4-(bromomethyl)-1-chloro-2-(trifluoromethyl)benzene

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

Procedure: The title compound was prepared in the manner analogous to Example 1F using 12C and 1-Chloro-4-(4-chloromethyl-phenoxymethyl)-2-trifluoromethyl-benzene prepared from 1-bromomethyl-4-chloro-3-trifluoromethyl-benzene and 4-hydroxymethyl-phenol in the manner analagous to Examples 14A and 14B. MS m/z 299 (M−237).

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

Procedure: The title compound was prepared in the manner analogous to Example 1F using 12C and 1-Chloro-4-(4-chloromethyl-phenoxymethyl)-2-trifluoromethyl-benzene prepared from 1-bromomethyl-4-chloro-3-trifluoromethyl-benzene and 4-hydroxymethyl-phenol in the manner analagous to Examples 14A and 14B. MS m/z 299 (M−237).

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-bromomethyl-1-chloro-2-trifluoromethyl-benzene (3.94 g, 14.4 mmol) and sodium cyanide (1.06 g, 21.6 mmol) in dimethyl sulfoxide (12 mL) was heated at 50° C. for one hour. The reaction mixture was then poured on ice water and extracted four times with dichloromethane. The combined organic phases were washed with water, dried over magnesium sulfate, filtered and concentrated, leading to (4-chloro-3-trifluoromethyl-phenyl)-acetonitrile (3.19 g, 14.4 mmol) as a dark red oil. This crude material was transformed into the title compound in accordance with the general method of example H2. White solid, MS (ISP) 224.1 (M−Cl)+. The reaction mixture was then poured on ice water extracted four times with dichloromethane The combined organic phases were washed with water dried over magnesium sulfate filtered concentrated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 4-(bromomethyl)-1-chloro-2-(trifluoromethyl)benzene (4.5 g, 16.45 mmol), potassium trifluoro(4-formylphenyl)borate (3.52 g, 16.62 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.672 g, 0.823 mmol) and Cs2CO3 (16.08 g, 49.4 mmol) in cyclopentyl methyl ether (100 mL) and water (100 mL). The mixture was charged with Argon and stirred for overnight at 80° C. The result mixture was cooled to room temperature and partitioned with water 100 mL and ethyl acetate 100 mL. The organic phase was washed by water, brine and dried over sodium sulfate, the solvent was removed and the residue was purified via flash column chromatography. Removed the solvent afforded the title compound (2.55 g). LC-MS (ESI): m/z 299 [M+H]+ The mixture was charged with Argon The result mixture was cooled to room temperature partitioned with water 100 mL and ethyl acetate 100 mL The organic phase was washed by water, brine dried over sodium sulfate the solvent was removed the residue was purified via flash column chromatography Removed the solvent

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 4-(bromomethyl)-1-chloro-2-(trifluoromethyl)benzene (4.5 g, 16.45 mmol), potassium trifluoro(4-formylphenyl)borate (3.52 g, 16.62 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.672 g, 0.823 mmol) and Cs2CO3 (16.08 g, 49.4 mmol) in cyclopentyl methyl ether (100 mL) and water (100 mL). The mixture was charged with Argon and stirred for overnight at 80° C. The result mixture was cooled to room temperature and partitioned with water 100 mL and ethyl acetate 100 mL. The organic phase was washed by water, brine and dried over sodium sulfate, the solvent was removed and the residue was purified via flash column chromatography. Removed the solvent afforded the title compound (2.55 g). LC-MS (ESI): m/z 299 [M+H]+ The mixture was charged with Argon The result mixture was cooled to room temperature partitioned with water 100 mL and ethyl acetate 100 mL The organic phase was washed by water, brine dried over sodium sulfate the solvent was removed the residue was purified via flash column chromatography Removed the solvent

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.053 g, 0.183 mmol) in DMF (1 mL) was added Cs2CO3 (0.0.071 g, 0.219 mmol) followed by 4-(bromomethyl)-1-chloro-2-(trifluoromethyl)benzene (0.050 g, 0.183 mmol). The reaction was stirred at 60° C. for 16 h. The mixture was filtered. The filtrate was concentrated under vacuum and purified by silica gel column chromatography to give the title compound as a white solid (0.048 g). LCMS m/z=480.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.49 (s, 9H), 2.21-2.34 (On, 1H), 2.50 (dd, J=15.73, 8.40 Hz, 1H), 2.73 (dd, J=15.79, 6.32 Hz, 1H), 2.81-2.93 (m, 1H), 3.64-3.77 (m, 1H), 3.94-4.05 (m, 1H), 4.06-4.17 (On, 1H), 5.10 (s, 2H), 6.84 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.40 Hz, 1H), 7.13 (d, J=8.72 Hz, 1H), 7.47-7.53 (m, 1H), 7.55-7.61 (m, 1H), 7.79 (s, 1H). The mixture was filtered The filtrate was concentrated under vacuum purified by silica gel column chromatography

