1,3-dibromo-5-chlorobenzene

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

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1-chloro-3,5-dibromobenzene (Esprit) (20 g, 0.074 mole) in anhydrous ethyl ether (150 mL) in a flame dried flask under N2 and at -78° C. was added 1.6 m butyl lithium in hexane dropwise, keeping the temperature below -78° C., then warmed to -30° C. Anhydrous DMF (6.8 g, 0.092 mole) was added dropwise, keeping the temperature below -20° C. After the addition was complete, the reaction was slowly warmed to 0° C., then stirred overnight at room temperature. The reaction mixture was poured slowly into chilled 10% aqueous HCl (160 mL). After stirring for 15 minutes, the ether was separated, washed with H2O (4×), dried over MgSO4 and removed under vacuum to yield 3-bromo-5-chlorobenzaldehyde (13 g) as a white solid. MS and NMR were consistent with the desired structure. the temperature below -78° C. the temperature below -20° C After the addition the reaction was slowly warmed to 0° C. The reaction mixture was poured slowly After stirring for 15 minutes the ether was separated washed with H2O (4×) dried over MgSO4 removed under vacuum

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,3-Dibromo-5-chlorobenzene (25 g, 93 mmol), dimethyl malonate (23.4 mL, 204 mmol), and copper(I) bromide (29.2 g, 204 mmol) were combined in 1,4-dioxane (300 mL) and cooled to 0° C. Sodium hydride (60% in mineral oil; 8.2 g, 204 mmol) was added slowly, and the reaction was stirred at room temperature for 20 minutes, and then stirred at 105° C. for 4 hours. After cooling to room temperature, the mixture was worked-up with CH2Cl2 and aqueous NH4OH. The organic layer was concentrated, and the residue was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the title compound. stirred at 105° C. for 4 hours After cooling to room temperature The organic layer was concentrated the residue was purified by silica gel chromatography (0-20% EtOAc in hexanes)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,3-Dibromo-5-chlorobenzene (25 g, 93 mmol), dimethyl malonate (23.4 mL, 204 mmol), and copper(I) bromide (29.2 g, 204 mmol) were combined in 1,4-dioxane (300 mL) and cooled to 0° C. Sodium hydride (60% in mineral oil; 8.2 g, 204 mmol) was added slowly, and the reaction was stirred at room temperature for 20 minutes, and then stirred at 105° C. for 4 hours. After cooling to room temperature, the mixture was worked-up with CH2Cl2 and aqueous NH4OH. The organic layer was concentrated, and the residue was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the title compound. stirred at 105° C. for 4 hours After cooling to room temperature The organic layer was concentrated the residue was purified by silica gel chromatography (0-20% EtOAc in hexanes)

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

Procedure: 1-Chloro-3,5-dibromobenzene and benzo[b]thiophene-2-carboxaldehyde were treated in a manner similar to Reference Example 1 to give the target compound. to give the target compound

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

Procedure: 1-Chloro-3,5-dibromobenzene and benzo[b]thiophene-2-carboxaldehyde were treated in a manner similar to Reference Example 1 to give the target compound. to give the target compound

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1-chloro-3,5-dibromobenzene (Esprit) (20 g, 0.074 mole) in anhydrous ethyl ether (150 mL) in a flame dried flask under N2 and at -78° C. was added 1.6 m butyl lithium in hexane dropwise, keeping the temperature below -78° C., then warmed to -30° C. Anhydrous DMF (6.8 g, 0.092 mole) was added dropwise, keeping the temperature below -20° C. After the addition was complete, the reaction was slowly warmed to 0° C., then stirred overnight at room temperature. The reaction mixture was poured slowly into chilled 10% aqueous HCl (160 mL). After stirring for 15 minutes, the ether was separated, washed with H2O (4×), dried over MgSO4 and removed under vacuum to yield 3-bromo-5-chlorobenzaldehyde (13 g) as a white solid. MS and NMR were consistent with the desired structure. the temperature below -78° C. the temperature below -20° C After the addition the reaction was slowly warmed to 0° C. The reaction mixture was poured slowly After stirring for 15 minutes the ether was separated washed with H2O (4×) dried over MgSO4 removed under vacuum

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

Procedure: 1-Chloro-3,5-dibromobenzene and benzo[b]thiophene-2-carboxaldehyde were treated in a manner similar to Reference Example 1 to give the target compound. to give the target compound

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1,3-dibromo-5-chlorobenzene (500 mg, 1.85 mmol) in THF (1 ml) was added cyclopropylmagnesium bromide (3698 μl, 0.5M solution in THF, 1.85 mmol) in a sealed tube and the reaction mixture was degassed with argon for 5 min before tetrakis(triphenylphosphine)palladium (0) (107 mg, 0.09 mmol) was added. The resulting solution was heated to 70° C. overnight, cooled to RT and then quenched with sat. NH4Cl solution and extracted with pentane. The organic phases were combined, washed with water and brine, dried over MgSO4 and filtered through a short pad of silica gel to give the desired product (272 mg, 64%) which did not require further purification. 1H NMR (CDCl3, 300 MHz): 7.28 (aptt, J=2.0 Hz, 1H), 7.08 (aptt, J=1.5 Hz, 1H), 6.97 (aptt, J=1.5 Hz, 1H), 1.83 (m, 1H), 1.04-0.97 (m, 2H), 0.72-0.67 (m, 2H). was added cooled to RT quenched with sat. NH4Cl solution extracted with pentane washed with water and brine dried over MgSO4 filtered through a short pad of silica gel

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

Procedure: 1-Chloro-3,5-dibromobenzene and benzo[b]thiophene-2-carboxaldehyde were treated in a manner similar to Reference Example 1 to give the target compound. to give the target compound

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1,3-dibromo-5-chlorobenzene (500 mg, 1.85 mmol) in THF (1 ml) was added cyclopropylmagnesium bromide (3698 μl, 0.5M solution in THF, 1.85 mmol) in a sealed tube and the reaction mixture was degassed with argon for 5 min before tetrakis(triphenylphosphine)palladium (0) (107 mg, 0.09 mmol) was added. The resulting solution was heated to 70° C. overnight, cooled to RT and then quenched with sat. NH4Cl solution and extracted with pentane. The organic phases were combined, washed with water and brine, dried over MgSO4 and filtered through a short pad of silica gel to give the desired product (272 mg, 64%) which did not require further purification. 1H NMR (CDCl3, 300 MHz): 7.28 (aptt, J=2.0 Hz, 1H), 7.08 (aptt, J=1.5 Hz, 1H), 6.97 (aptt, J=1.5 Hz, 1H), 1.83 (m, 1H), 1.04-0.97 (m, 2H), 0.72-0.67 (m, 2H). was added cooled to RT quenched with sat. NH4Cl solution extracted with pentane washed with water and brine dried over MgSO4 filtered through a short pad of silica gel

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