Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[C:4]([C:12](O)=[O:13])[C:3]1=[O:15].C(Cl)(=O)C([Cl:19])=O.CN(C)C=O>ClCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[C:4]([C:12]([Cl:19])=[O:13])[C:3]1=[O:15]
Reactant: Cn1c(=O)c(C(=O)O)cc2cccnc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(=O)c(C(=O)Cl)cc2cccnc21
Temperature: 40 °C
Reaction time: 1 h

Procedure:
1.0 g (4.9 mmol) of 1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-carboxylic acid was dissolved in dichloromethane (50 mL), and 1.0 mL (12 mmol) of oxalyl chloride was added thereto. Three droplets of N,N-dimethylformamide were added to the above mixture, and the resulting mixture was stirred for one hour at 40° C. The reaction solution was concentrated under reduced pressure, and thus 1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-carboxylic acid chloride was obtained. The acid chloride thus obtained was dissolved in acetonitrile (30 mL), and this solution was added to an acetonitrile (50 mL) solution of 0.60 g (5.4 mmol) of 1,3-cyclohexanedione and 0.82 mL (5.9 mmol) of triethylamine under ice cooling. The resulting mixture was stirred for one hour at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic phase was washed with water, an aqueous solution of sodium hydrogen carbonate, and water in this order, and then was dried and concentrated. The residue was washed with diisopropyl ether, and thus 0.83 g of the title compound was obtained as a light yellow solid (yield: 57%).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH:4]=1.Br[C:26]1[C:27]([F:37])=[CH:28][C:29]([F:36])=[C:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[C:27]([F:37])=[CH:28][C:29]([F:36])=[C:30]([S:32]([NH2:35])(=[O:33])=[O:34])[CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Product: NS(=O)(=O)c1cc(C#Cc2cnn3c(C(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (169 mg, 0.5 mmol) and commercially available 5-bromo-2,4-difluoro-benzenesulfonamide (136 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (76 mg, 29%). MS (ISN) 527.0 [(M−H)−]; mp 277° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[CH:10]([N+:15]([O-:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=1)[CH3:2].[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:20].S(=O)(=O)(O)O.O>C(Cl)Cl>[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[CH:10]([N+:15]([O-:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:24][CH:23]=1)[CH3:20]
Reactant: CCCCC(C(O)c1ccc(CC)cc1)[N+](=O)[O-]
Reactant: CCOc1ccccc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CCCCC(C(c1ccc(CC)cc1)c1ccc(OCC)cc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
25.1 g of 1-p-ethylphenyl-2-nitro-1-hexanol and 14.6 g of ethoxybenzene are dissolved in 80 ml of methylene chloride, and the solution is added dropwise at 0° C, with vigorous stirring, to 90 g of conc. sulphuric acid and 10 ml of water. After 2 hours' stirring at room temperature, the mixture is poured on to 400 ml of ice water. The product is taken up in methylene chloride and washed with saturated sodium bicarbonate solution. After the solvent has been removed by evaporation, the oil remaining behind is dried in high vacuum at 60° C for 2 hours. There is obtained the compound of the formula ##STR7## as viscous, dark yellow oil having a refractive index of nD22 = 1.5452.
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].[Mg].[CH3:6][C:7]1[CH:12]([CH:13]=[O:14])[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][CH:8]=1.[NH4+].[Cl-]>CCOCC>[CH3:6][C:7]1[CH:12]([CH:13]([OH:14])[CH2:3][CH:2]=[CH2:1])[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][CH:8]=1
Reactant: C=CCCl
Reactant: CC1=CCCC(C)(C)C1C=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CCC(O)C1C(C)=CCCC1(C)C
Reaction time: 3 h

Procedure:
Allyl chloride (5 ml.) was added under nitrogen to a suspension of magnesium (28.8 g.) in 300 ml. of dry ether. According to the usual procedure of a Grignard reaction, allyl chloride (85 g.) and α-cyclocitral (152 g.) in 100 ml. of dry ether were added at such a rate as to maintain the solvent at reflux. At this temperature, the mixture was left during 3 h. and poured then into an NH4Cl aqueous solution.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[C:28]([S:31][CH2:32][CH:33]([C:37]([F:40])([F:39])[F:38])[C:34](O)=[O:35])(=[O:30])[CH3:29]>ClCCl>[C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:34](=[O:35])[CH:33]([C:37]([F:38])([F:39])[F:40])[CH2:32][S:31][C:28](=[O:30])[CH3:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CC(=O)SCC(C(=O)O)C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)SCC(C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(F)(F)F
Temperature: 0 °C

