chloride was added dropwise and the mixture was stirred at room temperature for 15 minutes. This reaction mixture was diluted with water and extracted with 2 portions of ethyl acetate. The pooled organic layer was washed with water and saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate/diisopropyl ether to provide 1.1 g of the title compound. Yield 90%.
Reaction SMILES: [CH3:1][CH:2]1[S:6](=[O:8])(=[O:7])[NH:5][CH2:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[CH3:31])[CH2:20][CH2:19]2)=[O:17])=[C:12]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:11]=1>>[CH3:31][C:25]1[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=1[N:21]1[CH2:20][CH2:19][N:18]([C:16]([C:13]2[CH:14]=[CH:15][C:10]([N:5]3[CH2:4][CH2:3][CH:2]([CH3:1])[S:6]3(=[O:8])=[O:7])=[CH:11][C:12]=2[S:32]([CH3:35])(=[O:34])=[O:33])=[O:17])[CH2:23][CH2:22]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: CC1CCNS1(=O)=O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCC(C)S4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 21.2 %

Procedure:
Using 5-methylisothiazolidine 1,1-dioxide (360 mg) described in Preparation Example 5 and (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (803 mg) described in Preparation Example 110 and by the reaction and treatment in the same manner as in Example 4, the title compound (191 mg) was obtained.
Reaction SMILES: ClC(Cl)(Cl)COC([N:7]1[C:13]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]=2[C:11](=[O:20])[N:10]2[CH2:21][CH2:22][CH2:23][C@H:9]2[C@@H:8]1O)=O>C1COCC1.CCOC(C)=O>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:13]2[N:7]=[CH:8][CH:9]3[CH2:23][CH2:22][CH2:21][N:10]3[C:11](=[O:20])[C:12]=2[CH:17]=1
Reactant: COc1ccc2c(c1)C(=O)N1CCC[C@H]1[C@H](O)N2C(=O)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(=O)N1CCCC1C=N2
Reaction time: 2 h
Yield: 89.3 %

Procedure:
10% Cd/Pb couple (2.50 g, 20 mmol Cd) was added to a rapidly stirring solution of 95 (1.71 g, 4.03 mmol) in a mixture of THF (30 mL) and 1N NH4OAc (30 mL). Upon addition, the solution turned cloudy and after 2 hours TLC showed the reaction to be complete. The reaction mixture was diluted with EtOAc (150 mL) and dried over anhydrous MgSO4. The solids were filtered and rinsed with EtOAc (50 mL). Removal of excess solvent by rotary evaporation under reduced pressure afforded the product as a yellow solid (0.84 g, 3.6 mmol, 90%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:5]O.N1C=CC=CC=1.S(Cl)([Cl:22])=O>CCOCC>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[CH2:5][Cl:22]
Reactant: COc1cc(Br)c(OC)c(CO)c1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: COc1cc(Br)c(OC)c(CCl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.3 %

Procedure:
To a solution of 8.18 gm (33.11 mmol) of 3-bromo-2,5-dimethoxybenzyl alcohol and 0.8 ml pyridine in 100 ml ether was added dropwise a solution of 8.5 ml (116 mmol) thionyl chloride in 20 ml ether. After stirring at ambient temperature for 20 hours, the reaction mixture was poured onto ice. The ether extract was washed with brine, dried (NaSO4), filtered and concentrated in vacuo to give 7.59 gm of a colorless oil. A portion, 3.9 gm, was purified by silica gel chromatography using 3:7 CH2 Cl2 :hexane to yield 3.62 gm of a white solid.
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][N:10]([C@@H:13]2[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:17]([O:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:14]2[O:15][CH3:16])[C:9](=[O:39])[N:8]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].CC(C)=[O:42]>O.C(O)(=O)C>[OH:42][C:2]([CH2:3][CH2:4][CH2:5][CH3:6])=[CH:1][C:7]1[CH:12]=[CH:11][N:10]([C@@H:13]2[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:38])[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@@H:17]([O:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:14]2[O:15][CH3:16])[C:9](=[O:39])[N:8]=1
Reactant: CCCCC#Cc1ccn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC)c(=O)n1
Reactant: CC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCCCC(O)=Cc1ccn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC)c(=O)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 19 %

