4-(chloromethyl)-1-propan-2-yloxy-2-(trifluoromethyl)benzene

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

Procedure: Ethyl 2-(2-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (0.107 g, 0.391 mmol) was dissolved in anhydrous DMF (3.91 mL, 0.391 mmol). Cesium carbonate (0.166 g, 0.509 mmol) was added followed by 4-(chloromethyl)-1-isopropoxy-2-(trifluoromethyl)benzene (0.122 mL, 0.587 mmol) to give a suspension. The reaction was heated at 50° C. for 5 h. The solvent was evaporated in vacuo to give a residue which was dissolved in EtOAc (50 mL) and water (20 mL). The organic layer was washed with water (20 mL), brine (20 mL), and dried over MgSO4. The solvent was evaporated in vacuo to give an oil which was purified by silica gel column chromatography to give the title compound as an oil (0.154 g). LCMS m/z=490.4 [M+H]+; 1H NMR (400 MHz, Acetonitrile-d3) α ppm 1.24 (t, J=7.14 Hz, 3H), 1.32 (d, J=6.06 Hz, 6H), 1.50-1.64 (m, 1H), 2.1 (m, 3H), 2.55 (dd, J=15.73, 8.02 Hz, 1H), 2.86 (dd, J=15.66, 5.94 Hz, 1H), 3.33-3.47 (m, 1H), 3.79-3.88 (m, 1H), 4.06-4.21 (m, 3H), 4.74 (dt, J=12.09, 6.02 Hz, 1H), 5.04 (s, 2H), 6.13 (s, 1H), 6.81 (dd, J=8.78, 2.46 Hz, 1H), 7.04 (d, J=2.40 Hz, 1H), 7.16 (d, J=8.59 Hz, 1H), 7.19 (d, J=8.84 Hz, 1H), 7.62 (d, J=8.59 Hz, 1H), 7.66 (d, J=1.89 Hz, 1H). to give a suspension The solvent was evaporated in vacuo to give a residue which The organic layer was washed with water (20 mL), brine (20 mL) dried over MgSO4 The solvent was evaporated in vacuo to give an oil which was purified by silica gel column chromatography

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

Procedure: To a mixture of tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (1.86 mmol) and cesium carbonate (2.8 mmol) in DMA (7.45 mL) was added 4-(chloromethyl)-1-isopropoxy-2-(trifluoromethyl)benzene (1.96 mmol). The reaction was stirred at 80° C. for 16 h. The mixture was filtered through Celite®. The solvent was removed under vacuum. The residue was purified by silica gel column chromatography to give the title compound as a solid. LCMS m/z=504.2 [M+H]+; 1H NMR (400 MHz, DMSO-db) δ ppm 1.28 (d, J=5.94 Hz, 6H), 1.44 (s, 9H), 2.14-2.25 (m, 1H), 2.51-2.58 (m, 1H), 2.59-2.67 (m, 1H), 2.71-2.81 (m, 1H), 3.57 (m, 1H), 3.91-3.99 (m, 1H), 4.06-4.13 (m, 1H), 4.72-4.83 (m, 1H), 5.05 (s, 2H), 5.99 (s, 1H), 6.75 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.40 Hz, 1H), 7.18 (d, J=8.72 Hz, 1H), 7.28 (d, J=9.22 Hz, 1H), 7.62-7.68 (m, 2H). The mixture was filtered through Celite® The solvent was removed under vacuum The residue was purified by silica gel column chromatography

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (4-isopropoxy-3-(trifluoromethyl)phenyl)methanol (11.27 mmol) in toluene (20 mL) was added thionyl chloride (67.7 mmol). The reaction was stirred at 75° C. for 3 h. The mixture was diluted with hexanes, washed with water (twice), saturated NaHCO3, dried over MgSO4, and filtered. The solvent was removed under vacuum to give the title compound as an oil (10.4 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (d, J=6.06 Hz, 6H), 4.75-4.85 (m, 3H), 7.30 (d, J=8.46 Hz, 1H), 7.63-7.70 (m, 2H). washed with water (twice), saturated NaHCO3 dried over MgSO4 filtered The solvent was removed under vacuum

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (4-isopropoxy-3-(trifluoromethyl)phenyl)methanol (11.27 mmol) in toluene (20 mL) was added thionyl chloride (67.7 mmol). The reaction was stirred at 75° C. for 3 h. The mixture was diluted with hexanes, washed with water (twice), saturated NaHCO3, dried over MgSO4, and filtered. The solvent was removed under vacuum to give the title compound as an oil (10.4 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (d, J=6.06 Hz, 6H), 4.75-4.85 (m, 3H), 7.30 (d, J=8.46 Hz, 1H), 7.63-7.70 (m, 2H). washed with water (twice), saturated NaHCO3 dried over MgSO4 filtered The solvent was removed under vacuum

