5-bromo-2-ethylbenzaldehyde

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

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

Procedure: A suspension of 5-bromo-2-ethylbenzaldehyde (1.0 g, 4.7 mmol), 2,4-dichlorophenyl boronic acid (1.34 g, 7.0 mmol) and sodium carbonate (0.99 g, 7.98 mmol) in a mixed solvent system of 1,2-dimethoxyethane (12 ml) and distilled water (4 ml) is stirred under a nitrogen atmosphere, then flushed with nitrogen (×2). [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II)chloride (1.15 g, 1.41 mmol) is then added in one portion and the suspension is again flushed with nitrogen, then heated at reflux overnight. After cooling to room temperature the reaction mixture is diluted with distilled water (10 ml) and extracted with dichloromethane (10 ml). The aqueous phase is extracted again with dichloromethane (×2), and the combined organic fractions are finally washed with brine then dried over magnesium sulfate. The crude product is purified by flash column chromatography (isohexane to 75:25 isohexane/ethyl acetate ratio eluant) to afford 2′,4′-dichloro-4-ethylbiphenyl-3-carbaldehyde as a yellow oil. distilled water (4 ml) flushed with nitrogen (×2) the suspension is again flushed with nitrogen heated at reflux overnight is diluted with distilled water (10 ml) extracted with dichloromethane (10 ml) The aqueous phase is extracted again with dichloromethane (×2) the combined organic fractions are finally washed with brine then dried over magnesium sulfate The crude product is purified by flash column chromatography (isohexane to 75:25 isohexane/ethyl acetate ratio eluant)

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

Procedure: To an ice-cold solution of dihydro-2,2,5,5-tetramethyl-3(2H)-furanone (13.4 g, 94.34 mmol) in anhydrous 1,2-dimethoxyethane (32 ml) is added sodium methoxide (5.6 g, 103.8 mmol) in one portion, and the reaction mixture is stirred at this temperature for 5 minutes. To the resulting slurry is then added a solution of 5-bromo-2-ethyl-benzaldehyde (20 g, 94.34 mmol) in 1,2-dimethoxyethane (32 ml) dropwise over 10 minutes. The solution is next stirred at 0° C. for 1 hour, then diluted with diethyl ether and washed with 2M hydrochloric acid (×2). Organic fractions are combined, dried over magnesium sulphate, filtered and the filtrate evaporated in vacuo to afford 4-(5-bromo-2-ethylbenzylidene)-2,2,5,5-tetramethyldihydrofuran-3-one (30.2 g) as a yellow liquid. next stirred at 0° C. for 1 hour washed with 2M hydrochloric acid (×2) dried over magnesium sulphate filtered the filtrate evaporated in vacuo

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-bromo-1-ethyl-2-iodobenzene (31.8 g, 103 mmol) (described in WO 2008/071405) in anhydrous tetrahydrofuran (250 ml) at −20° C. is added isopropyl magnesium chloride (55 ml, 110 mmol, 2M solution in tetrahydrofuran) dropwise over 10 minutes. Once the addition is complete the reaction mixture is stirred at −20° C. for 3 hours, followed by dropwise addition of anhydrous N,N-dimethylformamide (16.0 ml, 200 mmol). The reaction mixture is stirred at room temperature for a further 2.5 hours, then left to stand overnight. 2M hydrochloric acid (90 ml) is added and the crude product is extracted into dichloromethane. Organics are combined, dried over magnesium sulfate then filtered and the filtrate evaporated under reduced pressure to afford 5-bromo-2-ethyl-benzaldehyde (21.20 g) as an orange liquid. Once the addition The reaction mixture is stirred at room temperature for a further 2.5 hours left to stand overnight the crude product is extracted into dichloromethane dried over magnesium sulfate then filtered the filtrate evaporated under reduced pressure

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-bromo-1-ethyl-2-iodobenzene (31.8 g, 103 mmol) (described in WO 2008/071405) in anhydrous tetrahydrofuran (250 ml) at −20° C. is added isopropyl magnesium chloride (55 ml, 110 mmol, 2M solution in tetrahydrofuran) dropwise over 10 minutes. Once the addition is complete the reaction mixture is stirred at −20° C. for 3 hours, followed by dropwise addition of anhydrous N,N-dimethylformamide (16.0 ml, 200 mmol). The reaction mixture is stirred at room temperature for a further 2.5 hours, then left to stand overnight. 2M hydrochloric acid (90 ml) is added and the crude product is extracted into dichloromethane. Organics are combined, dried over magnesium sulfate then filtered and the filtrate evaporated under reduced pressure to afford 5-bromo-2-ethyl-benzaldehyde (21.20 g) as an orange liquid. Once the addition The reaction mixture is stirred at room temperature for a further 2.5 hours left to stand overnight the crude product is extracted into dichloromethane dried over magnesium sulfate then filtered the filtrate evaporated under reduced pressure

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

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 4-amino-benzoic acid methyl ester (1 g, 6 mmol) and 5-bromo-2-ethyl-benzaldehyde (1.2 g, 5.6 mmol) in acetonitrile (40 mL) were added isobutene (1.7 mL, 24 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (0.55 g, 0.9 mmol). The resulting mixture was stirred at 85° C. for 16 h in sealed tube. The mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL×2) and brine (50 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2-(5-bromo-2-ethyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (1.5 g, 64%) as a light yellow solid: MS (ESI) M+1=416.0. washed with water (50 mL×2) and brine (50 mL×2) dried over anhydrous sodium sulfate The solvent was removed in vacuo the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether)

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

Procedure: Pyridine-4-boronic acid (75 mg, 0.52 mmol) is coupled to aryl bromide 235 (111 mg, 0.52 mmol) using Method A to give the title compound.

