8-azabicyclo[3.2.1]octan-3-one;hydrochloride

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

Procedure: A slurry of 8-azabicyclo[3.2.1]octan-3-one hydrochloride salt (0.52 g, 3.2 mmol) and methyl 4-(bromomethyl)benzoate (0.75 g, 3.3 mmol) in 30 mL of acetonitrile was stirred as solid potassium carbonate (1.9 g, 13.6 mmol) was added. After 4 days, the reaction was filtered. The filtrate was concentrated. Purification by chromatography on silica gel using hexane gave 0.66 g of methyl 4-[(3-oxo-8-azabicyclo[3.2.1]oct-8-yl)methyl]-benzoate. was added the reaction was filtered The filtrate was concentrated Purification by chromatography on silica gel

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

Procedure: A slurry of 8-azabicyclo[3.2.1]octan-3-one hydrochloride salt (0.52 g, 3.2 mmol) and methyl 4-(bromomethyl)benzoate (0.75 g, 3.3 mmol) in 30 mL of acetonitrile was stirred as solid potassium carbonate (1.9 g, 13.6 mmol) was added. After 4 days, the reaction was filtered. The filtrate was concentrated. Purification by chromatography on silica gel using hexane gave 0.66 g of methyl 4-[(3-oxo-8-azabicyclo[3.2.1]oct-8-yl)methyl]-benzoate. was added the reaction was filtered The filtrate was concentrated Purification by chromatography on silica gel

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-chloro-2-cyclopropyl-5-phenyl-thieno[2,3-d]pyrimidine (0.30 g, 1.05 mmol, ex Enamine), nortropinone hydrochloride (0.25 g, 1.57 mmol) and triethylamine (0.44 mL, 3.14 mmol) in ethanol (4 mL) was heated to 140° C. for 30 min in a microwave. Heating was repeated. Further portions of triethylamine (0.44 mL, 3.14 mmol) and nortropinone hydrochloride (0.25 g, 1.57 mmol) were added and the mixture was stirred at room temperature for 3 nights. It was diluted with ethyl acetate (20 mL) and water (20 mL). The layers were separated and the aqueous was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (1×20 mL), dried (magnesium sulfate, filtered and evaporated to give a brown oil (512 mg). This was purified by silica chromatography (10 g cartridge; eluent petroleum ether 40-60/ethyl acetate 0 to 100%; all output collected) to give 8-(2-cyclopropyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-oneas a yellow solid (0.15 g). m/z [M+H]+ 376.0. Retention time 4.98 min (LCMS method+ve 6 min). Heating The layers were separated the aqueous was extracted with ethyl acetate (2×20 mL) The combined organic layers were washed with brine (1×20 mL) dried (magnesium sulfate filtered evaporated

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-chloro-2-cyclopropyl-5-phenyl-thieno[2,3-d]pyrimidine (0.30 g, 1.05 mmol, ex Enamine), nortropinone hydrochloride (0.25 g, 1.57 mmol) and triethylamine (0.44 mL, 3.14 mmol) in ethanol (4 mL) was heated to 140° C. for 30 min in a microwave. Heating was repeated. Further portions of triethylamine (0.44 mL, 3.14 mmol) and nortropinone hydrochloride (0.25 g, 1.57 mmol) were added and the mixture was stirred at room temperature for 3 nights. It was diluted with ethyl acetate (20 mL) and water (20 mL). The layers were separated and the aqueous was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (1×20 mL), dried (magnesium sulfate, filtered and evaporated to give a brown oil (512 mg). This was purified by silica chromatography (10 g cartridge; eluent petroleum ether 40-60/ethyl acetate 0 to 100%; all output collected) to give 8-(2-cyclopropyl-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-oneas a yellow solid (0.15 g). m/z [M+H]+ 376.0. Retention time 4.98 min (LCMS method+ve 6 min). Heating The layers were separated the aqueous was extracted with ethyl acetate (2×20 mL) The combined organic layers were washed with brine (1×20 mL) dried (magnesium sulfate filtered evaporated

