1-cyclohexylethanone

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred suspension of 1-bromo-4-cyclohexyloxy-benzene (3.92 mmol, 1.0 g), cyclohexylmethylketone (5.92 mmol, 0.83 mL), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.88 mmol, 1.17 g), tris(dibenzylideneacetone)dipalladium(0) (0.78 mmol, 0.72 g), and potassium t-butoxide (7.84 mmol, 0.88 g) were heated to 90° C. for 12 h in a sealed vial. The reaction was cooled and partitioned in water (50 mL) and diethyl ether (50 mL). The mixture was filtered through fluted filter paper and the layers were separated. The aqueous layer was washed with diethyl ether (3×20 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified on a 24 g SiO2 cartridge using an ethyl acetate/hexanes gradient to give 1-cyclohexyl-2-(4-cyclohexyloxy-phenyl)-ethanone (0.35 g). The reaction was cooled partitioned in water (50 mL) The mixture was filtered through fluted filter paper the layers were separated The aqueous layer was washed with diethyl ether (3×20 mL) The combined organic layers were washed with brine (10 mL) dried (Na2SO4) filtered concentrated under reduced pressure The crude product was purified on a 24 g SiO2 cartridge

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

Procedure: The title compound was prepared by a method similar to Step 3 of Example 17, using (2R)-1-{(2S,4R)-4-hydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonyl-N-((3R)-3-piperidylmethyl)pyrrolidine-2-carboxamide and cyclohexyl methyl ketone. The compound was obtained as a white solid. The compound was obtained as a white solid

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

Procedure: Using the apparatus, catalyst and method of Examples 16-18, cyclohexane carboxylic acid and acetone in a molar ratio of 1:2.76 was introduced into the system after purging with acetone. Methyl cyclohexyl ketone was produced and identified as in Examples 16-18. was introduced into the system after purging with acetone

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

Procedure: The title compound was prepared as described in General Method 2 using 17.40 g (138 mmol) of cyclohexyl methyl ketone, 29.26 g (138 mmol) of 4-benzyloxybenzaldehyde, 3.17 g of barium hydroxide (anhydrous), and 300 mL of 95% EtOH. The reaction was heated at reflux for eight hours. The crude product was recrystallized from EtOAc. The 25.85 g of product, contaminated with some 4-benzyloxybenzaldehyde, was taken on without further purification. The reaction was heated at reflux for eight hours The crude product was recrystallized from EtOAc was taken on without further purification

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

Procedure: To a 0.5N potassium bis-trimethylsilylamide solution in toluene (9.2 ml, 4.60 mmol, 2.5 eq) is added dropwise at -78° C. cyclohexyl methyl ketone (0.58 g, 4.60 mmol, 2.5 eq) in THF (9 ml) with stirring under a nitrogen atmosphere over 10 minutes. After 20 minutes stirring at the same temperature, 18-crown-6 (1.216 g, 4.60 mmol, 2.5 eq) in THF (10 ml) is dropwise added to the mixture over two minutes. Further, the dipeptidealdehyde [14a] (1.0 g, 1.83 mmol) in THF (10 ml) is dropwise added over 15 minutes at -78° C., and the mixture is stirred for one hour at the same temperature. The reaction is quenched by adding a solution of acetic acid (0.60 g, 10 mmol, 5.5 eq) in THF (10 ml) and after the addition of saturated aqueous ammonium chloride (30 ml) the mixture is extracted with ethyl acetate (50 ml×3). The organic layer is washed with saturated aqueous sodium chloride, dried over MgSO4, concentrated to dryness in vacuo, and purified with silica gel chromatography (Lobar column, CH2Cl2 :MeOH=95:5) to obtain Boc-His(Ts)-1(S)-cyclohexylmethyl-2(S)-hydroxy-4-oxo-4-cyclohexyl-butylamide [10b] (0.18 g, 15%) in amorphous powder. is dropwise added to the mixture over two minutes the mixture is stirred for one hour at the same temperature The reaction is quenched is extracted with ethyl acetate (50 ml×3) The organic layer is washed with saturated aqueous sodium chloride dried over MgSO4 concentrated to dryness in vacuo purified with silica gel chromatography (Lobar column, CH2Cl2 :MeOH=95:5)

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

Procedure: The title compound was prepared by a method similar to Step 3 of Example 17, using (2R)-1-{(2S,4R)-4-hydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonyl-N-((3R) -3-piperidyl-methyl)pyrrolidine-2-carboxamide and cyclohexyl methyl ketone. The compound was obtained as a white solid. The compound was obtained as a white solid

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

Procedure: The title compound was prepared by a method similar to Step 3 of Example 17, using (2R)-1-{(2S,4R)-4-hydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonyl-N-((3R) -3-piperidyl-methyl)pyrrolidine-2-carboxamide and cyclohexyl methyl ketone. The compound was obtained as a white solid. The compound was obtained as a white solid

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

Procedure: A mixture of 3.0 g (23.8 mmol) of cyclohexyl methyl ketone and 4.56 g (26.2 mmol) of t-butoxybis(dimethylamino)methane (Bredereck's reagent) was stirred at 60□C overnight. The reaction mixture was then concentrated to give 4.0 g (93% yield) of 1-cyclohexyl-3-dimethylamino-propenone as an orange oil as indicated by 1H NMR. This product was used in the next reaction without any further purification. The reaction mixture was then concentrated

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

Procedure: A mixture of 3.0 g (23.8 mmol) of cyclohexyl methyl ketone and 4.56 g (26.2 mmol) of t-butoxybis(dimethylamino)methane (Bredereck's reagent) was stirred at 60□C overnight. The reaction mixture was then concentrated to give 4.0 g (93% yield) of 1-cyclohexyl-3-dimethylamino-propenone as an orange oil as indicated by 1H NMR. This product was used in the next reaction without any further purification. The reaction mixture was then concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An oily suspension (50% by weight; 3.1 g) of sodium hydride is added at a temperature in the region of -5° C. to a solution, maintained under a nitrogen atmosphere, of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (10 g) in anhydrous dimethylformamide (180 cc), and the suspension obtained is stirred for 30 minutes at a temperature in the region of 0° C. A solution of cyclohexyl methyl ketone (8.2 g) in anhydrous dimethylformamide (20 cc) is then added and stirring is continued for 6 hours at a temperature in the region of 0° C. and then for 16 hours at a temperature in the region of 20° C. The reaction mixture is then poured into distilled water (800 cc). The solid obtained is separated by filtration, washed with water, dried in the air, and then recrystallized in acetonitrile and finally purified by chromatography under pressure (50 kPa) on silica gel (0.04-0.063 mm; 140 g) contained in a column 2.8 cm in diameter. Elution is performed with methylene chloride, collecting 20-cc fractions. Fractions 25 to 62 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The solid obtained is taken up with ethyl ether (100 cc) and separated by filtration. 3-(2-Cyclohexyl-2- oxoethyl)-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (4.8 g), m.p. 140° C., is obtained. the suspension obtained stirring is continued for 6 hours at a temperature in the region of 0° C. for 16 hours at a temperature in the region of 20° C The reaction mixture is then poured into distilled water (800 cc) The solid obtained is separated by filtration washed with water dried in the air recrystallized in acetonitrile finally purified by chromatography under pressure (50 kPa) on silica gel (0.04-0.063 mm; 140 g) Elution collecting 20-cc fractions concentrated to dryness under reduced pressure (2.7 kPa) at 40° C The solid obtained separated by filtration