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

Procedure: Ethyl 2-(2-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (0.107 g, 0.391 mmol) was dissolved in anhydrous DMF (3.91 mL, 0.391 mmol). Cesium carbonate (0.166 g, 0.509 mmol) was added followed by 4-(chloromethyl)-1-isopropoxy-2-(trifluoromethyl)benzene (0.122 mL, 0.587 mmol) to give a suspension. The reaction was heated at 50° C. for 5 h. The solvent was evaporated in vacuo to give a residue which was dissolved in EtOAc (50 mL) and water (20 mL). The organic layer was washed with water (20 mL), brine (20 mL), and dried over MgSO4. The solvent was evaporated in vacuo to give an oil which was purified by silica gel column chromatography to give the title compound as an oil (0.154 g). LCMS m/z=490.4 [M+H]+; 1H NMR (400 MHz, Acetonitrile-d3) δ ppm 1.24 (t, J=7.14 Hz, 3H), 1.32 (d, J=6.06 Hz, 6H), 1.50-1.64 (m, 1H), 2.1 (m, 3H), 2.55 (dd, J=15.73, 8.02 Hz, 1H), 2.86 (dd, J=15.66, 5.94 Hz, 1H), 3.33-3.47 (m, 1H), 3.79-3.88 (m, 1H), 4.06-4.21 (m, 3H), 4.74 (dt, J=12.09, 6.02 Hz, 1H), 5.04 (s, 2H), 6.13 (s, 1H), 6.81 (dd, J=8.78, 2.46 Hz, 1H), 7.04 (d, J=2.40 Hz, 1H), 7.16 (d, J=8.59 Hz, 1H), 7.19 (d, J=8.84 Hz, 1H), 7.62 (d, J=8.59 Hz, 1H), 7.66 (d, J=1.89 Hz, 1H). to give a suspension The solvent was evaporated in vacuo to give a residue which The organic layer was washed with water (20 mL), brine (20 mL) dried over MgSO4 The solvent was evaporated in vacuo to give an oil which was purified by silica gel column chromatography

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

Procedure: To a mixture of tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (1.86 mmol) and cesium carbonate (2.8 mmol) in DMA (7.45 mL) was added 4-(chloromethyl)-1-isopropoxy-2-(trifluoromethyl)benzene (1.96 mmol). The reaction was stirred at 80° C. for 16 h. The mixture was filtered through Celite®. The solvent was removed under vacuum. The residue was purified by silica gel column chromatography to give the title compound as a solid. LCMS m/z=504.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (d, J=5.94 Hz, 6H), 1.44 (s, 9H), 2.14-2.25 (m, 1H), 2.51-2.58 (m, 1H), 2.59-2.67 (m, 1H), 2.71-2.81 (m, 1H), 3.57 (m, 1H), 3.91-3.99 (m, 1H), 4.06-4.13 (m, 1H), 4.72-4.83 (m, 1H), 5.05 (s, 2H), 5.99 (s, 1H), 6.75 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.40 Hz, 1H), 7.18 (d, J=8.72 Hz, 1H), 7.28 (d, J=9.22 Hz, 1H), 7.62-7.68 (m, 2H). The mixture was filtered through Celite® The solvent was removed under vacuum The residue was purified by silica gel column chromatography

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (4-isopropoxy-3-(trifluoromethyl)phenyl)methanol (11.27 mmol) in toluene (20 mL) was added thionyl chloride (67.7 mmol). The reaction was stirred at 75° C. for 3 h. The mixture was diluted with hexanes, washed with water (twice), saturated NaHCO3, dried over MgSO4, and filtered. The solvent was removed under vacuum to give the title compound as an oil (10.4 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (d, J=6.06 Hz, 6H), 4.75-4.85 (m, 3H), 7.30 (d, J=8.46 Hz, 1H), 7.63-7.70 (m, 2H). washed with water (twice), saturated NaHCO3 dried over MgSO4 filtered The solvent was removed under vacuum

