(2S,6R)-2,6-dimethyloxan-4-one

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

Procedure: 10 g of 2,6-dimethyl-gamma-pyrone are dissolved in 200 ml of methanol and then 0.8 g of palladium-on-charcoal at 10% is added. The reaction mixture is stirred for 24 hours under 25 atmospheres of hydrogen. The medium is filtered and then the solvent is evaporated off. 8.81 g of cis-2,6-dimethyltetrahydro-pyran-4-one are recovered. Yield=88%. The medium is filtered the solvent is evaporated off 8.81 g of cis-2,6-dimethyltetrahydro-pyran-4-one are recovered

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

Procedure: A solution of 2,6-dimethyl-4-pyrone (5.0 g, 40.3 mmol) in ethanol was charged with Pd/C (0.86 g, 0.40 mmol). The mixture was subjected to pressurized H2 conditions using a parr hydrogenator (50 psi) and the mixture was shaken overnight. Afterwards, the mixture was filtered through a pad of celite, and the filtrate was concentrated. The crude material was purified by column chromatography using 5% to 60% EtOAc-hexanes eluent. The desired fractions were combined and concentrated to give cis-2,6-dimethyldihydro-2H-pyran-4(3H)-one as a colorless oil. Step 2: A solution of cis-2,6-dimethyldihydro-2H-pyran-4(3H)-one (2.05 g, 16.0 mmol) and hydroxylamine chloride (0.73 mL, 17.6 mmol) in methanol was heated to 60° C. for 2 h. After the mixture was cooled to RT, a spatula full of Raney nickel (0.19 g, 3.20 mmol) was added to the reaction mixture. The reaction was subjected to H2 atmosphere using a balloon. The mixture was stirred overnight at 50° C. The reaction mixture was filtered through a pad of celite. The filtrate was acidified with HCl (4.0 mL, 15.99 mmol)-4N in dioxane, and the resulting solution was concentrated. The resulting solid was washed with ether and filtered to give cis-2,6-dimethyltetrahydro-2H-pyran-4-amine hydrochloride as a white solid. The titled compound was prepared by following the procedure described in Example 10, Step 2 to give (2R)-3-(2-amino-6-o-tolylquinolin-3-yl)-N-(cis-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-methylpropanamide. MS (ESI, pos. ion) m/z: 433 (M+1). Afterwards, the mixture was filtered through a pad of celite the filtrate was concentrated The crude material was purified by column chromatography concentrated

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

Procedure: A solution of 2,6-dimethyl-4-pyrone (5.0 g, 40.3 mmol) in ethanol was charged with Pd/C (0.86 g, 0.40 mmol). The mixture was subjected to pressurized H2 conditions using a parr hydrogenator (50 psi) and the mixture was shaken overnight. Afterwards, the mixture was filtered through a pad of celite, and the filtrate was concentrated. The crude material was purified by column chromatography using 5% to 60% EtOAc-hexanes eluent. The desired fractions were combined and concentrated to give cis-2,6-dimethyldihydro-2H-pyran-4(3H)-one as a colorless oil. Step 2: A solution of cis-2,6-dimethyldihydro-2H-pyran-4(3H)-one (2.05 g, 16.0 mmol) and hydroxylamine chloride (0.73 mL, 17.6 mmol) in methanol was heated to 60° C. for 2 h. After the mixture was cooled to RT, a spatula full of Raney nickel (0.19 g, 3.20 mmol) was added to the reaction mixture. The reaction was subjected to H2 atmosphere using a balloon. The mixture was stirred overnight at 50° C. The reaction mixture was filtered through a pad of celite. The filtrate was acidified with HCl (4.0 mL, 15.99 mmol)-4N in dioxane, and the resulting solution was concentrated. The resulting solid was washed with ether and filtered to give cis-2,6-dimethyltetrahydro-2H-pyran-4-amine hydrochloride as a white solid. The titled compound was prepared by following the procedure described in Example 10, Step 2 to give (2R)-3-(2-amino-6-o-tolylquinolin-3-yl)-N-(cis-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-methylpropanamide. MS (ESI, pos. ion) m/z: 433 (M+1). Afterwards, the mixture was filtered through a pad of celite the filtrate was concentrated The crude material was purified by column chromatography concentrated

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

Procedure: 2,6-Dimethyl-4H-pyran-4-one (2.0 g, 16 mmol) was dissolved in ethanol (10 mL) and purged under nitrogen. Palladium on carbon (5%, 200 mg) was then added and the reaction mixture stirred under hydrogen gas (40 psi) for 24 hours. The reaction mixture was filtered over CELITE, rinsed with ethanol, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5 to 30% EtOAc/hexanes) to afford cis-2,6-dimethyltetrahydro-4H-pyran-4-one as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ 3.77-3.70 (m, 2H), 2.38-2.32 (m, 2H), 2.25-2.20 (m, 2H), 1.32 (d, J=6.1 Hz, 6H). purged under nitrogen Palladium on carbon (5%, 200 mg) was then added The reaction mixture was filtered over CELITE rinsed with ethanol concentrated under reduced pressure The residue was purified by column chromatography on silica gel (5 to 30% EtOAc/hexanes)