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-chloro-5-phenyl-thieno[2,3-d]pyrimidine (1.00 g, 4.05 mmol), nortropinone hydrochloride (0.983 g, 6.08 mmol) and triethylamine (1.71 mL, 12.2 mmol) in THF (20 mL) was heated to 70° C. overnight. Ethanol (20 mL) was added and the mixture was heated to 70° C. for 3 hr. Further batches of nortropinone hydrochloride (0.983 g, 6.08 mmol) and triethylamine (1.71 mL, 12.2 mmol) were added and the mixture was heated to 70° C. overnight. Further batches of nortropinone hydrochloride (0.983 g, 6.08 mmol) and triethylamine (1.71 mL, 12.2 mmol) were added and the mixture was heated to 70° C. over 3 nights. It was cooled to room temperature and diluted with dichloromethane (40 mL) and water (40 mL). The layers were separated and the aqueous was extracted with dichloromethane (2×40 mL). The combined organic layers were washed with brine (1×40 mL), filtered through a hydrophobic frit and evaporated to give a brown oil. Mass: 3.21 g. This was purified by silica chromatography (100 g cartridge; eluent petrol/ethyl acetate 0 to 40%). Fractions corresponding to the main peak were combined and evaporated to give 8-(5-phenylthieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-one as a white solid (0.99 g). the mixture was heated to 70° C. for 3 hr the mixture was heated to 70° C. overnight the mixture was heated to 70° C. over 3 nights It was cooled to room temperature The layers were separated the aqueous was extracted with dichloromethane (2×40 mL) The combined organic layers were washed with brine (1×40 mL) filtered through a hydrophobic frit evaporated to give a brown oil This was purified by silica chromatography (100 g cartridge; eluent petrol/ethyl acetate 0 to 40%) evaporated

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-chloro-5-phenyl-thieno[2,3-d]pyrimidine (1.00 g, 4.05 mmol), nortropinone hydrochloride (0.983 g, 6.08 mmol) and triethylamine (1.71 mL, 12.2 mmol) in THF (20 mL) was heated to 70° C. overnight. Ethanol (20 mL) was added and the mixture was heated to 70° C. for 3 hr. Further batches of nortropinone hydrochloride (0.983 g, 6.08 mmol) and triethylamine (1.71 mL, 12.2 mmol) were added and the mixture was heated to 70° C. overnight. Further batches of nortropinone hydrochloride (0.983 g, 6.08 mmol) and triethylamine (1.71 mL, 12.2 mmol) were added and the mixture was heated to 70° C. over 3 nights. It was cooled to room temperature and diluted with dichloromethane (40 mL) and water (40 mL). The layers were separated and the aqueous was extracted with dichloromethane (2×40 mL). The combined organic layers were washed with brine (1×40 mL), filtered through a hydrophobic frit and evaporated to give a brown oil. Mass: 3.21 g. This was purified by silica chromatography (100 g cartridge; eluent petrol/ethyl acetate 0 to 40%). Fractions corresponding to the main peak were combined and evaporated to give 8-(5-phenylthieno[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-one as a white solid (0.99 g). the mixture was heated to 70° C. for 3 hr the mixture was heated to 70° C. overnight the mixture was heated to 70° C. over 3 nights It was cooled to room temperature The layers were separated the aqueous was extracted with dichloromethane (2×40 mL) The combined organic layers were washed with brine (1×40 mL) filtered through a hydrophobic frit evaporated to give a brown oil This was purified by silica chromatography (100 g cartridge; eluent petrol/ethyl acetate 0 to 40%) evaporated

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

Procedure: A slurry of 8-azabicyclo[3.2.1]octan-3-one hydrochloride salt (0.52 g, 3.2 mmol) and methyl 4-(bromomethyl)benzoate (0.75 g, 3.3 mmol) in 30 mL of acetonitrile was stirred as solid potassium carbonate (1.9 g, 13.6 mmol) was added. After 4 days, the reaction was filtered. The filtrate was concentrated. Purification by chromatography on silica gel using hexane gave 0.66 g of methyl 4-[(3-oxo-8-azabicyclo[3.2.1]oct-8-yl)methyl]-benzoate. was added the reaction was filtered The filtrate was concentrated Purification by chromatography on silica gel