Procedure:
L-proline tert-butyl ester (5.1 g.) is dissolved in dichloromethane (40 ml.) and the solution is stirred and chilled in an ice bath. Dicyclohexylcarbodiimide (6.2 g.) dissolved in dichloromethane (15 ml.) is added followed immediately by a solution of 3-acetylthio-2-trifluoromethylpropanoic acid (6.5 g.) in dichloromethane ( ml.). After fifteen minutes stirring in the ice bath and sixteen hours at room temperature, the precipitate formed is filtered off and the filtrate is concentrated to dryness in vacuo. The residue is dissolved in ethyl acetate and washed neutral. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo to give N-(3-acetylthio-2-trifluoromethylpropanoyl)-L-proline tertbutyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[F:12].[NH2:13][C:14]1[N:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:26]([N:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:9](=[O:11])[CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:12])[CH:4]=3)=[N:19][CH:18]=2)[CH2:25][CH2:24]1)(=[O:28])[CH3:27]
Reactant: O=C(O)Cc1ccc(Cl)c(F)c1
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(Cl)c(F)c3)nc2)CC1
Temperature: 25 °C

Procedure:
To a mixture of 2-(4-chloro-3-fluorophenyl)acetic acid 168-1 (188 mg, 1.0 mmol), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 (220 mg, 1.0 mmol) and HATU (400 mg, 1.05 mmol) in DMF (4 mL) was added DIEA (521 uL, 3.0 mmol) and the mixture was stirred at room temperature over night. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over Na2SO4 and the solvent was evaporated. The residue was subject to silica gel flash chromatography to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-chloro-3-fluorophenyl)acetamide 168-2. MS m/z 391.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([NH:15][CH:16]2[CH:21]3[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]3)[CH2:17]2)=[O:14])[C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([NH+:15]([O-:32])[CH:16]2[CH:21]3[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]3)[CH2:17]2)=[O:14])[C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1COc2c(cc(Cl)cc2C(=O)NC2CN3CCC2CC3)N1
Solvent: ClC(Cl)Cl
Product: O=C1COc2c(cc(Cl)cc2C(=O)[NH+]([O-])C2CN3CCC2CC3)N1
Reaction time: 0.5 h

Procedure:
To a solution of 4.8 g of 6-chloro-3,4-dihydro-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide in 150 ml of chloroform is added portionwise 3.7 g of metachloroperbenzoic acid under cooling and stirring. After 0.5 hour, ammonia gas is bubbled through the reaction solution under stirring and the precipitate is filtered off. The mother liquor is distilled off under reduced pressure followed by recrystallizing the residue from ethanol-isopropyl ether to give 6-chloro-3,4-dihydro-3-oxo-N-(3-quinuclidinyl)-2H-1,4-benzoxazine-8-carboxamide N-oxide.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[CH2:6]([O:8][C:9]([C:11]1[C:12]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:13]([CH2:32][CH2:33][CH2:34][OH:35])[N:14]2[C:19]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[N:15]2)=[O:10])[CH3:7]>C(N(C(C)C)CC)(C)C.CC#N>[CH2:6]([O:8][C:9]([C:11]1[C:12]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:13]([CH2:32][CH2:33][CH2:34][O:35][C:4](=[O:5])[NH:3][CH2:1][CH3:2])[N:14]2[C:19]=1[C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][C:16]([N:26]1[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1)=[N:15]2)=[O:10])[CH3:7]
Reactant: CCN=C=O
Reactant: CCOC(=O)c1c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn2c1CCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCNC(=O)OCCCc1c(C(=O)OCC)c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn12
Temperature: 50 °C

