5-bromo-2-chlorophenol

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: To 1.70 g (6.5 mmol) of triphenylphosphine in 25 mL of CH2Cl2 at 0° C. was added 1.14 g (6.5 mmol) of diethylazodicarboxylate. After 10 minutes, 390 mg (6.5 mmol) of isopropanol was added, followed rapidly by 1.03 g (5.0 mmol) of 3-Bromo-6-chlorophenol. The reaction was complete within three hours, and was partitioned between ether and water. The phases were separated, and the ether phase was diluted with hexanes and washed twice with 10% aqueous methanol and once with brine. The ether/hexanes phase was dried over Na2SO4, filtered, and concentrated in vacuo to yield product as a clear oil. The reaction was complete within three hours was partitioned between ether and water The phases were separated the ether phase was diluted with hexanes washed twice with 10% aqueous methanol and once with brine The ether/hexanes phase was dried over Na2SO4 filtered concentrated in vacuo to yield product as a clear oil

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

Procedure: To 1.70 g (6.5 mmol) of triphenylphosphine in 25 mL of CH2Cl2 at 0° C. was added 1.14 g (6.5 mmol) of diethylazodicarboxylate. After 10 minutes, 390 mg (6.5 mmol) of isopropanol was added, followed rapidly by 1.03 g (5.0 mmol) of 3-Bromo-6-chlorophenol. The reaction was complete within three hours, and was partitioned between ether and water. The phases were separated, and the ether phase was diluted with hexanes and washed twice with 10% aqueous methanol and once with brine. The ether/hexanes phase was dried over Na2SO4, filtered, and concentrated in vacuo to yield product as a clear oil. The reaction was complete within three hours was partitioned between ether and water The phases were separated the ether phase was diluted with hexanes washed twice with 10% aqueous methanol and once with brine The ether/hexanes phase was dried over Na2SO4 filtered concentrated in vacuo to yield product as a clear oil

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

Procedure: To 50 mL of a 1M solution of boron tribromide in CH2Cl2 at 0° C. was added 5.71 g (25.8 mmol) of 5-Bromo-2-chloroanisole. After 2 hours, the reaction was allowed to warm to room temperature. After 5 hours, the solution was cooled to 0° C., and quenched with methanol. The resulting solution was partitioned between water and ethyl acetate, and the phases were separated. The aqueous phase was back-extracted once with ethyl acetate. The combined ethyl acetate phases were diluted with one volume of ether, and were extracted twice with 1M NaOH. The combined basic aqueous phases were acidified with 12M HCl, and were extracted once with ethyl acetate. The final ethyl acetate phase was washed once with brine, dried over MgSO4, filtered, and concentrated to give the phenol as a tan solid. 1H NMR (DMSO-d6, 400 MHz) 10.66 (s, 1H), 7.27 (d, 1H), 7.08 (s, 1H), 6.95 (d, 1H) ppm. After 5 hours the solution was cooled to 0° C. quenched with methanol The resulting solution was partitioned between water and ethyl acetate the phases were separated The aqueous phase was back-extracted once with ethyl acetate The combined ethyl acetate phases were diluted with one volume of ether were extracted twice with 1M NaOH were extracted once with ethyl acetate The final ethyl acetate phase was washed once with brine dried over MgSO4 filtered concentrated

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-bromo-2-chlorophenol (543 mg, 2.62 mmol), bromocyclopropane (836 μl, 10.47 mmol) and caesium carbonate (1.701 g, 5.24 mmol) in N,N-dimethylacetamide (7.5 ml) was stirred for 47 h at 150° C. After 25.25 h further bromocyclopropane (836 μl, 10.47 mmol) was added. The reaction mixture was poured onto ice-water (40 ml) and set to pH=2 with aqueous HCl (1 N, 9.5 ml). This mixture was extracted with TBME (twice 50 ml). The organic layers were washed with brine (40 ml), combined and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 67:33) afforded the title compound (570 mg, 87%) as a light yellow oil. MS m/e: 248.0 [M+H]+ The reaction mixture was poured onto ice-water (40 ml) This mixture was extracted with TBME (twice 50 ml) The organic layers were washed with brine (40 ml) dried over sodium sulfate Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 67:33)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-Bromo-2-chlorophenol (500 mg, 2410 μmol) and (2-chloroethyl)(methyl)sulfane (262 μl, 2651 μmol) were combined with cesium carbonate (942 mg, 2892 μmol) in DMF and heated to 100° C. for 2 h. The mixture was then filtered and purified using reverse phase chromatography. This purified material was carried forward to the next step. The mixture was then filtered purified

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-Bromo-2-chlorophenol (500 mg, 2410 μmol) and (2-chloroethyl)(methyl)sulfane (262 μl, 2651 μmol) were combined with cesium carbonate (942 mg, 2892 μmol) in DMF and heated to 100° C. for 2 h. The mixture was then filtered and purified using reverse phase chromatography. This purified material was carried forward to the next step. The mixture was then filtered purified

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

Procedure: To a solution of ethyl {5-[2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl]-2H-tetrazol-2-yl}acetate (44 mg, 0.132 mmol), 5-bromo-2-chlorophenol (32.9 mg, 0.158 mmol) and triphenylphosphine (45 mg, 0.172 mmol) in THF (660 μL) was added diethyl azodicarboxylate (27.2 μL, 0.172 mmol). The mixture was heated at 50° C. for 4 h. The solvent was evaporated and the crude product was purified by Combiflash chromatography (SiO2-12 g, gradient elution of 10-50% EtOAc/hexanes over 30 min) to afford the title product as a solid. MS: m/z 422, 424 (MH+). The solvent was evaporated the crude product was purified by Combiflash chromatography (SiO2-12 g, gradient elution of 10-50% EtOAc/hexanes over 30 min)

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

Procedure: The title compound was prepared in a similar manner as described for Intermediate 1 from tert-butyl 4-hydroxypiperidine-1-carboxylate and 5-bromo-2-chlorophenol.

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-Bromo-2-chlorophenol (500 mg, 2410 μmol) and (2-chloroethyl)(methyl)sulfane (262 μl, 2651 μmol) were combined with cesium carbonate (942 mg, 2892 μmol) in DMF and heated to 100° C. for 2 h. The mixture was then filtered and purified using reverse phase chromatography. This purified material was carried forward to the next step. The mixture was then filtered purified

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-Bromo-2-chlorophenol (500 mg, 2410 μmol) and (2-chloroethyl)(methyl)sulfane (262 μl, 2651 μmol) were combined with cesium carbonate (942 mg, 2892 μmol) in DMF and heated to 100° C. for 2 h. The mixture was then filtered and purified using reverse phase chromatography. This purified material was carried forward to the next step. The mixture was then filtered purified