2-phenylacetohydrazide

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

Procedure: The following representative compounds in Table 1 were synthesized according to (i) the foregoing procedures by selecting appropriate starting materials (for example, 4-fluoro mandelic acid derivatives (e.g., examples 12-1 and 12-3) were synthesized using commercially available 4-fluoromandelic acid) and (ii) known organic synthesis techniques (for example, treatment of commercially available α-phenylacetic acid methyl ester with hydrazine hydrate in ethanol under with heating provides phenyl-acetic acid hydrazide (see, e.g., Pandeye, S, N.; Manjula, H.; Stables, J. P.; Pharmazie; 2001, 56, 121-124) and treatment of phenyl acetic acid hydrazide with a substituted benzaldehyde in ethanol with heating and in the presence of catalytic acetic acid provides the corresponding substituted phenyl-acetic acid benzylidenehydrazide (see, e.g., Stephanidou-Stephanatou, J.; Lefkopoulou, S; Journal of Heterocyclic Chemistry; 1982; 19; 705-711.0)). The following representative compounds in Table 1 were synthesized were synthesized with heating

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

Procedure: 2-Phenylacetohydrazide (1.01 g) was added to a solution of anhydrous toluene (11 mL) and 8-methoxy-2,3,4,5,6,7-hexahydroazocine (0.96 mL). The mixture was warmed to 60° C. for 3 hours and heated to 110° C. overnight. The solution was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography to give 3-benzyl-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine as a white solid. heated to 110° C. overnight The solution was cooled to room temperature concentrated The residue was purified by silica gel chromatography

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

Procedure: To 4-chlorobutyryl chloride (1.12 ml, 10 mmol) in dry DCM (10 ml) was added, dropwise, over 40 min, a mixture of phenylacetic hydrazide (1.5 g, 10 mmol) and DIPEA (1.77 ml, 10.2 mmol) in dry DCM (40 ml) at room temperature. A dense white precipitate formed. After a further 20 min. 2M HCl (30 ml) was added and the title compound (white solid) was filtered off, washed with water and dried (2.24 g). A dense white precipitate formed After a further 20 min the title compound (white solid) was filtered off washed with water dried (2.24 g)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl-2-ethoxy-2-iminoacetate (1.318 g, 9.08 mmol) and phenyl acetic acid hydrazide (1.364 g, 9.08 mmol) were mixed together in ethanol (20 ml) and stirred at 80° C. for 1 h. Ethanol was evaporated. The residue was dissolved in n-butanol (20 ml). The reaction mixture was stirred at 150° C. for 20 h, then solvents were evaporated. Ethanol was evaporated The residue was dissolved in n-butanol (20 ml) The reaction mixture was stirred at 150° C. for 20 h solvents were evaporated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl-2-ethoxy-2-iminoacetate (1.318 g, 9.08 mmol) and phenyl acetic acid hydrazide (1.364 g, 9.08 mmol) were mixed together in ethanol (20 ml) and stirred at 80° C. for 1 h. Ethanol was evaporated. The residue was dissolved in n-butanol (20 ml). The reaction mixture was stirred at 150° C. for 20 h, then solvents were evaporated. Ethanol was evaporated The residue was dissolved in n-butanol (20 ml) The reaction mixture was stirred at 150° C. for 20 h solvents were evaporated

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

Procedure: Following the procedure as described in Preparation 13, making variations as required to replace benzohydrazide with 2-phenylacetohydrazide to react with 2-benzamidoisonicotinic acid, N-(4-(2-(2-phenylacetyl)hydrazinecarbonyl)pyridin-2-yl)benzamide was obtained in 65% yield: MS (ES+) m/z 374.9 (M+1). as described in Preparation 13

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

Procedure: The title compound was prepared in analogy to Preparation 11 in 0.18 g yield starting from phenylacetic hydrazide (0.5 g) and N,N′-dimethyl-5-hexenimidamide hydrochloride (0.62 g). MS (m/z): 242 [MH]+. yield