Procedure:
Ethyl isocyanate (50 μL, 0.063 mmol) and diisopropylethyl amine (1 drop) were added to a solution of 41 (30 mg, 0.062 mmol) in CH3CN (10 mL). The reaction mixture was heated at 50° C. for 18 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 35% EtOAc/hexane) to provide the title compound as a white solid. 1H NMR (DMSO-d6) δ 0.89 (t, J=7.1 Hz, 3H), 0.99 (t, J=7.2 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H), 1.91 (m, 2H), 2.96 (m, 2H), 3.22 (m, 2H), 3.53 (m, 6H), 3.71 (m, 4H), 3.96 (m, 2H), 4.19 (q, J=7.1 Hz, 2H), 6.78 (s, 1H), 7.00 (m, 1H), 7.41 (m, 2H), 7.46 (m, 3H). Mass Spectrum (ESI+) m/e=553.2 (M+H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]4[CH:19]=3)=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1.[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[O:22].C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]4[C:19]=3[CH:21]([OH:22])[C:20]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C=O
Reactant: c1ccn2cc(-c3ccc4c(c3)CCCO4)nc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)c1c(-c2ccc3c(c2)CCCO3)nc2ccccn12
Temperature: 80 °C
Yield: 80 %

Procedure:
A mixture of 2-(3,4-dihydro-2H-1-benzopyran-6-yl)-imidazo[1,2-a]pyridine (19b) (50 mg, 0.2 mmol), ethyl glyoxylate 50% in toluene (0.20 mL, 1.0 mmol) and p-toluenesulfonic acid (6 mg, 0.03 mmol) in ethanol (1 mL) was heated at 80° C. for 1 hour. Ethyl glyoxylate 50% in toluene (0.10 mL, 0.5 mmol) was added and the heating was maintained for one supplementary hour. The mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (10 mL), washed with a saturated solution of sodium hydrogencarbonate (5 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 40/60) to provide the desired hydroxyl-ester (19c) (56 mg, 0.159 mmol, 80%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O[C:13]1[CH:18]=CC(C(C2C=CC(O)=CC=2)(C)C)=C[CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[OH:11][C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][CH:9]=1)[C:1]([CH3:4])([CH3:2])[CH2:3][C:13]2([CH3:18])[CH3:14]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1(C)CC(C)(C)c2cc(O)ccc21
Yield: 19.9 %

Procedure:
172.5 g of 4-tert.-butylphenol, 57.5 g of 2,2-bis-(4-hydroxyphenyl)-propane and 20 g of p-toluene sulphonic acid are stirred in an autoclave for 6 hours at around 180° C. After cooling, the reaction mixture is repeatedly washed with about 250 ml of 10 % by weight aqueous sodium hydrogen carbonate solution to remove the catalyst, and then subjected to fractional distillation in vacuo. 9.3 g (0.05 mol) of 5-hydroxy-1,1,3,3-tetramethyl indane are isolated from 157.7 g of reaction mixture.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]=3[CH:11]=2)=[O:9])[CH:5]=C[CH:7]=1.C(N(CCCC)CCCC)CCC.[C]=O.[C:39]([O:42][CH2:43]C)(=[O:41])[CH3:40]>CO.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:20][C:16]1([CH3:21])[CH2:15][CH2:14][C:13]([CH3:22])([CH3:23])[C:12]2[CH:11]=[C:10]([C:8]([C:4]3[CH:5]=[C:40]([CH:7]=[CH:2][CH:3]=3)[C:39]([O:42][CH3:43])=[O:41])=[O:9])[CH:19]=[CH:18][C:17]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)c3cccc(I)c3)ccc21
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CCCCN(CCCC)CCCC
Solvent: CO
Product: COC(=O)c1cccc(C(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)c1

