4-(bromomethyl)-2,5-difluorobenzonitrile

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

Procedure: The title compound was synthesized from 4-chloro-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (300 mg, 1.0 mmol), cesium carbonate (390 mg, 1.20 mmol), and 4-(bromomethyl)-2,5-difluorobenzonitrile (278 mg, 1.20 mmol) according to the procedure described for 4-chloro-N-(2,3-difluoro-4-(oxazol-2-yl)benzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 20) to give 4-chloro-N-(4-cyano-2,5-difluorobenzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (350 mg, 77%). 1H NMR (400 MHz, CDCl3) δ ppm 7.74 (m, 2H), 7.59 (dd, J=8.81, 5.79 Hz, 1H), 7.51 (m, 2H), 7.28 (dd, J=8.69, 4.91 Hz, 1H), 4.48 (d, J=15.80 Hz, 1H), 4.39 (d, J=15.80 Hz, 1H), 3.64 (ddd, J=14.00, 9.00, 4.00 Hz, 1H), 3.55 (ddd, J=11.83, 4.78, 3.53 Hz, 1H), 3.16 (ddd, J=11.52, 9.13, 2.27 Hz, 1H), 2.40 (br. s., 1H), 1.68 (d, J=10.58 Hz, 3H), 1.30-1.45 (m, 2H), 0.99-1.21 (m, 4H).

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

Procedure: The title compound was synthesized from 4-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (200 mg, 0.66 mmol), cesium carbonate (257 mg, 0.79 mmol), and 4-(bromomethyl)-2,5-difluorobenzonitrile (183 mg, 0.79 mmol) according to the procedure described for N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-4-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 11) to give 4-chloro-N-(4-cyano-2,5-difluorobenzyl)-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (130 mg, 43%). 1H NMR (400 MHz, CDCl3) δ ppm 7.74 (m, 2H), 7.59 (dd, J=8.81, 5.79 Hz, 1H), 7.51 (m, 2H), 7.28 (dd, J=8.56, 5.04 Hz, 1H), 4.48 (d, J=13.00 Hz, 1H), 4.39 (d, J=14.00 Hz, 1H), 3.64 (td, J=11.58, 3.02 Hz, 1H), 3.55 (ddd, J=11.77, 4.72, 3.40 Hz, 1H), 3.15 (ddd, J=11.58, 9.19, 2.14 Hz, 1H), 2.41 (t, J=6.00 Hz, 1H), 1.68 (d, J=10.58 Hz, 3H), 1.30-1.52 (m, 2H), 0.98-1.19 (m, 4H). Analytical HPLC R.T.=23.37 min. MS [M+H]+=455; [M+Na]+=477.

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

Procedure: To a stirred solution of 2,5-difluoro-4-(bromomethyl)benzonitrile (Preparation 22, 530 mg, 2.30 mmol) and 3,4-dichlorophenol (375 mg, 2.30 mmol) in acetone (12 mL) was added potassium carbonate (954 mg, 6.90 mmol). The mixture was stirred at room temperature for 36 hours. The reaction mixture was then poured into water (25 mL) and extracted with EtOAc (3×25 mL). The combined organics were dried over sodium sulphate and evaporated to yield the crude product as a yellow oil, which was purified by silica gel chromatography eluting with 50% heptanes in DCM to afford the title compound as a white solid (153 mg, 22%). extracted with EtOAc (3×25 mL) The combined organics were dried over sodium sulphate evaporated to yield the crude product as a yellow oil, which was purified by silica gel chromatography eluting with 50% heptanes in DCM

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

Procedure: To a stirred solution of 2,5-difluoro-4-(hydroxymethyl)benzonitrile (Preparation 21, 390 mg, 2.30 mmol) in DCM (12 mL) was added phosphorus tribromide (0.238 mL, 2.53 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with DCM to 30 mL and washed with saturated aqueous sodium bicarbonate (30 mL). The organic layer was dried over sodium sulphate, and evaporated to afford the title compound as a yellow oil, which was used in the next step without further purification (530 mg, 99%). washed with saturated aqueous sodium bicarbonate (30 mL) The organic layer was dried over sodium sulphate evaporated