Procedure:
4-(1-Hexyn-1-yl)-1-(2-O-methyl-3,5,-di-O-benzoyl-β-D-ribofuranosyl)pyrimidin-2-one was dissolved in acetone (40 ml) and to this solution was added mercuric sulfate dissolved in H2O (10 ml) and acetic acid (10 ml). This solution was stirred at room temperature for 5 hours. The reaction was purified by silica gel column chromatography. Pooling of appropriate fractions and concentration gave 225 mg (19%) of the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[CH2:11][C:12]([O:14]CC)=O.[C:17]([O:20][C:21](=O)[CH3:22])(=[O:19])[CH3:18].Cl>O1CCCC1>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[CH2:11][C:12](=[O:14])[CH2:18][C:17]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)Cc1c(F)cccc1Cl
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)Cc1c(F)cccc1Cl
Yield: 35.8 %

Procedure:
Into a mixture of 9.6 g of sodium hydride (60% in oil) and 200 ml of tetrahydrofuran, 21.7 g of ethyl 2-chloro-6-fluorophenylacetate were added dropwise under reflux. Then, a solution of 12.3 g of acetic anhydride in 40 ml tetrahydrofuran was added thereto and refluxed under heating for 10 hours. The reaction mixture was cooled, poured into iced dil. hydrochloric acid and extracted with t-butyl methyl ether. The organic layer was washed with dil. hydrochloric acid, aqueous saturated sodium bicarbonate solution, dil. hydrochloric acid and water, subsequently, dried over sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 9.27 g of ethyl (2-chloro-6-fluorophenyl)acetoacetate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10]C(=O)C.CC(O)=O.[N:18](OCCC(C)C)=O>C1(C)C=CC=CC=1>[CH3:8][C:6]1[CH:7]=[C:2]2[C:3](=[C:4]([CH3:9])[CH:5]=1)[NH:10][N:18]=[CH:1]2
Reactant: CC(=O)Nc1c(C)cc(C)cc1C
Reactant: CC(C)CCON=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2[nH]ncc2c1
Yield: 100.3 %

Procedure:
N-(2,4,6-trimethyl-phenyl)-acetamide (23.8 g, 133 mmol) (prepared as described in Example 12) was dissolved in a mixture of toluene (300 mL) and glacial AcOH (10.4 g, 173 mmol, 1.3 eq) and then treated slowly with isoamyl nitrite (20.3 g, 23.2 mL, 173 mmol, 1.3 eq). The mixture was heated at reflux overnight or until all the starting material was consumed as judged by TLC (30% EtOAc-hexanes). The solution was then poured into H2O (1.3 L) and extracted with EtOAc (2×300 mL). The combined organic extracts were then washed with saturated aq. NaHCO3 solution (2×200 mL) and brine (1×100 mL). The extracts were dried (MgSO4), filtered, and concentrated to provide 19.5 g of 5,7-dimethyl-1H-indazole 2 as a red waxy solid. This material was carried on without additional purification. RP-HPLC Method: 2-100% B in 2 minutes
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][CH2:38][S:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][N:41]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][CH2:38][S:39][C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][N:41]=2)=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: NCCSc1ccc(C(F)(F)F)cn1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)NCCSc2ccc(C(F)(F)F)cn2)cc1
Reaction time: 1 h
Yield: 83.8 %

Procedure:
4-geranyloxybenzoic acid(6.17 g) was dissolved in chloroform(80 ml) and triethylamine(6.24 ml), and then diphenylphosphinic chloride(4.29 ml) was added thereto while being cooled with ice. After being stirred for 1 hour, the mixture, with 2-(2-aminoethylthio)-5-(trifluoromethyl)pyridine(5.00 g) added thereto, was stirred for 4 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 9.02 g of the aimed compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].[Cl:32][CH2:33][CH2:34][CH2:35][C:36](Cl)=[O:37].C(N(CC)CC)C>C(Cl)Cl>[Cl:32][CH2:33][CH2:34][CH2:35][C:36]([NH:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26](=[O:31])[C:27]([CH3:28])([CH3:30])[CH3:29])=[O:37]
Reactant: O=C(Cl)CCCCl
Reactant: CC(C)(C)C(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1NC(=O)CCCCl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a magnetically stirred solution of 0.300 g (0.63 mmol) of the product of Example 17 in 6 mL of CH2Cl2 at 0° C. was added 70 μL (0.63 mmol) of 4-chlorobutyryl chloride and 96 mg (0.95 mmol) of triethylamine. The reaction was stirred for 1.5 h and allowed to warm to room temperature. The reaction mixture was then partitioned between saturated aqueous NaHCO3 and EtOAc. The organic layer was separated, washed with aq. NaHCO3, brine, then dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0–20% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound. HPLC/MS: 577.0 (M+1), 578.9 (M+3); Rt=5.05 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([CH:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:26](O)=[O:27])=[C:13]([C:15]2[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=2[F:25])[N:14]=1)=[O:8].CN.O.O[N:35]1[C:39]2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([CH:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:26]([NH:35][CH3:39])=[O:27])=[C:13]([C:15]2[C:16]([F:25])=[C:17]([F:24])[C:18]([F:23])=[C:19]([F:22])[C:20]=2[F:21])[N:14]=1)=[O:8]
Reactant: O=C(Nc1nc(-c2c(F)c(F)c(F)c(F)c2F)c(C(=O)O)s1)c1cc(Br)ccc1O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1sc(NC(=O)c2cc(Br)ccc2O)nc1-c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.1 %