Procedure:
A solution of 3-iodophenyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)methanone (10.5 g, 25.1 mmol), palladium diacetate (564 mg, 2.5 mmol) and tributylamine (12 ml, 50.5 mmol) in methanol (500 ml) is heated for 3 h at 100° C. under a pressure of carbon monoxide (3 bar). After concentration on an evaporator under vacuum at 40° C., the oil obtained is diluted in ethyl acetate and washed three times with water. The product is purified by flash chromatography on a column of silica.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][P:8]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:19](I)[CH3:20]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:16])[CH:7]([P:8]([O:10][CH2:11][CH3:12])([O:13][CH2:14][CH3:15])=[O:9])[CH2:19][CH3:20])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)C(CC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
Diethylphosphonoacetic acid tert-butyl ester (1.0 g, 4.0 mmol) was dissolved in N,N-dimethylformamide (1.4 and 60% sodium hydride (0.17 g, 4.4 mmol) was added at 0° C. After stirring at room temperature for 30 minutes, the reaction mixture was cooled again to 0° C., ethyl iodide (0.33 mL, 4.1 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with 0.5N hydrochloric acid, water and saturated brine, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=57/43) to give the title compound (0.92 g, 3.3 mmol, 83%).
Reaction SMILES: [NH:1]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[C:2]1[C:8]1[O:9][CH2:10][C:11](=[O:19])[C:12]=1[C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1>CC(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:10]2[O:9][C:8]([C:2]3[NH:1][CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:12]([C:13]([O:15][CH:16]([CH3:17])[CH3:18])=[O:14])[C:11]2=[O:19])=[CH:21]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CC(C)OC(=O)C1=C(C2=CC=CC=CN2)OCC1=O
Solvent: CC(C)O
Product: CC(C)OC(=O)C1=C(C2=CC=CC=CN2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 51.4 %

Procedure:
To a stirred solution of isopropyl 2-azepinyl-4-oxo-4,5-dihydrofuran-3-carboxylate (0.033 g, 0.12 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.019 g, 0.13 mmol) in 2-propanol (1.0 mL), hexamethyleneimine (0.0014 mL, 0.012 mmol) was added at ambient temperature. The mixture was refluxed for 12 days. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.024 g, y. 49%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10]([N:12]([CH2:16][C:17]1[CH:18]=[C:19]([CH2:24][CH2:25]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:20]=[CH:21][C:22]=1[Cl:23])[CH:13]1[CH2:15][CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>CN(C=O)C>[C:5]([O:9][C:10](=[O:11])[N:12]([CH2:16][C:17]1[CH:18]=[C:19]([CH2:24][CH2:25][N:1]=[N+:2]=[N-:3])[CH:20]=[CH:21][C:22]=1[Cl:23])[CH:13]1[CH2:15][CH2:14]1)([CH3:7])([CH3:6])[CH3:8]
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(Cl)c(CN(C(=O)OC(C)(C)C)C3CC3)c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1cc(CCN=[N+]=[N-])ccc1Cl)C1CC1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 94.4 %

Procedure:
NaN3 (1.17 g, 18.0 mmol) was added to a sol. of toluene-4-sulfonic acid 2-{3-[(tert-butoxycarbonyl-cyclopropyl-amino)-methyl]-4-chloro-phenyl}-ethyl ester (2.16 g, 4.50 mmol) in DMF (45 mL). The mixture was heated to 65° C., and stirred at this temperature for 1.5 h. The mixture was allowed to cool to rt, and poured onto water. The mixture was extracted with TBME (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (heptane/EtOAc 95:5) yielded the title compound (1.49 g, 94%). LC-MS: tR=1.11 min; ES+: 336.43.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][CH2:9][C@@H:10]([C:27]([OH:29])=[O:28])[NH:11][C:12](=[O:26])[C:13]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)([CH3:15])[CH3:14])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:34]I.O>CN(C)C=O>[CH3:34][O:28][C:27](=[O:29])[C@H:10]([CH2:9][S:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=1)[NH:11][C:12](=[O:26])[C:13]([S:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)([CH3:15])[CH3:14]
Reactant: CI
Reactant: COc1ccc(CSC[C@H](NC(=O)C(C)(C)SCc2ccc(OC)cc2)C(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CSCc1ccc(OC)cc1)NC(=O)C(C)(C)SCc1ccc(OC)cc1
Reaction time: 1 h
Yield: 90 %