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

Procedure: The following representative compounds in Table 1 were synthesized according to (i) the foregoing procedures by selecting appropriate starting materials (for example, 4-fluoro mandelic acid derivatives (e.g., examples 12-1 and 12-3) were synthesized using commercially available 4-fluoromandelic acid) and (ii) known organic synthesis techniques (for example, treatment of commercially available α-phenylacetic acid methyl ester with hydrazine hydrate in ethanol under with heating provides phenyl-acetic acid hydrazide (see, e.g., Pandeye, S, N.; Manjula, H.; Stables, J. P.; Pharmazie; 2001, 56, 121-124) and treatment of phenyl acetic acid hydrazide with a substituted benzaldehyde in ethanol with heating and in the presence of catalytic acetic acid provides the corresponding substituted phenyl-acetic acid benzylidenehydrazide (see, e.g., Stephanidou-Stephanatou, J.; Lefkopoulou, S; Journal of Heterocyclic Chemistry; 1982; 19; 705-711.0)). The following representative compounds in Table 1 were synthesized were synthesized with heating

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

Procedure: The following representative compounds in Table 1 were synthesized according to (i) the foregoing procedures by selecting appropriate starting materials (for example, 4-fluoro mandelic acid derivatives (e.g., examples 12-1 and 12-3) were synthesized using commercially available 4-fluoromandelic acid) and (ii) known organic synthesis techniques (for example, treatment of commercially available α-phenylacetic acid methyl ester with hydrazine hydrate in ethanol under with heating provides phenyl-acetic acid hydrazide (see, e.g., Pandeye, S, N.; Manjula, H.; Stables, J. P.; Pharmazie; 2001, 56, 121-124) and treatment of phenyl acetic acid hydrazide with a substituted benzaldehyde in ethanol with heating and in the presence of catalytic acetic acid provides the corresponding substituted phenyl-acetic acid benzylidenehydrazide (see, e.g., Stephanidou-Stephanatou, J.; Lefkopoulou, S; Journal of Heterocyclic Chemistry; 1982; 19; 705-711.0)). The following representative compounds in Table 1 were synthesized were synthesized with heating

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

Procedure: 2-Phenylacetohydrazide (1.01 g) was added to a solution of anhydrous toluene (11 mL) and 8-methoxy-2,3,4,5,6,7-hexahydroazocine (0.96 mL). The mixture was warmed to 60° C. for 3 hours and heated to 110° C. overnight. The solution was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography to give 3-benzyl-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine as a white solid. heated to 110° C. overnight The solution was cooled to room temperature concentrated The residue was purified by silica gel chromatography

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

Procedure: 2-Phenylacetohydrazide (1.01 g) was added to a solution of anhydrous toluene (11 mL) and 8-methoxy-2,3,4,5,6,7-hexahydroazocine (0.96 mL). The mixture was warmed to 60° C. for 3 hours and heated to 110° C. overnight. The solution was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography to give 3-benzyl-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine as a white solid. heated to 110° C. overnight The solution was cooled to room temperature concentrated The residue was purified by silica gel chromatography

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 2-(2-(5-chloro-1H-indol-3-yl)ethylamino)-2-oxoacetic acid (0.350 mg; 1.31 mmol) in chloroform (20 mL) was added thionyl chloride (0.955 mL; 13.12 mmol) and the mixture was stirred at 80° C. for 3 h and was then evaporated to dryness. The resulting 2-(2-(5-chloro-1H-indol-3-yl)ethylamino)-2-oxoacetyl chloride (0.180 g, 0.631 mmol) was dissolved in dichloromethane (12 mL) and a mixture of triethylamine (0.355 mL; 2.53 mmol) and 2-phenylacetic acid hydrazide (0.092 g; 0.600 mmol) in dichloromethane (2 mL) was added at 0° C. The mixture was stirred at room temperature for 3 days and p-toluenesulfonyl chloride (0.122 g, 0.631 mmol) was added. The resulting mixture was stirred 18 h at room temperature, diluted with dichloromethane, washed with an aqueous solution of sodium carbonate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluent 12 to 100% ethyl acetate in heptane) to give 0.006 g (2.5%) of 5-benzyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1,3,4-oxadiazole-2-carboxamide as a white solid. was then evaporated to dryness was added at 0° C The mixture was stirred at room temperature for 3 days The resulting mixture was stirred 18 h at room temperature washed with an aqueous solution of sodium carbonate concentrated under reduced pressure The residue was purified by flash column chromatography on silica gel (eluent 12 to 100% ethyl acetate in heptane)