Procedure:
A mixture of 2-(5-bromo-2-hydroxybenzoyl)amino-4-(pentafluorophenyl)-thiazole-5-carboxylic acid (0.20 g, 0.48 mmol), methylamine 40% methanol solution (0.2 ml), 1-hydroxybenzotriazole hydrate (96.7 mg, 0.72 mmol), WSC.HCl (137.2 mg, 0.72 mmol) and tetrahydrofuran (15 mL) was stirred at room temperature for 18 hours. The reaction mixture was poured into 2 N hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=1:2), and crystallized (dichloromethane/n-hexane) to give the title compound (87.9 mg, 42.6%) as a white powder.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:18][O-:19].[Na+].[Na]>CO>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:19][CH3:18])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
1.5 g of 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile are added to a solution of sodium methylate in methanol prepared from 0.16 g of sodium and 20 ml of absolute methanol, and the mixture is heated to reflux temperature for 1 hour. The solvent is subsequently distilled off, the residue is treated with water and the resulting aqueous mixture is extracted three times with methylene chloride. The combined extracts are washed with water, dried over anhydrous sodium sulphate and evaporated. In this manner there is obtained methyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH:42]3[CH2:44][CH2:43]3)[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH:42]3[CH2:43][CH2:44]3)[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C3CC3)c2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C4CC4)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(2-cyclopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K60) (253 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous off-white substance (328 mg, 79%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=[C:11]3[C:17]=2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:4][CH:3]=1.[C:21]1([CH2:27][CH2:28][CH:29]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=[C:11]3[C:17]=2[CH2:16][CH2:15][N:14]([CH2:29][CH2:28][CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]3)=[CH:4][CH:3]=1
Reactant: O=CCCc1ccccc1
Reactant: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCNCC2
Product: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCN(CCCc1ccccc1)CC2

Procedure:
The title compound (142 mg) was prepared from 3-(4-fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 190) and 3-phenyl-propionaldehyde as in Example 35. MS (ESI): exact mass calculated for C25H30FN3, 391.24; found, m/z 392.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.45-7.41 (m, 2H), 7.35-7.26 (m, 6H), 7.22-7.19 (m, 1H), 4.46 (m, 1H), 3.79-3.76 (m, 1H), 3.67-3.63 (m, 1H), 3.46-3.43 (m, 1H), 3.35-3.29 (m, 5H), 2.90-2.87 (m, 1H), 2.83-2.73 (m, 3H), 2.19-2.12 (m, 2H), 1.44 (t, J=6.7 Hz, 6H).
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]2(C#N)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=NN=N1.[N+:15]([CH3:18])([O-:17])=[O:16].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[N+:15]([CH2:18][C:7]1([CH2:6][C:5]#[N:1])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([O-:17])=[O:16]
Reactant: N#CC1(Cc2nnn[nH]2)CCCCC1
Reactant: C[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CCC1(C[N+](=O)[O-])CCCCC1
Yield: 70.7 %

Procedure:
The nitrile (compound 2, 0.78 g, 6.44 mmol), nitromethane (0.80 g, 13.11 mmol) and tetrabutyl ammonium fluoride (1.0 M in tetrahydrofuran, 10 mL, 10 mmol) were heated in 20 mL tetrahydrofuran to 70° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid and water, dried over magnesium sulphate, filtered, and evaporated to dryness. The residue was purified by chromatography on silica eluting with heptane/ethyl acetate 3:1 to give the required product as a yellow oil (0.83 g, 71%).