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

Procedure: A slurry of 8-azabicyclo[3.2.1]octan-3-one hydrochloride salt (0.52 g, 3.2 mmol) and methyl 4-(bromomethyl)benzoate (0.75 g, 3.3 mmol) in 30 mL of acetonitrile was stirred as solid potassium carbonate (1.9 g, 13.6 mmol) was added. After 4 days, the reaction was filtered. The filtrate was concentrated. Purification by chromatography on silica gel using hexane gave 0.66 g of methyl 4-[(3-oxo-8-azabicyclo[3.2.1]oct-8-yl)methyl]-benzoate. was added the reaction was filtered The filtrate was concentrated Purification by chromatography on silica gel

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

Procedure: A slurry of 8-azabicyclo[3.2.1]octan-3-one hydrochloride salt (0.52 g, 3.2 mmol) and methyl 4-(bromomethyl)benzoate (0.75 g, 3.3 mmol) in 30 mL of acetonitrile was stirred as solid potassium carbonate (1.9 g, 13.6 mmol) was added. After 4 days, the reaction was filtered. The filtrate was concentrated. Purification by chromatography on silica gel using hexane gave 0.66 g of methyl 4-[(3-oxo-8-azabicyclo[3.2.1]oct-8-yl)methyl]-benzoate. was added the reaction was filtered The filtrate was concentrated Purification by chromatography on silica gel

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of nortropinone hydrochloride (1 g, 6.187 mmol) in acetic anhydride was stirred at 70° C. for 3 h. Water was added, the mixture was boiled for 30 min and cooled down to room temperature. CH2Cl2 and 1N aqueous NaOH was added until pH 9 was reached. The mixture was extracted 2 times with CH2Cl2, the combined organic layers were dried over Na2SO4, filtrated and the solution was evaporated to dryness to give 0.7 g of 8-Acetyl-8-aza-bicyclo[3.2.1]octan-3-one (4a). the mixture was boiled for 30 min cooled down to room temperature The mixture was extracted 2 times with CH2Cl2 the combined organic layers were dried over Na2SO4 filtrated the solution was evaporated to dryness

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of nortropinone hydrochloride (1 g, 6.187 mmol) in acetic anhydride was stirred at 70° C. for 3 h. Water was added, the mixture was boiled for 30 min and cooled down to room temperature. CH2Cl2 and 1N aqueous NaOH was added until pH 9 was reached. The mixture was extracted 2 times with CH2Cl2, the combined organic layers were dried over Na2SO4, filtrated and the solution was evaporated to dryness to give 0.7 g of 8-Acetyl-8-aza-bicyclo[3.2.1]octan-3-one (4a). the mixture was boiled for 30 min cooled down to room temperature The mixture was extracted 2 times with CH2Cl2 the combined organic layers were dried over Na2SO4 filtrated the solution was evaporated to dryness

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

Procedure: In DCM were dissolved N-benzyl-4-((3-chloro-4-methoxybenzyl)amino)-2-(methyl sulfinyl)pyrimidine-5-formamide (222 mg, 0.5 mmol) and DIEA (0.25 mL, 1.35 mmol). 3-oxo-8-azabicyclo[3.2.1] octane hydrochloride salt (90 mg, 0.6 mmol) was dissolved in THF and added to the reaction mixture at 0° C. The reaction was conducted at ambient temperature, followed by addition of water and extraction with ethyl acetate. The organic phase was washed sequentially with water and brine, and dried over sodium sulfate. The solvent was removed by rotary evaporation. Purification was performed by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give a white solid (50 mg, 19% yield). added to the reaction mixture at 0° C was conducted at ambient temperature The organic phase was washed sequentially with water and brine dried over sodium sulfate The solvent was removed by rotary evaporation Purification