cyclohexanecarboxamide

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

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

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

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

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

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: cis-4-Hydroxy-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (500 mg, 1.05 mmol), ammonium chloride (112 mg, 2.09 mmol), 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (795 mg, 2.09 mmol), and diisopropylethylamine (730 μl, 4.18 mmol) were taken-up in dimethylformamide (4.2 mL) under argon. The vessel was sealed and stirred at 65° C. for 4 hours. Upon cooling, the reaction mixture was diluted with water, and the resulting precipitate was collected via filtration. The solids were washed with water and diethyl ether and dried in vacuo overnight to afford cis-4-hydroxy-4-[5-(3-methyl-5-{[4-Orifluoromethyl)pyrimidin-2-yl]amino}-phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxamide (437.6 mg, 0.916 mmol, 88% yield) as a white solid. MS ESI: [M+H]+ m/z 478.1. The vessel was sealed Upon cooling the resulting precipitate was collected via filtration The solids were washed with water and diethyl ether dried in vacuo overnight

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

Procedure: In substantially the same manner as in Reference Example 31, cyclohexanecarboxamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-cyclohexyloxazole as an oily product. The yield was 2.7%.

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

Procedure: Cyclohexanecarboxamide (1 g, 7.86 mmol) and Lawesson's Reagent (2 g, 4.94 mmol) in THF (50 mL) was heated at 70° C. for 3 h. Silica was added and the volatiles were removed under reduced pressure. The residue was column chromatographed with EtOAc/DCM to afford cyclohexanecarbothioamide (0.557 g, 49% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.67 (br. s., 1H), 6.91 (br. s., 1H), 2.56 (tt, J=11.8, 3.3 Hz, 1H), 1.90-2.02 (m, 2H), 1.78-1.90 (m, 2H), 1.71 (d, J=12.0 Hz, 1H), 1.51 (qd, J=12.3, 2.8 Hz, 2H), 1.16-1.40 (m, 3H), e/z (ES+): 144 [M+H]+. Silica was added the volatiles were removed under reduced pressure chromatographed with EtOAc/DCM

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

Procedure: A solution of cyclohexanecarboxylic acid (1.00 g, 7.80 mmol) in EtOAc (10 mL) was treated with CDI (1.581 g, 9.75 mmol), stirred at RT for 20 minutes, treated with ammonium hydroxide (5.00 mL, 70.0 mmol) and stirred for 20 minutes. The mixture was treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford cyclohexanecarboxamide (1.109 g, 112%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 5.61 (s, 2H), 2.13 (m, 1H), 1.89 (m, 2H), 1.78 (m, 2H), 1.66 (m, 1H), 1.42 (m, 2H), 1.24 (m, 3H). stirred for 20 minutes The mixture was treated with satd NaHCO3, extracted with EtOAc (2×) the combined organics were dried over Na2SO4 concentrated to dryness

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

Procedure: A solution of cyclohexanecarboxylic acid (1.00 g, 7.80 mmol) in EtOAc (10 mL) was treated with CDI (1.581 g, 9.75 mmol), stirred at RT for 20 minutes, treated with ammonium hydroxide (5.00 mL, 70.0 mmol) and stirred for 20 minutes. The mixture was treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford cyclohexanecarboxamide (1.109 g, 112%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 5.61 (s, 2H), 2.13 (m, 1H), 1.89 (m, 2H), 1.78 (m, 2H), 1.66 (m, 1H), 1.42 (m, 2H), 1.24 (m, 3H). stirred for 20 minutes The mixture was treated with satd NaHCO3, extracted with EtOAc (2×) the combined organics were dried over Na2SO4 concentrated to dryness

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An oven-dried resealable Schlenk tube containing a stirbar was charged with CuI (20 mg, 0.1 mmol, 10 mol %), cyclohexanecarboxamide (153 mg, 1.2 mmol), 5-bromopyrimidine (160 mg, 1 mmol), and K3PO4 (425 mg, 2 mmol), evacuated and backfilled with argon. N,N′-Dimethylethylenediamine (8.9 mg, 0.1 mmol) and dioxane (1 ml) were injected, and under a flow of argon, the septum was replaced by a Teflon screw cap. The tube was sealed, and the mixture was stirred and heated in an oil bath at 110° C. for 16 h. The contents of the tube were then partitioned between water and dichloromethane. The aqueous layer was separated, and extracted two times with additional dichloromethane. The organics were then combined, dried over Na2SO4, filtered, concentrated under reduced pressure. The residue was chromatographed on silica gel followed by recrystallization from dichloromethane/hexane to give 154 mg (75%) of the title compound as a solid. 1H NMR (CDCl3, 300 MHz): δ 9.02 (s, 2H), 8.97 (s, 1H), 7.40 (br s, 1H), 2.32 (tt, 1H, J=3.6, 11.4 Hz), 2.10-1.20 (m, 10H). An oven-dried resealable Schlenk tube containing a stirbar evacuated screw cap The tube was sealed The contents of the tube were then partitioned between water and dichloromethane The aqueous layer was separated extracted two times with additional dichloromethane dried over Na2SO4 filtered concentrated under reduced pressure The residue was chromatographed on silica gel followed by recrystallization from dichloromethane/hexane

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

Procedure: To 90 ml of tetrahydrofuran, 11.1 g (87 mmol) of cyclohexanecarboxamide and 17.6 g (43.5 mmol) of Lawesson's reagent were suspended, followed by heating under refluxing for 3 hours. The reaction liquid was cooled to room temperature, followed by adding 14.4 g (87 mmol) of ethyl 2-chloro-3-oxobutanate and heating under refluxing for further 3 hours. The reaction liquid was poured into ice water and extracted with diethyl ether. The organic layer was washed with water, dilute hydrochloric acid, an aqueous solution of sodium carbonate and saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentrating under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:5) to obtain 20.3 g (yield: 92%) of ethyl 2-cyclohexyl-4-methylthiazole-5-carboxylate. by heating under refluxing for 3 hours The reaction liquid heating under refluxing for further 3 hours The reaction liquid extracted with diethyl ether The organic layer was washed with water, dilute hydrochloric acid by drying over anhydrous magnesium sulfate concentrating under reduced pressure The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:5)