cyclobutanecarbohydrazide

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

Procedure: A mixture of 6.06 gm (0.05 mole) of 4-acetylpyridine, 5.7 gm (0.05 mole) of cyclobutanecarboxylic acid hydrazide, and 100 ml of absolute ethanol is refluxed 5 hours. The reaction mixture is evaporated in vacuo to give a solid. The product is crystallized from ethanol/ethylacetate/diethylether to give 2.92 gm (27%) of the title compound; mp 138.6°. is refluxed 5 hours The reaction mixture is evaporated in vacuo to give a solid The product is crystallized from ethanol/ethylacetate/diethylether

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

Procedure: A mixture of 6.06 gm (0.05 mole) of 4-acetylpyridine, 5.7 gm (0.05 mole) of cyclobutanecarboxylic acid hydrazide, and 100 ml of absolute ethanol is refluxed 5 hours. The reaction mixture is evaporated in vacuo to give a solid. The product is crystallized from ethanol/ethylacetate/diethylether to give 2.92 gm (27%) of the title compound; mp 138.6°. is refluxed 5 hours The reaction mixture is evaporated in vacuo to give a solid The product is crystallized from ethanol/ethylacetate/diethylether

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

Procedure: To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added cyclobutanecarbohydrazide 199 (0.155 g, 1.358 mmol), 1-hydroxybenzotriazole (0.186 g, 1.358 mmol) and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue, which was subjected to chromatography to give 200 (0.34 g, quant. yield) as a white foam. concentrated to provide a residue, which

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

Procedure: The title compound was prepared analogous to Example 4, Step 2, starting from methyl 2-(4-(4′-aminobiphenyl-4-yl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (500 mg, 1.48 mmol) with 1,1′-thiocarbonyldipyridin-2(1H)-one (379 mg, 1.63 mmol) and cyclobutanecarbohydrazide (254 mg, 2.22 mmol). Water titration of the crude residue affords the title compound as off-white solid after drying (696 mg, 93% yield). LC/MS, ESI-MS(+): 508.4, RT: 1.29 (Condition E). The title compound was prepared analogous to Example 4, Step 2

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a reaction vial containing methyl 2-(4-(4-(2-aminopyrimidin-5-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (40 mg, 0.11 mmol) was added dichloromethane (1 ml) at room temperature. 1,1′-thiocarbonyldipyridin-2(1H)-one (29 mg, 0.12 mmol) was added and the resulting mixture was heated to 50° C. for overnight. The mixture was cool down to room temperature and cyclobutanecarbohydrazide (19 mg, 0.17 mmol) was then added and stirred at room temperature for another hour. The content was then concentrated to dryness and the resulting residue was taken up in MeOH to form a nice slurry. The slurry was filtered and washed with small amount of MeOH to afford the title compound as off-white solid after drying (48 mg, 83% yield). LC/MS, ESI-MS(+): 510.4, RT: 1.26 (Condition E) The mixture was cool down to room temperature The content was then concentrated to dryness to form a nice slurry The slurry was filtered washed with small amount of MeOH

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a reaction vial containing methyl 2-(4-(4-(2-aminopyrimidin-5-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (40 mg, 0.11 mmol) was added dichloromethane (1 ml) at room temperature. 1,1′-thiocarbonyldipyridin-2(1H)-one (29 mg, 0.12 mmol) was added and the resulting mixture was heated to 50° C. for overnight. The mixture was cool down to room temperature and cyclobutanecarbohydrazide (19 mg, 0.17 mmol) was then added and stirred at room temperature for another hour. The content was then concentrated to dryness and the resulting residue was taken up in MeOH to form a nice slurry. The slurry was filtered and washed with small amount of MeOH to afford the title compound as off-white solid after drying (48 mg, 83% yield). LC/MS, ESI-MS(+): 510.4, RT: 1.26 (Condition E) The mixture was cool down to room temperature The content was then concentrated to dryness to form a nice slurry The slurry was filtered washed with small amount of MeOH

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

Procedure: To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0250 g, 0.905 mmol) in DCM (15.0 mL) were added cyclobutanecarbohydrazide 199 (0.155 g, 1.358 mmol), 1-hydroxybenzotriazole (0.186 g, 1.358 mmol) and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue, which was subjected to chromatography to give 200 (0.34 g, quant. yield) as a white foam. concentrated to provide a residue, which

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

Procedure: A mixture of 6.06 gm (0.05 mole) of 4-acetylpyridine, 5.7 gm (0.05 mole) of cyclobutanecarboxylic acid hydrazide, and 100 ml of absolute ethanol is refluxed 5 hours. The reaction mixture is evaporated in vacuo to give a solid. The product is crystallized from ethanol/ethylacetate/diethylether to give 2.92 gm (27%) of the title compound; mp 138.6°. is refluxed 5 hours The reaction mixture is evaporated in vacuo to give a solid The product is crystallized from ethanol/ethylacetate/diethylether

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

Procedure: A mixture of 6.06 gm (0.05 mole) of 4-acetylpyridine, 5.7 gm (0.05 mole) of cyclobutanecarboxylic acid hydrazide, and 100 ml of absolute ethanol is refluxed 5 hours. The reaction mixture is evaporated in vacuo to give a solid. The product is crystallized from ethanol/ethylacetate/diethylether to give 2.92 gm (27%) of the title compound; mp 138.6°. is refluxed 5 hours The reaction mixture is evaporated in vacuo to give a solid The product is crystallized from ethanol/ethylacetate/diethylether

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

Procedure: To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added cyclobutanecarbohydrazide 199 (0.155 g, 1.358 mmol), 1-hydroxybenzotriazole (0.186 g, 1.358 mmol) and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue, which was subjected to chromatography to give 200 (0.34 g, quant. yield) as a white foam. concentrated to provide a residue, which

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

Procedure: The title compound was prepared analogous to Example 4, Step 2, starting from methyl 2-(4-(4′-aminobiphenyl-4-yl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (500 mg, 1.48 mmol) with 1,1′-thiocarbonyldipyridin-2(1H)-one (379 mg, 1.63 mmol) and cyclobutanecarbohydrazide (254 mg, 2.22 mmol). Water titration of the crude residue affords the title compound as off-white solid after drying (696 mg, 93% yield). LC/MS, ESI-MS(+): 508.4, RT: 1.29 (Condition E). The title compound was prepared analogous to Example 4, Step 2

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a reaction vial containing methyl 2-(4-(4-(2-aminopyrimidin-5-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (40 mg, 0.11 mmol) was added dichloromethane (1 ml) at room temperature. 1,1′-thiocarbonyldipyridin-2(1H)-one (29 mg, 0.12 mmol) was added and the resulting mixture was heated to 50° C. for overnight. The mixture was cool down to room temperature and cyclobutanecarbohydrazide (19 mg, 0.17 mmol) was then added and stirred at room temperature for another hour. The content was then concentrated to dryness and the resulting residue was taken up in MeOH to form a nice slurry. The slurry was filtered and washed with small amount of MeOH to afford the title compound as off-white solid after drying (48 mg, 83% yield). LC/MS, ESI-MS(+): 510.4, RT: 1.26 (Condition E) The mixture was cool down to room temperature The content was then concentrated to dryness to form a nice slurry The slurry was filtered washed with small amount of MeOH