1-bromo-2-ethoxybenzene

Conditions: temp:100.01; pressure:0.00; stir:

Conditions: temp:100.01; pressure:0.00; stir:

Conditions: temp:100.01; pressure:0.00; stir:

Conditions: temp:100.01; pressure:0.00; stir:

Conditions: temp:100.01; pressure:0.00; stir:

Conditions: temp:-11.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an argon atmosphere, magnesium (1.25 g, 51.5 mmol) was suspended in 100 ml of tetrahydrofuran, which was then refluxed. Under reflux, 50 ml of a tetrahydrofuran solution of bromophenetole (10 g, 50 mmol) was dropped and refluxed for 2 hours. After cooling to −11° C., a solution of trimethoxyborane (5.6 ml, 50 mmol) in 50 ml of tetrahydrofuran was dropped at −11 to −8° C. Stirring was conducted at −10° C. for 1 hour. At room temperature, palladium (II) acetate (64 mg, 0.285 mmol) and subsequently triphenylphosphine (299 mg, 1.14 mmol) were added and stirred at room temperature for 30 minutes. 5-Bromo-2-fluorobenzaldehyde (5.79 g, 28.5 mmol) and subsequently 30 ml of an aqueous solution of potassium carbonate (20.7 g, 150 mmol) were added at room temperature and heated under reflux for 5 hours. After cooling to room temperature, 170 ml of a 2N hydrochloric acid was dropped at 20 to 30° C. After phase separation had occurred, the water layer was extracted with 80 ml of toluene. The organic layers were combined and washed with two 100-ml portions of saturated brine. To the organic layer, 1.0 g of activated carbon (Shirasagi A) and tri-n-butylphosphine (0.71 ml) were added and stirred at 70° C. for 20 minutes. After filtration, the residue was washed with 50 ml of toluene and then the filtrate was concentrated under vacuum. Ten milliliters of ethanol was added and then 5 ml of water was added under reflux. After cooling, the resultant was stirred while cooling in ice. The resultant was filtered under reduced pressure and the residue was washed with 20 ml of ethanol containing 50% of water. The residue was dried under vacuum (40° C.) to yield 5.7 g (Yield 82%) of 5-(4-ethoxyphenyl)-2-fluorobenzaldehyde. which was then refluxed Under reflux refluxed for 2 hours stirred at room temperature for 30 minutes heated under reflux for 5 hours After cooling to room temperature After phase separation the water layer was extracted with 80 ml of toluene washed with two 100-ml portions of saturated brine To the organic layer, 1.0 g of activated carbon (Shirasagi A) and tri-n-butylphosphine (0.71 ml) were added stirred at 70° C. for 20 minutes After filtration the residue was washed with 50 ml of toluene the filtrate was concentrated under vacuum Ten milliliters of ethanol was added 5 ml of water was added under reflux After cooling the resultant was stirred while cooling in ice The resultant was filtered under reduced pressure the residue was washed with 20 ml of ethanol containing 50% of water The residue was dried under vacuum (40° C.)

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

Procedure: 4 g (164 mmol) of magnesium turnings and 5% of the total amount of 2-bromo-1-ethoxybenzene were put into 20 ml of ether and, after addition of a little iodine, were heated until the reaction started. 33.1 g (165 mmol) of 2-bromo-1-ethoxybenzene dissolved in 100 ml of ether were slowly added dropwise to the boiling solution in such a way that the reaction continued with gentle boiling. Then, while cooling slightly to 20° C., 15 g (54.9 mmol) of 5-iodoisatin in 400 ml of anhydrous tetrahydrofuran were added dropwise. The mixture was then stirred at room temperature for 2 h. The reaction solution was poured into an aqueous NH4Cl solution with stirring. This aqueous phase was extracted several times with ethyl acetate, and the combined aqueous phase was washed four times with water, dried and concentrated in vacuo, resulting in the product as a crystalline precipitate. 19.2 g of the product were obtained. were heated until the reaction were slowly added dropwise to the boiling solution in such a way that the reaction with stirring This aqueous phase was extracted several times with ethyl acetate the combined aqueous phase was washed four times with water dried concentrated in vacuo resulting in the product as a crystalline precipitate