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

Procedure: To a solution of 1H-1,2,4-triazol-5-amine (1.6 g) in acetic acid (30 mL) was added (2R,6S)-2,6-dimethyltetrahydro-4H-pyran-4-one (2.5 g) at room temperature, and the mixture was stirred for 30 min. After stirring, sodium triacetoxyborohydride (5.2 g) was added, and the mixture was stirred at room temperature for 20 hr. Acetic acid was evaporated and ethyl acetate and water were added to the residue. The mixture was neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in a small amount of ethyl acetate, and the mixture was crystallized from diisopropyl ether. The resulting solid was collected by filtration, washed with diisopropyl ether, and dried by heating under reduced pressure to give the title compound as a pale-yellow solid (1.6 g, 49%). After stirring the mixture was stirred at room temperature for 20 hr Acetic acid was evaporated ethyl acetate and water were added to the residue extracted with ethyl acetate The organic layer was washed with water and saturated brine dried over anhydrous magnesium sulfate concentrated The residue was dissolved in a small amount of ethyl acetate the mixture was crystallized from diisopropyl ether The resulting solid was collected by filtration washed with diisopropyl ether dried by heating under reduced pressure

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

Procedure: To a solution of 3-methyl-1H-1,2,4-triazol-5-amine (1.6 g) in acetic acid (30 mL) was added (2R,6S)-2,6-dimethyltetrahydro-4H-pyran-4-one (2.5 g) at room temperature, and the mixture was stirred for 30 min. Sodium triacetoxyborohydride (5.2 g) was added, and the mixture was stirred at room temperature for 20 hr. Acetic acid was evaporated and ethyl acetate and water were added to the residue. The mixture was neutralized with sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in a small amount of ethyl acetate, and the mixture was crystallized from diisopropyl ether. The resulting solid was collected by filtration, washed with diisopropyl ether, and dried by heating under reduced pressure to give the title compound as a pale-yellow solid (0.75 g, 22%). the mixture was stirred at room temperature for 20 hr Acetic acid was evaporated ethyl acetate and water were added to the residue the mixture was extracted with ethyl acetate The organic layer was washed with water and saturated brine dried over anhydrous magnesium sulfate concentrated The residue was dissolved in a small amount of ethyl acetate the mixture was crystallized from diisopropyl ether The resulting solid was collected by filtration washed with diisopropyl ether dried by heating under reduced pressure

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

Procedure: To a solution of 3-methyl-1H-1,2,4-triazol-5-amine (1.6 g) in acetic acid (30 mL) was added (2R,6S)-2,6-dimethyltetrahydro-4H-pyran-4-one (2.5 g) at room temperature, and the mixture was stirred for 30 min. Sodium triacetoxyborohydride (5.2 g) was added, and the mixture was stirred at room temperature for 20 hr. Acetic acid was evaporated and ethyl acetate and water were added to the residue. The mixture was neutralized with sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in a small amount of ethyl acetate, and the mixture was crystallized from diisopropyl ether. The resulting solid was collected by filtration, washed with diisopropyl ether, and dried by heating under reduced pressure to give the title compound as a pale-yellow solid (0.75 g, 22%). the mixture was stirred at room temperature for 20 hr Acetic acid was evaporated ethyl acetate and water were added to the residue the mixture was extracted with ethyl acetate The organic layer was washed with water and saturated brine dried over anhydrous magnesium sulfate concentrated The residue was dissolved in a small amount of ethyl acetate the mixture was crystallized from diisopropyl ether The resulting solid was collected by filtration washed with diisopropyl ether dried by heating under reduced pressure

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

Procedure: 10 g of 2,6-dimethyl-gamma-pyrone are dissolved in 200 ml of methanol and then 0.8 g of palladium-on-charcoal at 10% is added. The reaction mixture is stirred for 24 hours under 25 atmospheres of hydrogen. The medium is filtered and then the solvent is evaporated off. 8.81 g of cis-2,6-dimethyltetrahydro-pyran-4-one are recovered. Yield=88%. The medium is filtered the solvent is evaporated off 8.81 g of cis-2,6-dimethyltetrahydro-pyran-4-one are recovered

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

Procedure: Prepared in analogy to Example A62(b) from 2-benzyl-5-bromo-2,3-dihydro-1H-isoindole (Example A62(a)) and (2R,6S)-2,6-dimethyl-tetrahydro-pyran-4-one. Brown solid. MS (m/e): 338.4 ([M+H]+, 100%).

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

Procedure: Prepared in analogy to Example A62(b) from 2-benzyl-5-bromo-2,3-dihydro-1H-isoindole (Example A62(a)) and (2R,6S)-2,6-dimethyl-tetrahydro-pyran-4-one. Brown solid. MS (m/e): 338.4 ([M+H]+, 100%).

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

Procedure: The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and (2R,6S)-2,6-dimethyl-tetrahydro-pyran-4-one using decaborane yielded the title compound as a white solid. MS (ESI): m/z=391.1 [M+H]+.

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

Procedure: To a solution of 1H-1,2,4-triazol-5-amine (1.6 g) in acetic acid (30 mL) was added (2R,6S)-2,6-dimethyltetrahydro-4H-pyran-4-one (2.5 g) at room temperature, and the mixture was stirred for 30 min. After stirring, sodium triacetoxyborohydride (5.2 g) was added, and the mixture was stirred at room temperature for 20 hr. Acetic acid was evaporated and ethyl acetate and water were added to the residue. The mixture was neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in a small amount of ethyl acetate, and the mixture was crystallized from diisopropyl ether. The resulting solid was collected by filtration, washed with diisopropyl ether, and dried by heating under reduced pressure to give the title compound as a pale-yellow solid (1.6 g, 49%). After stirring the mixture was stirred at room temperature for 20 hr Acetic acid was evaporated ethyl acetate and water were added to the residue extracted with ethyl acetate The organic layer was washed with water and saturated brine dried over anhydrous magnesium sulfate concentrated The residue was dissolved in a small amount of ethyl acetate the mixture was crystallized from diisopropyl ether The resulting solid was collected by filtration washed with diisopropyl ether dried by heating under reduced pressure