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.053 g, 0.183 mmol) in DMF (1 mL) was added Cs2CO3 (0.0.071 g, 0.219 mmol) followed by 4-(bromomethyl)-1-chloro-2-(trifluoromethyl)benzene (0.050 g, 0.183 mmol). The reaction was stirred at 60° C. for 16 h. The mixture was filtered. The filtrate was concentrated under vacuum and purified by silica gel column chromatography to give the title compound as a white solid (0.048 g). LCMS m/z=480.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.49 (s, 9H), 2.21-2.34 (On, 1H), 2.50 (dd, J=15.73, 8.40 Hz, 1H), 2.73 (dd, J=15.79, 6.32 Hz, 1H), 2.81-2.93 (m, 1H), 3.64-3.77 (m, 1H), 3.94-4.05 (m, 1H), 4.06-4.17 (On, 1H), 5.10 (s, 2H), 6.84 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.40 Hz, 1H), 7.13 (d, J=8.72 Hz, 1H), 7.47-7.53 (m, 1H), 7.55-7.61 (m, 1H), 7.79 (s, 1H). The mixture was filtered The filtrate was concentrated under vacuum purified by silica gel column chromatography

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3.94 g of 4-bromomethyl-1-chloro-2-trifluoromethyl-benzene (14.4 mmol) and 1.06 g sodium cyanide (21.6 mmol) were suspended in 12 ml DMSO under argon and stirring and heated to 50° C. for 1 h. The reaction mixture was then poured on water/ice and extracted four times with DCM. The combined organic phases were washed with water, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 3.188 g of (4-chloro-3-trifluoromethyl-phenyl)-acetonitrile as a dark red oil, which was directly used in the next step. The reaction mixture was then poured on water/ice extracted four times with DCM The combined organic phases were washed with water dried with magnesium sulfate filtered concentrated in vacuo

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3.94 g of 4-bromomethyl-1-chloro-2-trifluoromethyl-benzene (14.4 mmol) and 1.06 g sodium cyanide (21.6 mmol) were suspended in 12 ml DMSO under argon and stirring and heated to 50° C. for 1 h. The reaction mixture was then poured on water/ice and extracted four times with DCM. The combined organic phases were washed with water, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 3.188 g of (4-chloro-3-trifluoromethyl-phenyl)-acetonitrile as a dark red oil, which was directly used in the next step. The reaction mixture was then poured on water/ice extracted four times with DCM The combined organic phases were washed with water dried with magnesium sulfate filtered concentrated in vacuo

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3.94 g of 4-bromomethyl-1-chloro-2-trifluoromethyl-benzene (14.4 mmol) and 1.06 g sodium cyanide (21.6 mmol) were suspended in 12 ml DMSO under argon and stirring and heated to 50° C. for 1 h. The reaction mixture was then poured on water/ice and extracted four times with DCM. The combined organic phases were washed with water, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 3.188 g of (4-chloro-3-trifluoromethyl-phenyl)-acetonitrile as a dark red oil, which was directly used in the next step. The reaction mixture was then poured on water/ice extracted four times with DCM The combined organic phases were washed with water dried with magnesium sulfate filtered concentrated in vacuo

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.053 g, 0.183 mmol) in DMF (1 mL) was added Cs2CO3 (0.0.071 g, 0.219 mmol) followed by 4-(bromomethyl)-1-chloro-2-(trifluoromethyl)benzene (0.050 g, 0.183 mmol). The reaction was stirred at 60° C. for 16 h. The mixture was filtered. The filtrate was concentrated under vacuum and purified by silica gel column chromatography to give the title compound as a white solid (0.048 g). LCMS m/z=480.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.49 (s, 9H), 2.21-2.34 (m, 1H), 2.50 (dd, J=15.73, 8.40 Hz, 1H), 2.73 (dd, J=15.79, 6.32 Hz, 1H), 2.81-2.93 (m, 1H), 3.64-3.77 (m, 1H), 3.94-4.05 (m, 1H), 4.06-4.17 (m, 1H), 5.10 (s, 2H), 6.84 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.40 Hz, 1H), 7.13 (d, J=8.72 Hz, 1H), 7.47-7.53 (m, 1H), 7.55-7.61 (m, 1H), 7.79 (s, 1H). The mixture was filtered The filtrate was concentrated under vacuum purified by silica gel column chromatography

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

Procedure: The title compound was prepared by Procedure B in two steps from 2-chloro-benzimidazole, 4-chloro-3-trifluoromethylbenzyl bromide and 3,4-difluorobenzylamine. The product was isolated by preparative LCMS to give the title compound as the free base (off-white solid, mp 158-161° C.). MS(ES+) m/z 452 ([M+1]+, 100). 1NMR (DMSO-d6) δ 4.55 (s, 2H), 5.36 (s, 2H), 6.87-6.98 (m, 2H), 7.13-7.37 (m, 6H), 7.50-7.55 (m, 1H), 7.68-7.71 (m, 2H). The product was isolated by preparative LCMS