2-oxocyclohexane-1-carbonitrile

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluoro-aniline (1.11 g, 10.0 mmol), cyano-ketone (Example 32) (1.25 g, 10.2 mmol), calcium chloride (1.5 g, 13.5 mmol) and T.H.F. (20 ml) were heated under reflux for 17 hours. After cooling, the mixture was filtered and the solvent evaporated. Kugelrohr distillation (135° C., 0.08 mmHg) gave the product as a pale yellow powder. (20 ml) were heated under reflux for 17 hours After cooling the mixture was filtered the solvent evaporated Kugelrohr distillation (135° C., 0.08 mmHg)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (2-methylphenyl)hydrazine hydrochloride (464 mg, 2.92 mmol) in ethanol (2 mL) was added 2-oxocyclohexanecarbonitrile (300 mg, 2.44 mmol), and the mixture was heated to 60° C. and stirred for 16 h. The flask was then cooled to rt and the solvent was evaporated to give a solid. The crude residue of 2-(2-methylphenyl)-4,5,6,7-tetrahydro-2H-indazol-3-amine hydrochloride (449 mg, 70%) was used in the next step with no further purification. ES-MS m/z 228.2 (MH+); HPLC RT (min) 1.22. The flask was then cooled to rt the solvent was evaporated to give a solid The crude residue of 2-(2-methylphenyl)-4,5,6,7-tetrahydro-2H-indazol-3-amine hydrochloride (449 mg, 70%) was used in the next step with no further purification

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (2-methylphenyl)hydrazine hydrochloride (464 mg, 2.92 mmol) in ethanol (2 mL) was added 2-oxocyclohexanecarbonitrile (300 mg, 2.44 mmol), and the mixture was heated to 60° C. and stirred for 16 h. The flask was then cooled to rt and the solvent was evaporated to give a solid. The crude residue of 2-(2-methylphenyl)-4,5,6,7-tetrahydro-2H-indazol-3-amine hydrochloride (449 mg, 70%) was used in the next step with no further purification. ES-MS m/z 228.2 (MH+); HPLC RT (min) 1.22. The flask was then cooled to rt the solvent was evaporated to give a solid The crude residue of 2-(2-methylphenyl)-4,5,6,7-tetrahydro-2H-indazol-3-amine hydrochloride (449 mg, 70%) was used in the next step with no further purification

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-oxocyclohexanecarbonitrile (615 mg, 5.0 mmol) and urea (600 mg, 10.0 mmol) in 1.25 N HCl in EtOH (20 mL) was refluxed over night. After it was cooled down to 0° C., the precipitation was collected by filtration, washed with EtOH/H2O, and dried under vacuum overnight to give the product as a white solid. 1H NMR (400 MHz, CD3OD) δ 1.67-1.80 (m, 4H), 2.25-2.29 (m, 2H), 2.38-2.42 (m, 2H). MS 167 (MH+). the precipitation was collected by filtration washed with EtOH/H2O dried under vacuum overnight

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-oxocyclohexanecarbonitrile (615 mg, 5.0 mmol) and urea (600 mg, 10.0 mmol) in 1.25 N HCl in EtOH (20 mL) was refluxed over night. After it was cooled down to 0° C., the precipitation was collected by filtration, washed with EtOH/H2O, and dried under vacuum overnight to give the product as a white solid. 1H NMR (400 MHz, CD3OD) δ 1.67-1.80 (m, 4H), 2.25-2.29 (m, 2H), 2.38-2.42 (m, 2H). MS 167 (MH+). the precipitation was collected by filtration washed with EtOH/H2O dried under vacuum overnight

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Fluoro-aniline (1.11 g, 10.0 mmol), cyano-ketone (Example 32) (1.25 g, 10.2 mmol), calcium chloride (1.5 g, 13.5 mmol) and T.H.F. (20 ml) were heated under reflux for 17 hours. After cooling, the mixture was filtered and the solvent evaporated. Kugelrohr distillation (135° C., 0.08 mmHg) gave the product as a pale yellow powder. (20 ml) were heated under reflux for 17 hours After cooling the mixture was filtered the solvent evaporated Kugelrohr distillation (135° C., 0.08 mmHg)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of resin bound PPh3 (Polymer Laboratories, 1.48 mmol/g, 150-300 μM; 3.8 g, 5.7 mmol) in THF (35 mL) at 0° C. was treated with diethyl azodicarboxylate (40% wt. in hexane; 2.60 mL, 5.7 mmol), ethyl glycolate (0.54 mL, 5.7 mmol) and a solution of 2-oxo-cyclohexanecarbonitrile (0.5 g, 4.1 mmol) in THF (10 mL). The reaction mixture warmed to rt over 12 h. Filtration and concentration afforded the uncyclized intermediate, which was dissolved in THF (25 mL) and added drop-wise to a slurry of sodium hydride (95%; 0.29 g, 11.4 mmol) in THF (10 mL) at 0° C. The reaction mixture was heated to 40° C. for 12 h. The reaction was quenched with satd. aq. NH4Cl (5 mL) and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were dried (by using, for example, Na2SO4) and concentrated. Purification by FCC (50% EtOAc/hexanes) afforded the desired product as a pale yellow solid (0.36 g). MS: 210.2. 1H NMR (400 MHz, CD3OD) δ ppm 4.26 (q, J=7.1, Hz, 2H), 2.55-2.47 (m, 2H), 2.35-2.28 (m, 2H), 1.90-1.79 (m, 2H), 1.79-1.71 (m, 2H), 1.33 (t, J=7.1, Hz, 3H). at 0° C. Filtration and concentration afforded the uncyclized intermediate, which The reaction mixture was heated to 40° C. for 12 h The reaction was quenched with satd aq. NH4Cl (5 mL) and the mixture was extracted with EtOAc (3×50 mL) The combined organic layers were dried (by using, for example, Na2SO4) concentrated Purification by FCC (50% EtOAc/hexanes)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-oxocyclohexanecarbonitrile (615 mg, 5.0 mmol) and urea (600 mg, 10.0 mmol) in 1.25 N HCl in EtOH (20 mL) was refluxed over night. After it was cooled down to 0° C., the precipitation was collected by filtration, washed with EtOH/H2O, and dried under vacuum overnight to give the product as a white solid. 1H NMR (400 MHz, CD3OD) δ1.67-1.80 (m, 4H), 2.25-2.29 (m, 2H), 2.38-2.42 (m, 2H). MS 167 (MH+). the precipitation was collected by filtration washed with EtOH/H2O dried under vacuum overnight

