8-methoxy-2,3,4,5,6,7-hexahydroazocine

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:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Anhydrous toluene was added to a mixture of 1-(4-chlorophenyl)cyclohexanecarbohydrazide (62 mg) and 8-methoxy-2,3,4,5,6,7-hexahydroazocine (40.1 mg). The reaction vessel was heated to 120° C. overnight, whereupon it was cooled to room temperature and the solvent was evaporated. The crude product was purified by column chromatography to give 3-(1-phenylcyclohexyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (2-51) as a white solid. was cooled to room temperature the solvent was evaporated The crude product was purified by column chromatography

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

Procedure: 2,2,2-Triphenylacetohydrazide (48.2 mg, 0.159 mmol) was dissolved in anhydrous toluene (3 mL) and stirred at room temperature under nitrogen. 8-Methoxy-2,3,4,5,6,7-hexahydroazocine (24.7 mg, 0.175 mmole) was added and the solution was stirred at 120° C. overnight and 200° C. for two days. After cooling, the toluene was removed by evaporation and crude product was purified by silica gel chromatography (100% ethyl acetate→5% methanol in ethyl acetate→10% methanol in ethyl acetate) to give the product (2-1) as a white solid (12.4 mg). the solution was stirred at 120° C. overnight and 200° C. for two days After cooling the toluene was removed by evaporation and crude product was purified by silica gel chromatography (100% ethyl acetate→5% methanol in ethyl acetate→10% methanol in ethyl acetate)

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 0.700 mL of the 0.3 M solution of 4-pentylbicyclo[2.2.2]octane-1-carbohydrazide in DMF (crude, prepared as in step A above) was added 8-methoxy-2,3,4,5,6,7-hexahydroazocine (29.6 mg, 1 eq) and the reaction was heated to 130° C. overnight. After this time the solvent was removed under reduced pressure and the residue was chromatographed on C-18 reverse phase (gradient 90% water to 100% acetonitrile, 0.1% TFA). The fractions containing the compound were determined by LCMS, added to 200 mL of methylene chloride, and extracted with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate and evaporated under diminished pressure. The residue was lyophilized from benzene to afford 3-(4-pentylbicyclo[2.2.2]oct-1-yl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (1-C); MS (ESI+)=300.3 (M+1) After this time the solvent was removed under reduced pressure the residue was chromatographed on C-18 reverse phase (gradient 90% water to 100% acetonitrile, 0.1% TFA) The fractions containing the compound added to 200 mL of methylene chloride extracted with saturated sodium bicarbonate The organic layer was dried over magnesium sulfate evaporated under diminished pressure

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

Procedure: 3-(Methoxymethoxy)-1-(2-thienyl)cyclobutanecarbohydrazide (5.45 g) and 8-methoxy-2,3,4,5,6,7-hexahydroazocine (4.51 g) were heated in toluene (60 ml) at 110° C. for 19 hours. After concentration, the concentrate was purified by silica gel column chromatography (methanol:chloroform=2:98) to obtain 3-[3-(methoxymethoxy)-1-(2-thienyl)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (6.14 g). After concentration the concentrate was purified by silica gel column chromatography (methanol:chloroform=2:98)

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

Procedure: 3-(Methoxymethoxy)-1-(2-thienyl)cyclobutanecarbohydrazide (5.45 g) and 8-methoxy-2,3,4,5,6,7-hexahydroazocine (4.51 g) were heated in toluene (60 ml) at 110° C. for 19 hours. After concentration, the concentrate was purified by silica gel column chromatography (methanol:chloroform=2:98) to obtain 3-[3-(methoxymethoxy)-1-(2-thienyl)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (6.14 g). After concentration the concentrate was purified by silica gel column chromatography (methanol:chloroform=2:98)

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

Procedure: 1-(1-Benzylpiperidin-4-yl)cyclopentane-1-carbohydrazide (1.04 g) and 8-methoxy-2,3,4,5,6,7-hexahydroazocine (1.46 g) were reacted in toluene (10 ml) under heating to obtain 3-[1-(1-benzyl-4-piperidinyl)cyclopentyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (0.686 g). The resulting compound was reacted in ethanol under a hydrogen atmosphere using 10% palladium-active carbon (0.14 g) as a catalyst and, after filtration through celite, the resulting solution was concentrated to obtain 3-(1-piperidin-4-ylcyclopentyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (0.610 g). under heating

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

Procedure: 1-(1-Benzylpiperidin-4-yl)cyclopentane-1-carbohydrazide (573 mg) and 8-methoxy-2,3,4,5,6,7-hexahydroazocine (671 mg) were stirred in toluene (10 ml) at 110° C. for 21 hours. The reaction solution was subjected to evaporation under reduced pressure and the resulting crude product was purified by column chromatography (chloroform:methanol=97:3). The resulting solid washed with hexane to obtain 255 mg of 3-[1-(1-benzyl-4-piperidinyl)cyclopentyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (white solid). The reaction solution was subjected to evaporation under reduced pressure the resulting crude product was purified by column chromatography (chloroform:methanol=97:3) The resulting solid washed with hexane

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:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Anhydrous toluene was added to a mixture of 1-(4-chlorophenyl)cyclohexanecarbohydrazide (62 mg) and 8-methoxy-2,3,4,5,6,7-hexahydroazocine (40.1 mg). The reaction vessel was heated to 120° C. overnight, whereupon it was cooled to room temperature and the solvent was evaporated. The crude product was purified by column chromatography to give 3-(1-phenylcyclohexyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (2-51) as a white solid. was cooled to room temperature the solvent was evaporated The crude product was purified by column chromatography

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Anhydrous toluene was added to a mixture of 1-(4-chlorophenyl)cyclohexanecarbohydrazide (62 mg) and 8-methoxy-2,3,4,5,6,7-hexahydroazocine (40.1 mg). The reaction vessel was heated to 120° C. overnight, whereupon it was cooled to room temperature and the solvent was evaporated. The crude product was purified by column chromatography to give 3-(1-phenylcyclohexyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (2-51) as a white solid. was cooled to room temperature the solvent was evaporated The crude product was purified by column chromatography