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

Procedure: To a solution of (4-isopropoxy-3-(trifluoromethyl)phenyl)methanol (181 g, 773 mmol) in toluene (1 L) was added SOCl2 (338 mL, 4637 mmol) (slight exotherm to 35° C. after addition of SOCl2) and was stirred overnight in a 2-L round bottomed flask. The reaction mixture was concentrated in vacuo and diluted with hexanes (1 L). The solution was washed with sat. NaHCO3 (2×750 mL), dried over MgSO4, and filtered. The solvents were removed under reduced pressure to give 4-(chloromethyl)-1-isopropoxy-2-(trifluoromethyl)benzene (194 g, 768 mmol, 99% yield) as an orange oil. Optionally the product can be further purified by distillation (bp=85° C. at 0.1 mTorr) to obtain a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.37 (d, J=6.1 Hz, 6 H), 4.56 (s, 2H) 4.65 (sep, J=6.1 Hz, 1 H), 6.98 (d, J=8.6 Hz, 1 H), 7.48 (dd, J1=8.6, J2=2.3 Hz, 1 H), 7.57 (d, J=2.2 Hz, 1 H). The reaction mixture was concentrated in vacuo diluted with hexanes (1 L) The solution was washed with sat. NaHCO3 (2×750 mL) dried over MgSO4 filtered The solvents were removed under reduced pressure

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

Procedure: Ethyl 2-(2-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (0.107 g, 0.391 mmol) was dissolved in anhydrous DMF (3.91 mL, 0.391 mmol). Cesium carbonate (0.166 g, 0.509 mmol) was added followed by 4-(chloromethyl)-1-isopropoxy-2-(trifluoromethyl)benzene (0.122 mL, 0.587 mmol) to give a suspension. The reaction was heated at 50° C. for 5 h. The solvent was evaporated in vacuo to give a residue which was dissolved in EtOAc (50 mL) and water (20 mL). The organic layer was washed with water (20 mL), brine (20 mL), and dried over MgSO4. The solvent was evaporated in vacuo to give an oil which was purified by silica gel column chromatography to give the title compound as an oil (0.154 g). LCMS m/z=490.4 [M+H]+; 1H NMR (400 MHz, Acetonitrile-d3) α ppm 1.24 (t, J=7.14 Hz, 3H), 1.32 (d, J=6.06 Hz, 6H), 1.50-1.64 (m, 1H), 2.1 (m, 3H), 2.55 (dd, J=15.73, 8.02 Hz, 1H), 2.86 (dd, J=15.66, 5.94 Hz, 1H), 3.33-3.47 (m, 1H), 3.79-3.88 (m, 1H), 4.06-4.21 (m, 3H), 4.74 (dt, J=12.09, 6.02 Hz, 1H), 5.04 (s, 2H), 6.13 (s, 1H), 6.81 (dd, J=8.78, 2.46 Hz, 1H), 7.04 (d, J=2.40 Hz, 1H), 7.16 (d, J=8.59 Hz, 1H), 7.19 (d, J=8.84 Hz, 1H), 7.62 (d, J=8.59 Hz, 1H), 7.66 (d, J=1.89 Hz, 1H). to give a suspension The solvent was evaporated in vacuo to give a residue which The organic layer was washed with water (20 mL), brine (20 mL) dried over MgSO4 The solvent was evaporated in vacuo to give an oil which was purified by silica gel column chromatography

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

Procedure: To a mixture of tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (1.86 mmol) and cesium carbonate (2.8 mmol) in DMA (7.45 mL) was added 4-(chloromethyl)-1-isopropoxy-2-(trifluoromethyl)benzene (1.96 mmol). The reaction was stirred at 80° C. for 16 h. The mixture was filtered through Celite®. The solvent was removed under vacuum. The residue was purified by silica gel column chromatography to give the title compound as a solid. LCMS m/z=504.2 [M+H]+; 1H NMR (400 MHz, DMSO-db) δ ppm 1.28 (d, J=5.94 Hz, 6H), 1.44 (s, 9H), 2.14-2.25 (m, 1H), 2.51-2.58 (m, 1H), 2.59-2.67 (m, 1H), 2.71-2.81 (m, 1H), 3.57 (m, 1H), 3.91-3.99 (m, 1H), 4.06-4.13 (m, 1H), 4.72-4.83 (m, 1H), 5.05 (s, 2H), 5.99 (s, 1H), 6.75 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.40 Hz, 1H), 7.18 (d, J=8.72 Hz, 1H), 7.28 (d, J=9.22 Hz, 1H), 7.62-7.68 (m, 2H). The mixture was filtered through Celite® The solvent was removed under vacuum The residue was purified by silica gel column chromatography

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (4-isopropoxy-3-(trifluoromethyl)phenyl)methanol (11.27 mmol) in toluene (20 mL) was added thionyl chloride (67.7 mmol). The reaction was stirred at 75° C. for 3 h. The mixture was diluted with hexanes, washed with water (twice), saturated NaHCO3, dried over MgSO4, and filtered. The solvent was removed under vacuum to give the title compound as an oil (10.4 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (d, J=6.06 Hz, 6H), 4.75-4.85 (m, 3H), 7.30 (d, J=8.46 Hz, 1H), 7.63-7.70 (m, 2H). washed with water (twice), saturated NaHCO3 dried over MgSO4 filtered The solvent was removed under vacuum