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of resin bound PPh3 (Polymer Laboratories, 1.48 mmol/g, 150-300 μM; 3.8 g, 5.7 mmol) in THF (35 mL) at 0° C. was treated with diethyl azodicarboxylate (40% wt. in hexane; 2.60 mL, 5.7 mmol), ethyl glycolate (0.54 mL, 5.7 mmol) and a solution of 2-oxo-cyclohexanecarbonitrile (0.5 g, 4.1 mmol) in THF (10 mL). The reaction mixture warmed to rt over 12 h. Filtration and concentration afforded the uncyclized intermediate, which was dissolved in THF (25 mL) and added drop-wise to a slurry of sodium hydride (95%; 0.29 g, 11.4 mmol) in THF (10 mL) at 0° C. The reaction mixture was heated to 40° C. for 12 h. The reaction was quenched with satd. aq. NH4Cl (5 mL) and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were dried (by using, for example, Na2SO4) and concentrated. Purification by FCC (50% EtOAc/hexanes) afforded the desired product as a pale yellow solid (0.36 g). MS: 210.2. 1H NMR (400 MHz, CD3OD) δ ppm 4.26 (q, J=7.1, Hz, 2H), 2.55-2.47 (m, 2H), 2.35-2.28 (m, 2H), 1.90-1.79 (m, 2H), 1.79-1.71 (m, 2H), 1.33 (t, J=7.1, Hz, 3H). at 0° C. Filtration and concentration afforded the uncyclized intermediate, which The reaction mixture was heated to 40° C. for 12 h The reaction was quenched with satd aq. NH4Cl (5 mL) and the mixture was extracted with EtOAc (3×50 mL) The combined organic layers were dried (by using, for example, Na2SO4) concentrated Purification by FCC (50% EtOAc/hexanes)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-oxocyclohexanecarbonitrile (615 mg, 5.0 mmol) and urea (600 mg, 10.0 mmol) in 1.25 N HCl in EtOH (20 mL) was refluxed over night. After it was cooled down to 0° C., the precipitation was collected by filtration, washed with EtOH/H2O, and dried under vacuum overnight to give the product as a white solid. 1H NMR (400 MHz, CD3OD) δ1.67-1.80 (m, 4H), 2.25-2.29 (m, 2H), 2.38-2.42 (m, 2H). MS 167 (MH+). the precipitation was collected by filtration washed with EtOH/H2O dried under vacuum overnight

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3.6 parts of 4-chlorophenylhydrazine and 2.0 parts of triethylamine in 20.0 parts of toluene was stirred at room temperature for fifteen minutes. To the mixture was added 2.5 parts of 2-cyanocyclohexanone, prepared from commercial 2-chlorocyclohexanone and potassium cyanide [von R. E. Meyer, Helv. Chim. Acta., 16, 1291 (1933)], and a few drops of acetic acid. After refluxing for 2 hours, followed by stirring at room temperature overnight, the reaction mixture was evaporated to remove toluene and was treated with water, extracted with diethyl ether, dried over anhydrous magnesium sulfate and concentrated. Recrystallization from ethanol/water gave 2.6 parts of the compound, m.p. 140°-142°. After refluxing for 2 hours by stirring at room temperature overnight the reaction mixture was evaporated to remove toluene was treated with water extracted with diethyl ether dried over anhydrous magnesium sulfate concentrated Recrystallization from ethanol/water gave 2.6 parts of the compound, m.p. 140°-142°

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3.6 parts of 4-chlorophenylhydrazine and 2.0 parts of triethylamine in 20.0 parts of toluene was stirred at room temperature for fifteen minutes. To the mixture was added 2.5 parts of 2-cyanocyclohexanone, prepared from commercial 2-chlorocyclohexanone and potassium cyanide [von R. E. Meyer, Helv. Chim. Acta., 16, 1291 (1933)], and a few drops of acetic acid. After refluxing for 2 hours, followed by stirring at room temperature overnight, the reaction mixture was evaporated to remove toluene and was treated with water, extracted with diethyl ether, dried over anhydrous magnesium sulfate and concentrated. Recrystallization from ethanol/water gave 2.6 parts of the compound, m.p. 140°-142°. After refluxing for 2 hours by stirring at room temperature overnight the reaction mixture was evaporated to remove toluene was treated with water extracted with diethyl ether dried over anhydrous magnesium sulfate concentrated Recrystallization from ethanol/water gave 2.6 parts of the compound, m.p. 140°-142°