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

Procedure: To 5-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-ol (Preparation 3a) (50 mg) in dimethylformamide (2 ml) at room temperature was added sodium hydride (60% dispersion in oil, 10 mg) and bromophenetole (49.5 mg). The mixture was stirred for 2 hrs. The reaction was diluted with water (10 ml) and extracted with ethyl acetate (10 ml). The organic fraction was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 g) eluted with ether to yield the title compound as a white solid (20 mg). extracted with ethyl acetate (10 ml) The organic fraction was dried over magnesium sulfate filtered concentrated under reduced pressure The residue was purified by column chromatography on silica (10 g) eluted with ether

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

Procedure: To 5-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-ol (Preparation 3a) (50 mg) in dimethylformamide (2 ml) at room temperature was added sodium hydride (60% dispersion in oil, 10 mg) and bromophenetole (49.5 mg). The mixture was stirred for 2 hrs. The reaction was diluted with water (10 ml) and extracted with ethyl acetate (10 ml). The organic fraction was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 g) eluted with ether to yield the title compound as a white solid (20 mg). extracted with ethyl acetate (10 ml) The organic fraction was dried over magnesium sulfate filtered concentrated under reduced pressure The residue was purified by column chromatography on silica (10 g) eluted with ether

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

Procedure: A mixture of 17.5 g of 2-bromophenol, 66 ml of diethyl sulphate and 170 ml of 10% NaOH solution is refluxed for 2 hours. After cooling the reaction mixture to RT, it is extracted with EtOAc, the organic phase is washed with 2N NaOH solution and dried over Na2SO4, and the solvent is evaporated off under vacuum. 19.6 g of the expected product are obtained. is refluxed for 2 hours it is extracted with EtOAc the organic phase is washed with 2N NaOH solution dried over Na2SO4 the solvent is evaporated off under vacuum

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

Procedure: Into a 250-mL 3-necked round-bottom flask, maintained with an inert atmosphere of nitrogen, was placed Mg (1.0 g, 41.67 mmol, 2.09 equiv) and I2 (10 mg). Then a solution of 1-bromo-2-ethoxybenzene (4.0 g, 19.89 mmol, 1.00 equiv) in 25 mL THF was added dropwise and the resulting mixture was heated to reflux for 0.5 hr. After the reaction was complete, the resulting mixture was cooled to 0° C. and then oxirane (50 mL) was added in one portion. The reaction mixture was stirred overnight at room temperature. The reaction was then quenched by the addition of 50 mL of NH4Cl (aq.) and extracted with 3×50 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). Purification afforded 2.14 g (65%) of 2-(2-ethoxyphenyl)ethan-1-ol as a yellow oil. Into a 250-mL 3-necked round-bottom flask, maintained with an inert atmosphere of nitrogen the resulting mixture was heated to reflux for 0.5 hr The reaction was then quenched by the addition of 50 mL of NH4Cl (aq.) extracted with 3×50 mL of ethyl acetate dried over anhydrous sodium sulfate concentrated under vacuum Purification

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

Procedure: Into a 500-mL round-bottom flask was placed CH3COCH3 (200 mL), 2-bromophenol (10.38 g, 60.00 mmol, 1.00 equiv), iodoethane (28.08 g, 180.04 mmol, 3.00 equiv) and potassium carbonate (33.12 g, 239.64 mmol, 3.99 equiv). The resulting solution was heated to reflux overnight in an oil bath. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100). Purification afforded 11.48 g (95%) of 1-bromo-2-ethoxybenzene as a colorless oil. Into a 500-mL round-bottom flask was placed The resulting solution was heated to reflux overnight in an oil bath The solids were filtered out The filtrate was concentrated under vacuum Purification