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

Procedure: A stirred suspension of 2-ethylbenzaldehyde (0.98 mL, 7.45 mmol) and AlCl3 (1.74 g, 13 mmol) in DCM (4.5 mL) at 0° C. is treated with a solution of Br2 (0.38 mL, 7.45 mmol) in DCM (4.5 mL) dropwise over 6 h then stirred 16 h at RT. After this time, the reaction mixture is poured over ice-water (50 mL), the layers separated and the aqueous layer extracted with DCM (3×50 mL). The organic phases are combined and washed with 2M HCl (100 mL), aqueous NaHCO3 (100 mL) and brine (100 mL), dried over Na2SO4 then the solvents removed in vacuo. Purification by column chromatography (gradient elution—100% heptane increasing to 10% EtOAc in heptane) gives the title compound. the layers separated the aqueous layer extracted with DCM (3×50 mL) washed with 2M HCl (100 mL), aqueous NaHCO3 (100 mL) and brine (100 mL) dried over Na2SO4 the solvents removed in vacuo Purification by column chromatography (gradient elution—100% heptane increasing to 10% EtOAc in heptane)

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

Procedure: A stirred suspension of 2-ethylbenzaldehyde (0.98 mL, 7.45 mmol) and AlCl3 (1.74 g, 13 mmol) in DCM (4.5 mL) at 0° C. is treated with a solution of Br2 (0.38 mL, 7.45 mmol) in DCM (4.5 mL) dropwise over 6 h then stirred 16 h at RT. After this time, the reaction mixture is poured over ice-water (50 mL), the layers separated and the aqueous layer extracted with DCM (3×50 mL). The organic phases are combined and washed with 2M HCl (100 mL), aqueous NaHCO3 (100 mL) and brine (100 mL), dried over Na2SO4 then the solvents removed in vacuo. Purification by column chromatography (gradient elution—100% heptane increasing to 10% EtOAc in heptane) gives the title compound. the layers separated the aqueous layer extracted with DCM (3×50 mL) washed with 2M HCl (100 mL), aqueous NaHCO3 (100 mL) and brine (100 mL) dried over Na2SO4 the solvents removed in vacuo Purification by column chromatography (gradient elution—100% heptane increasing to 10% EtOAc in heptane)

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

Procedure: To a solution of 2-ethyl-benzaldehyde (5.00 g, 37.3 mmol) in CH2Cl2 (23 mL) was carefully added AlCl3 (8.70 g, 65.2 mmol). The mixture was cooled to 0° C. and a solution of bromine (1.9 mL, 37.2 mmol) in CH2Cl2 (23 mL) was added over 6 hours. The reaction mixture was stirred at room temperature overnight. The mixture was poured onto an ice/water mixture and stirred for 10 minutes. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with 2 M HCl, saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (heptane/EtOAc) to afford INT 35. stirred for 10 minutes The aqueous layer was extracted with EtOAc (2×) The combined organic layers were washed with 2 M HCl, saturated aqueous NaHCO3 and brine dried over MgSO4 filtered concentrated The residue was purified by chromatography on silica gel (heptane/EtOAc) to afford INT 35

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

Procedure: A suspension of 5-bromo-2-ethylbenzaldehyde (1.0 g, 4.7 mmol), 2,4-dichlorophenyl boronic acid (1.34 g, 7.0 mmol) and sodium carbonate (0.99 g, 7.98 mmol) in a mixed solvent system of 1,2-dimethoxyethane (12 ml) and distilled water (4 ml) is stirred under a nitrogen atmosphere, then flushed with nitrogen (×2). [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II)chloride (1.15 g, 1.41 mmol) is then added in one portion and the suspension is again flushed with nitrogen, then heated at reflux overnight. After cooling to room temperature the reaction mixture is diluted with distilled water (10 ml) and extracted with dichloromethane (10 ml). The aqueous phase is extracted again with dichloromethane (×2), and the combined organic fractions are finally washed with brine then dried over magnesium sulfate. The crude product is purified by flash column chromatography (isohexane to 75:25 isohexane/ethyl acetate ratio eluant) to afford 2′,4′-dichloro-4-ethylbiphenyl-3-carbaldehyde as a yellow oil. distilled water (4 ml) flushed with nitrogen (×2) the suspension is again flushed with nitrogen heated at reflux overnight is diluted with distilled water (10 ml) extracted with dichloromethane (10 ml) The aqueous phase is extracted again with dichloromethane (×2) the combined organic fractions are finally washed with brine then dried over magnesium sulfate The crude product is purified by flash column chromatography (isohexane to 75:25 isohexane/ethyl acetate ratio eluant)