4-bromo-1-fluoro-2-methylbenzene

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

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

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

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 a solution of 5-bromo-2-fluorotoluene (15 g, 0.079 mole) in CCl4 (150 mL) was added NBS (14.2 g, 0.080 mole). The resulting reaction solution was heated under reflux with the starting material being completely consumed within 2 hr. CCl4 was removed under reduced pressure and the residue was diluted dissolved in ether, washed with brine (3×), dried over MgSO4, concentrated. Chromatographed/hexane yielded 5-bromo-2-fluorobenzyl bromide. The product was immediately used for the reaction below. The resulting reaction solution was heated under reflux with the starting material being completely consumed within 2 hr CCl4 was removed under reduced pressure the residue was diluted dissolved in ether washed with brine (3×) dried over MgSO4 concentrated Chromatographed/hexane

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

Procedure: 5-Bromo-2-fluorotoluene (6 g, 31.7 mmol) was dissolved in dry THF (50 mL) and cooled to −78° C. under N2. n-BuLi (14 mL, 2.5M solution in THF) was added slowly using a dry syringe. Cloudiness appeared. The reaction was stirred for 40 minutes at −78° C. Triisopropyl borate (22 mL, 95 mmol) was slowly added while stirring. The reaction was allowed to warm to room temperature. Stirring continued for an additional 2 hours. A pale yellow, cloudy solution formed. (TLC (1:2 ethyl acetate/hexanes)) indicated disappearance of the starting material. The reaction was quenched by adding 10% aqueous NaOH (200 mL). After stirring for 45 minutes, 10% citric acid solution (300 mL) was added until, pH ˜5.0. The product was extracted with ethyl acetate (500 mL). The organic phase was washed with brine and dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide an off white solid (yield: 4.1 g, 84%). while stirring to warm to room temperature Stirring continued for an additional 2 hours A pale yellow, cloudy solution formed The reaction was quenched by adding 10% aqueous NaOH (200 mL) After stirring for 45 minutes 10% citric acid solution (300 mL) was added until, pH ˜5.0 The product was extracted with ethyl acetate (500 mL) The organic phase was washed with brine dried over MgSO4 filtered The filtrate was concentrated under reduced pressure

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

Procedure: 5-Bromo-2-fluorotoluene (7.65 g) was added to concentrated sulfuric acid (40 ml), and potassium nitrate (4.2 g) was added portionwise to the mixture at -20° C. The temperature of the reaction mixture was given back to room temperature to conduct stirring for 3 days, and then poured into ice water to conduct extraction with ethyl acetate. After an organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off to obtain the title compound (9.9 g) as a pale yellow oil. was added portionwise to the mixture at -20° C was given back to room temperature extraction with ethyl acetate After an organic layer was dried over anhydrous magnesium sulfate the solvent was distilled off

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

Procedure: In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (4-fluoro-3-methyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 299.3 [M+H]+) was prepared from 5-bromo-2-fluorotoluene instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine. In analogy to the procedure described for the synthesis example 71 (step 1)

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

Procedure: A mixture of 5-bromo-2-fluorotoluene (10.0 g), cesium carbonate (45.0 g), 2-(2-propynyloxy)tetrahydropyran (11.2 ml), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (1.51 g), bis(acetonitrile)palladium(II) dichloride (274 mg) and acetonitrile (300 ml) was stirred at 85° C. for 10 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-90:10) to give the object product (8.08 g) as a yellow oil. the mixture was extracted with ethyl acetate washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (hexane:ethyl acetate=98:2-90:10)

Conditions: temp:79.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-bromo-2-fluorotoluene (5.00 g, 26.5 mmol), N-bromosuccinimide (5.18 g, 29.1 mmol), benzyl peroxide (0.205 g, 0.850 mmol) and carbon tetrachloride (50 mL) were loaded to a r.b. flask and set to reflux (79° C.) for 2 h. Once cooled the succinimide was filtered off and carbon tetrachloride removed via a dry ice-acetone cooled rotary evaporator. The residues were dissolved in dichloromethane (100 mL) and washed with distilled H2O (50 mL×3) and brine (50 mL). Dried over MgSO4 and solvent removed in vacuo to yield the title compound as a colourless liquid yellow (6.80 g, 96%), flask and set was filtered off carbon tetrachloride removed via a dry ice-acetone cooled rotary evaporator The residues were dissolved in dichloromethane (100 mL) washed with distilled H2O (50 mL×3) and brine (50 mL) Dried over MgSO4 and solvent removed in vacuo

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

Procedure: 5-Bromo-2-fluorotoluene (6 g, 31.7 mmol) was dissolved in dry THF (50 mL) and cooled to −78 C. under N2. n-BuLi (14 mL, 2.5M solution in THF) was added slowly using a dry syringe. Cloudiness appeared. The reaction was stirred for 40 minutes at −78° C. Triisopropyl borate (22 mL, 95 mmol) was slowly added while stirring. The reaction was allowed to warm to room temperature. Stirring continued for an additional 2 hours. A pale yellow, cloudy solution formed. (TLC (1:2 ethyl acetate/hexanes)) indicated disappearance of the starting material. The reaction was quenched by adding 10% aqueous NaOH (200 mL). After stirring for 45 minutes, 10% citric acid solution (300 mL) was added until, pH ˜5.0. The product was extracted with ethyl acetate (500 mL). The organic phase was washed with brine and dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide an off white solid (yield: 4.1 g, 84%). cooled to −78 C while stirring to warm to room temperature Stirring continued for an additional 2 hours A pale yellow, cloudy solution formed The reaction was quenched by adding 10% aqueous NaOH (200 mL) After stirring for 45 minutes 10% citric acid solution (300 mL) was added until, pH ˜5.0 The product was extracted with ethyl acetate (500 mL) The organic phase was washed with brine dried over MgSO4 filtered The filtrate was concentrated under reduced pressure