3,4,5-trifluorobenzonitrile

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:0.00; pressure:0.00; stir:

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

Procedure: A solution of 0.10 g (0.24 mmol) (−)-1-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-1-cyclohexyl-2-methyl-propan-2-ol (Example 88, intermediate b) and 38 mg (0.24 mmol) 3,4,5-trifluorobenzonitrile in 2 ml anhydrous tetrahydrofuran was cooled down to 0° C. Then, 0.53 ml (0.26 mmol) potassium bis(trimethylsilyl)amide (0.5 M solution in toluene) were added dropwise to the reaction mixture. The cooling bath was removed and stirring was continued for 18 h. The reaction mixture was poured onto aqueous saturated ammonium chloride solution and the phases were separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with n-heptane for 5 min., then with a gradient of dichloromethane:ethyl acetate (100:0 to 95:5). Light brown foam (45%). MS (Turbo Spray): m/z=556.2 [M+H]. The cooling bath was removed The reaction mixture was poured onto aqueous saturated ammonium chloride solution the phases were separated The aqueous layer was extracted three times with ethyl acetate The combined organic layers were washed with brine dried over magnesium sulfate filtered evaporated The residue was purified by silica gel chromatography eluting with n-heptane for 5 min.

Conditions: temp:210.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-(2-chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazol-4-amin (i.e. the product of Step B) (0.25 g, 1.0 mmol), 3,4,5-trifluorobenzonitrile (0.188 g, 1.2 mmol) and cesium carbonate (0.390 g, 1.2 mmol) in acetonitrile (3 mL) was heated at 210° C. in a Biotage Initiator™ microwave apparatus for 2 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered through a pad of silica gel on a sintered glass frit funnel. The filtrate was concentrated under reduced pressure and the resulting material was purified by silica gel chromatography (30% ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as a solid (0.065 g). After cooling to room temperature filtered through a pad of silica gel on a sintered glass frit funnel The filtrate was concentrated under reduced pressure the resulting material was purified by silica gel chromatography (30% ethyl acetate in hexanes as eluant)

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

Procedure: Using 1.5 g (9.55 mmol) of 3,4,5-trifluoro-benzonitrile and 3,5-dihydroxy-benzoic acid ethyl ester (1.73 g, 9.55 mmol) and following the procedure of Example 42(a) afforded 1.2 g of the required product. 1H NMR (DMSO-d6): δ 1.28 (3H, t), 4.27 (2H, q), 6.67 (1H, t), 6.92 (1H, s), 7.18 (1H, s), 8.08 (2H, d), 10.20 (1H, brs).

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

Procedure: Using 1.5 g (9.55 mmol) of 3,4,5-trifluoro-benzonitrile and 3,5-dihydroxy-benzoic acid ethyl ester (1.73 g, 9.55 mmol) and following the procedure of Example 42(a) afforded 1.2 g of the required product. 1H NMR (DMSO-d6): δ 1.28 (3H, t), 4.27 (2H, q), 6.67 (1H, t), 6.92 (1H, s), 7.18 (1H, s), 8.08 (2H, d), 10.20 (1H, brs).

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

Procedure: Using 0.5 g (0.89 mmol) of {4-[3-[4-tert-Butoxycarbonylaminomethylphenoxy]-5-hydroxybenzoylamino]-cyclohexyl}carbamic acid tert-butyl ester and 3,4,5-trifluoro-benzonitrile (0.34 g, 2.22 mmol) and following the procedure of Example 42(b) afforded 0.4 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (4H, m), 1.38 (18H, d), 1.78 (4H, m), 3.18 (1H, m), 3.64 (1H, m), 4.12 (2H, d), 6.74 (1H, d), 6.90 (1H, s), 7.02 (2H, d), 7.20 (2H, d), 7.28 (2H, d), 7.40 (1H, m), 8.08 (2H, d), 8.32 (1H, d).

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

Procedure: Using 0.5 g (0.89 mmol) of {4-[3-[4-tert-Butoxycarbonylaminomethylphenoxy]-5-hydroxybenzoylamino]-cyclohexyl}carbamic acid tert-butyl ester and 3,4,5-trifluoro-benzonitrile (0.34 g, 2.22 mmol) and following the procedure of Example 42(b) afforded 0.4 g of the required product. 1H NMR (DMSO-d6): δ 1.25 (4H, m), 1.38 (18H, d), 1.78 (4H, m), 3.18 (1H, m), 3.64 (1H, m), 4.12 (2H, d), 6.74 (1H, d), 6.90 (1H, s), 7.02 (2H, d), 7.20 (2H, d), 7.28 (2H, d), 7.40 (1H, m), 8.08 (2H, d), 8.32 (1H, d).