4-bromo-2-fluoro-1-propan-2-yloxybenzene

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

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl-2-chloroacetoacetate (2.0 mL, 16.2 mmol) was added to a cooled 0° C. suspension of NaH (0.65 g, 16.2 mmol, 60% dispersion in mineral oil) in THF (54 mL). After 15 min the solution was cooled to −40° C. and n-BuLi (10.0 mL, 16.2 mmol, 1.6M in hexanes) was added. The resulting dianion was stirred for an additional 30 min and then treated with a solution of 1-cyclopentyl-3-(3-fluoro-4-isopropoxyphenyl)propan-1-one (1.5 g, 5.4 mmol, compound was prepared analogously to Step 1 of Example A(82), where 4-(bromo)-2-fluoro-1-isopropoxybenzene was substituted in place of 2-Bromopyridine) in THF (10 ml). After stirring for 1 h at −40° C., the reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The organic layers were washed with brine, dried with Na2SO4 and concentrated to an orange oil that was used without further purification. After stirring for 1 h at −40° C. the reaction mixture was quenched with saturated NH4Cl extracted with EtOAc The organic layers were washed with brine dried with Na2SO4 concentrated to an orange oil that was used without further purification

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

Procedure: The title compound was prepared analogously to Example C(40), where 3-chloro-6-cyclopentyl-6-[2-(3-fluoro-4-isopropoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one, where 4-bromo-2-fluoro-1-isopropoxybenzene was) was substituted in place of 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one and 7-chloro-5-(trifluoromethyl)-1H-benzimidazole-2-thiol was substituted in place of 5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

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

Procedure: The title compound was prepared analogously to Example C(40), where 3-chloro-6-cyclopentyl-6-[2-(3-fluoro-4-isopropoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one, where 4-bromo-2-fluoro-1-isopropoxybenzene was) was substituted in place of 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one and 7-chloro-5-(trifluoromethyl)-1H-benzimidazole-2-thiol was substituted in place of 5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.

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

Procedure: Following the General Procedure-3, the titled compound (25 mg) was prepared from Intermediate 8 (150 mg, 0.35 mmol) and 4-bromo-2-fluoro-1-isopropoxybenzene (81 mg, 0.35 mmol) as a white solid. M.P.: 124-128° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.81 (d, J 1.4, 1H), 7.53-7.45 (m, 2H), 7.35-7.27 (m, 2H), 7.05 (t, J 8.6, 1H), 4.58 (septet, J 6.1, 1H), 4.15 (d, J 10.4, 2H), 3.20-3.10 (m, 1H), 2.99 (t, J 11.7, 2H), 2.15 (dd, J 2.8, 13.4, 2H), 1.97-1.86 (m, 2H), 1.56 (s, 9H), 1.39 (d, J 6.1, 6H).

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

Procedure: Following the General Procedure-3, the titled compound (25 mg) was prepared from Intermediate 8 (150 mg, 0.35 mmol) and 4-bromo-2-fluoro-1-isopropoxybenzene (81 mg, 0.35 mmol) as a white solid. M.P.: 124-128° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.81 (d, J 1.4, 1H), 7.53-7.45 (m, 2H), 7.35-7.27 (m, 2H), 7.05 (t, J 8.6, 1H), 4.58 (septet, J 6.1, 1H), 4.15 (d, J 10.4, 2H), 3.20-3.10 (m, 1H), 2.99 (t, J 11.7, 2H), 2.15 (dd, J 2.8, 13.4, 2H), 1.97-1.86 (m, 2H), 1.56 (s, 9H), 1.39 (d, J 6.1, 6H).

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

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 639 mg (2.74 mmol) 1-isopropyloxy-2-fluoro-4-bromobenzene (from Step A) in 10 mL of THF at −78° C. was treated with 1.64 mL of 2.0 M n-butyllithium in heptane. After stirring at −78° C. for 30 min, the mixture was poured onto 300 g of crushed dry ice and allowed to warm up to rt. The mixture was partitioned between 100 mL of 2.0 N NaOH and 100 mL of Et2O. The aqueous layer was separated, acidified using 5.0 N HCl to pH 2, and extracted with CH2Cl2 (3×50 mL). The organic layers were combined, dried over MgSO4, and concentrated to afford 380 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.41 (d, J=6.2, 6H), 4.65-4.73 (m, 1H), 7.00 (t, J=8.5, 1H), 7.79-7.87 (m, 2H). to warm up to rt The mixture was partitioned between 100 mL of 2.0 N NaOH and 100 mL of Et2O The aqueous layer was separated extracted with CH2Cl2 (3×50 mL) dried over MgSO4 concentrated