Procedure:
To a stirred solution of S-p-methoxybenzyl-N-(2-p-methoxybenzylthio-2-methylpropionyl)-L-cysteine (3.0 g) in dimethylformamide(20 ml), sodium hydride(0.3 g) was added under nitrogen atomosphere at room temperature and the mixture was stirred for 1 hour. Methyl iodide(0.5 ml) was added to the mixture. The reaction mixture was stirred for 4 hours at room temperature. Water(300 ml) was added to the reaction mixture and extracted with ether. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 2.8 g(90%) of the titled compound.
Reaction SMILES: COC(=O)[C@@H]1CCCN1C(=O)CCCCCCCCCCC/C=C\CCCCCCCC.[C:33]([OH:56])(=O)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:46]\[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54].[NH2:57][C:58]1[CH:66]=[CH:65][C:64]([Cl:67])=[CH:63][C:59]=1[C:60]([OH:62])=[O:61].C(Cl)Cl>N1C=CC=CC=1>[C:33]([NH:57][C:58]1[CH:66]=[CH:65][C:64]([Cl:67])=[CH:63][C:59]=1[C:60]([OH:62])=[O:61])(=[O:56])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:46]\[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)O
Agent: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)N1CCC[C@H]1C(=O)OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)Nc1ccc(Cl)cc1C(=O)O

Procedure:
In a manner similar to (i), erucic acid (1.05 g) was converted to its acid chloride, to which was added 2-amino-5-chlorobenzoic acid (530 mg). The mixture was stirred in pyridine (5 ml)-methylene chloride (2 ml) at room temperature for three hours. The solvent was concentrated and the residue was washed with 0.5N HCl and methanol. Resulting precipitates were dried, followed by recrystallization from ethanol to afford pale yellow crystals [550 mg (36%)], m.p. 159 to 162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12]3=[N:16][N:17]=[C:18]([CH3:19])[N:11]3[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].I[CH2:35][CH3:36]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH:13]([CH2:35][CH3:36])[C:12]3=[N:16][N:17]=[C:18]([CH3:19])[N:11]3[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]2=3)=[CH:4][CH:3]=1
Reactant: CCI
Reactant: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(=O)C2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1C(=O)N(c2ccc(Cl)cc2)c2ccccc2-n2c(C)nnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.3 %

Procedure:
Into a 50 mL flask evacuated and brimmed with dry nitrogen, was charged with a solution of 6-(4-chlorophenyl)-1-methyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-one (Example 1, step 5; 100 mg, 0.31 mmol) in anhydrous tetrahydrofuran (10 mL). To this mixture, was added lithium bis(trimethylsilyl)amide (tetrahydrofuran solution) (0.17 mL, 0.33 mmol) at −78° C. The mixture was stirred at the same temperature for 1 hour, and then warmed to room temperature, maintained at the same temperature for 2 hours. Iodoethane (92.04 mg, 0.59 mmol) was added. The mixture was stirred at room temperature for another 2 hours. The reaction was quenched by ammonium chloride aqueous (5 mL), extracted with ethyl acetate (5 mL*3). The crude product was purified by column chromatography (silica gel, dichloromethane/methanol=25:1) to give 6-(4-chlorophenyl)-4-ethyl-1-methyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-5(6H)-one as a light yellow solid (20.0 mg, 18%). LRMS (M+H)+: calcd 352.11. found 352.
Reaction SMILES: O=C[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[CH:11]([O:16][CH3:17])([O:14][CH3:15])OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:17][O:16][CH:11]([O:14][CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(OC)OC
Reactant: COC(=O)CCCCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)CCCCC(OC)OC
Reaction time: 48 h
Yield: 88 %

Procedure:
56 g (0.4 Mole) of cyclohexanone enolacetate in 500 ml of methanol was ozonised in a dry ice-acetone bath until the solution turned blue. 60 ml of dimethyl sulphide was added, and the cooling bath was removed. The temperature rose slowly to 48°, and after it had returned to room temperature, 40 ml of trimethyl orthoformate and 1 ml of acetyl chloride were added. The mixture was then left for 48 h at room temperature. Three identical batches were combined and the solvant was removed in vacuo. The residue was dissolved in ether, washed with brine containing a small amount of NaHCO3, dried (Na2SO4), and distilled to give 193 g of product, b.p. 56°-69°/0.1 Torr. The NMR spectrum indicated the presence of ca. 20% of methyl 6-oxohexanoate. The product was mixed with 100 ml of trimethyl orthoformate, 20 ml of methanol, and 0.5 g of p-toluene sulfonic acid. The mixture was left for 48 h at room temperature, then worked up as above yielding 201 g (88%) of methyl 6,6-dimethoxyhexanoate. b.p. 61°/0.1 Torr.