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

Procedure: To a stirred solution of 2,5-difluoro-4-(hydroxymethyl)benzonitrile (Preparation 21, 390 mg, 2.30 mmol) in DCM (12 mL) was added phosphorus tribromide (0.238 mL, 2.53 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with DCM to 30 mL and washed with saturated aqueous sodium bicarbonate (30 mL). The organic layer was dried over sodium sulphate, and evaporated to afford the title compound as a yellow oil, which was used in the next step without further purification (530 mg, 99%). washed with saturated aqueous sodium bicarbonate (30 mL) The organic layer was dried over sodium sulphate evaporated

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

Procedure: The title compound was synthesized from 4-chloro-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (300 mg, 1.0 mmol), cesium carbonate (390 mg, 1.20 mmol), and 4-(bromomethyl)-2,5-difluorobenzonitrile (278 mg, 1.20 mmol) according to the procedure described for 4-chloro-N-(2,3-difluoro-4-(oxazol-2-yl)benzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 20) to give 4-chloro-N-(4-cyano-2,5-difluorobenzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (350 mg, 77%). 1H NMR (400 MHz, CDCl3) δ ppm 7.74 (m, 2H), 7.59 (dd, J=8.81, 5.79 Hz, 1H), 7.51 (m, 2H), 7.28 (dd, J=8.69, 4.91 Hz, 1H), 4.48 (d, J=15.80 Hz, 1H), 4.39 (d, J=15.80 Hz, 1H), 3.64 (ddd, J=14.00, 9.00, 4.00 Hz, 1H), 3.55 (ddd, J=11.83, 4.78, 3.53 Hz, 1H), 3.16 (ddd, J=11.52, 9.13, 2.27 Hz, 1H), 2.40 (br. s., 1H), 1.68 (d, J=10.58 Hz, 3H), 1.30-1.45 (m, 2H), 0.99-1.21 (m, 4H).

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

Procedure: The title compound was synthesized from 4-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (200 mg, 0.66 mmol), cesium carbonate (257 mg, 0.79 mmol), and 4-(bromomethyl)-2,5-difluorobenzonitrile (183 mg, 0.79 mmol) according to the procedure described for N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-4-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 11) to give 4-chloro-N-(4-cyano-2,5-difluorobenzyl)-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (130 mg, 43%). 1H NMR (400 MHz, CDCl3) δ ppm 7.74 (m, 2H), 7.59 (dd, J=8.81, 5.79 Hz, 1H), 7.51 (m, 2H), 7.28 (dd, J=8.56, 5.04 Hz, 1H), 4.48 (d, J=13.00 Hz, 1H), 4.39 (d, J=14.00 Hz, 1H), 3.64 (td, J=11.58, 3.02 Hz, 1H), 3.55 (ddd, J=11.77, 4.72, 3.40 Hz, 1H), 3.15 (ddd, J=11.58, 9.19, 2.14 Hz, 1H), 2.41 (t, J=6.00 Hz, 1H), 1.68 (d, J=10.58 Hz, 3H), 1.30-1.52 (m, 2H), 0.98-1.19 (m, 4H). Analytical HPLC R.T.=23.37 min. MS [M+H]+=455; [M+Na]+=477.

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

Procedure: To a stirred solution of 2,5-difluoro-4-(bromomethyl)benzonitrile (Preparation 22, 530 mg, 2.30 mmol) and 3,4-dichlorophenol (375 mg, 2.30 mmol) in acetone (12 mL) was added potassium carbonate (954 mg, 6.90 mmol). The mixture was stirred at room temperature for 36 hours. The reaction mixture was then poured into water (25 mL) and extracted with EtOAc (3×25 mL). The combined organics were dried over sodium sulphate and evaporated to yield the crude product as a yellow oil, which was purified by silica gel chromatography eluting with 50% heptanes in DCM to afford the title compound as a white solid (153 mg, 22%). extracted with EtOAc (3×25 mL) The combined organics were dried over sodium sulphate evaporated to yield the crude product as a yellow oil, which was purified by silica gel chromatography eluting with 50% heptanes in DCM

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

Procedure: To a stirred solution of 2,5-difluoro-4-(hydroxymethyl)benzonitrile (Preparation 21, 390 mg, 2.30 mmol) in DCM (12 mL) was added phosphorus tribromide (0.238 mL, 2.53 mmol). The mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with DCM to 30 mL and washed with saturated aqueous sodium bicarbonate (30 mL). The organic layer was dried over sodium sulphate, and evaporated to afford the title compound as a yellow oil, which was used in the next step without further purification (530 mg, 99%). washed with saturated aqueous sodium bicarbonate (30 mL) The organic layer was dried over sodium sulphate evaporated