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-bromo-2-fluorophenol (10 g, 52.35 mmol) in THF (100 ml), isopropyl alcohol (4.8 ml, 62.62 mmol) and triphenylphosphine (20.6 g, 78.52 mmol) were added and heated to 45° C. followed by diisopropylazodicarboxylate (15.4 ml, 78.52 mmol). The mixture was refluxed for 1 h, concentrated and the residue was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as a colourless liquid (13.1 g, 99%) which was used without purification in the next step. The mixture was refluxed for 1 h concentrated the residue was purified by column chromatography with ethyl acetate

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl-2-chloroacetoacetate (2.0 mL, 16.2 mmol) was added to a cooled 0° C. suspension of NaH (0.65 g, 16.2 mmol, 60% dispersion in mineral oil) in THF (54 mL). After 15 min the solution was cooled to −40° C. and n-BuLi (10.0 mL, 16.2 mmol, 1.6M in hexanes) was added. The resulting dianion was stirred for an additional 30 min and then treated with a solution of 1-cyclopentyl-3-(3-fluoro-4-isopropoxyphenyl)propan-1-one (1.5 g, 5.4 mmol, compound was prepared analogously to Step 1 of Example A(82), where 4-(bromo)-2-fluoro-1-isopropoxybenzene was substituted in place of 2-Bromopyridine) in THF (10 ml). After stirring for 1 h at −40° C., the reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The organic layers were washed with brine, dried with Na2SO4 and concentrated to an orange oil that was used without further purification. After stirring for 1 h at −40° C. the reaction mixture was quenched with saturated NH4Cl extracted with EtOAc The organic layers were washed with brine dried with Na2SO4 concentrated to an orange oil that was used without further purification

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

Procedure: The title compound was prepared analogously to Example C(40), where 3-chloro-6-cyclopentyl-6-[2-(3-fluoro-4-isopropoxyphenyl)ethyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one, where 4-bromo-2-fluoro-1-isopropoxybenzene was) was substituted in place of 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one and 7-chloro-5-(trifluoromethyl)-1H-benzimidazole-2-thiol was substituted in place of 5-chloro-1-isopropyl-1H-benzimidazole-2-thiol. 1H NMR (300 MHz, DMSO-D6) δ: 1.26 (d, J=6.03 Hz, 6H), 1.43-1.71 (m, 8H), 2.16-2.22 (m, 2H), 2.39-2.42 (m, 1H), 2.53-2.69 (m, 3H), 2.70-2.75 (m, 1H), 3.70 (s, 3H), 4.50-4.58 (m, 1H), 6.93-6.96 (m, 1H), 7.02-7.08 (m, 2H), 7.11-7.15 (m, 2H), 7.41-7.44 (m, 1H). ESI-MS calcd for C29H32Cl2N2O4S: 558.2. Found (M+H+): 559.1. Anal. Calcd. For C29H32Cl2N2O4S.1.0H2O: C, 60.35; H, 5.94; N, 4.85; S, 5.56. Found: C, 60.46; H, 5.95; N, 4.74; S, 5.52.

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl-2-chloroacetoacetate (2.0 mL, 16.2 mmol) was added to a cooled 0° C. suspension of NaH (0.65 g, 16.2 mmol, 60% dispersion in mineral oil) in THF (54 mL). After 15 min the solution was cooled to −40° C. and n-BuLi (10.0 mL, 16.2 mmol, 1.6M in hexanes) was added. The resulting dianion was stirred for an additional 30 min and then treated with a solution of 1-cyclopentyl-3-(3-fluoro-4-isopropoxyphenyl)propan-1-one (1.5 g, 5.4 mmol, compound was prepared analogously to Step 1 of Example A(82), where 4-(bromo)-2-fluoro-1-isopropoxybenzene was substituted in place of 2-Bromopyridine) in THF (10 ml). After stirring for 1 h at −40° C., the reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The organic layers were washed with brine, dried with Na2SO4 and concentrated to an orange oil that was used without further purification. After stirring for 1 h at −40° C. the reaction mixture was quenched with saturated NH4Cl extracted with EtOAc The organic layers were washed with brine dried with Na2SO4 concentrated to an orange oil that was used without further purification