4-fluoro-2-methylbenzaldehyde

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

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

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 100.89 g of aluminum chloride (mol. Wt. 133.34; 756.6 mmol) and about 503.54 g of 3-fluorotoluene (mol. Wt. 110.13; 4,572 mmol) were charged to a 2 liter Parry -brand 4522 stainless steel reaction vessel. To this mixture was added 5 drops of concentrated HCl. The vessel was sealed, heated to 60° C., and purged three times with carbon monoxide with the pressure of the vessel increased to 200 psi for each purging. After the third purge, the vessel was vented and a final introduction of CO was made at a pressure of about 200 psi, the pressure at which the reaction was maintained for the total reaction time of about 17 hours (the reaction temperature was maintained at 60° C. for the duration as well). Once the reaction was complete, the resultant mixture (exhibiting a dark orange color) was poured into about 500 mL of ice water (which turned the solution a yellow color), to which was added 500 mL of cyclohexane. The top, organic layer was removed and washed three times with water using a separatory funnel and dried over magnesium sulfate. The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 3-fluorotoluene, and left about 79.65 g of a benzaldehyde mixture consisting of 4-fluoro-2-methylbenzaldehyde (88.4%) and 2-fluoro-4-methylbenzaldehyde (11.6%) (mol. Wt. 138.14; 576.6 mmol; yield of approximately 76.2%). The vessel was sealed purged three times with carbon monoxide with the pressure of the vessel increased to 200 psi for each purging After the third purge the pressure at which the reaction was maintained for the total reaction time of about 17 hours (the reaction temperature was maintained at 60° C. for the duration as well) was poured into about 500 mL of ice water (which was added 500 mL of cyclohexane The top, organic layer was removed washed three times with water using a separatory funnel dried over magnesium sulfate The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 3-fluorotoluene left about 79.65 g of a benzaldehyde mixture

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 100.89 g of aluminum chloride (mol. Wt. 133.34; 756.6 mmol) and about 503.54 g of 3-fluorotoluene (mol. Wt. 110.13; 4,572 mmol) were charged to a 2 liter Parr®-brand 4522 stainless steel reaction vessel. To this mixture was added 5 drops of concentrated HCl. The vessel was sealed, heated to 60° C., and purged three times with carbon monoxide with the pressure of the vessel increased to 200 psi for each purging. After the third purge, the vessel was vented and a final introduction of CO was made at a pressure of about 200 psi, the pressure at which the reaction was maintained for the total reaction time of about 17 hours (the reaction temperature was maintained at 60° C. for the duration as well). Once the reaction was complete, the resultant mixture (exhibiting a dark orange color) was poured into about 500 mL of ice water (which turned the solution a yellow color), to which was added 500 mL of cyclohexane. The top, organic layer was removed and washed three times with water using a separatory funnel and dried over magnesium sulfate. The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 3-fluorotoluene, and left about 79.65 g of a benzaldehyde mixture consisting of 4-fluoro-2-methylbenzaldehyde (88.4%) and 2-fluoro-4-methylbenzaldehyde (11.6%) (mol. Wt. 138.14; 576.6 mmol; yield of approximately 76.2%). The vessel was sealed purged three times with carbon monoxide with the pressure of the vessel increased to 200 psi for each purging After the third purge the pressure at which the reaction was maintained for the total reaction time of about 17 hours (the reaction temperature was maintained at 60° C. for the duration as well) was poured into about 500 mL of ice water (which was added 500 mL of cyclohexane The top, organic layer was removed washed three times with water using a separatory funnel dried over magnesium sulfate The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 3-fluorotoluene left about 79.65 g of a benzaldehyde mixture

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

Procedure: Dissolved 5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carbonitrile (58 mg) in 4 mL ethanol and added 0.250 mmol of 4-fluoro-2-methylbenzaldehyde followed by a single drop of piperidine. This solution was then heated to 85° C. for 17 hrs, then the ethanol was evaporated and the resulting product was scraped from the reaction vessels. The powder was then resuspended in 4 mL of MeOH and 3 eq. of sodium borohydride was added and left stirring overnight at room temperature. Then MeOH was then evaporated and the product C29 was scraped and collected. (50 mg) the ethanol was evaporated the resulting product was scraped from the reaction vessels left Then MeOH was then evaporated collected

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

Procedure: A stirred solution of 4-fluoro-2-methyl-benzaldehyde (20 g, 144.9 mmol) and malonic acid (30.1 g, 289.8 mmol) in pyridine (100 mL) was heated to 50° C. Piperidine (10 mL) was added and the reaction mixture was heated at 70° C. for 18 h. The reaction mixture was cooled RT and poured into chilled aqueous 1N HCl solution (1500 mL), the resulting precipitate was filtered and washed with petroleum ether 60-80 and dried in vacuo to obtain (E)-3-(4-fluoro-2-methylphenyl)acrylic acid (18 g, 69%) as an off white solid. The reaction mixture was cooled RT poured the resulting precipitate was filtered washed with petroleum ether 60-80 dried in vacuo

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

Procedure: A stirred solution of 4-fluoro-2-methyl-benzaldehyde (20 g, 144.9 mmol) and malonic acid (30.1 g, 289.8 mmol) in pyridine (100 mL) was heated to 50° C. Piperidine (10 mL) was added and the reaction mixture was heated at 70° C. for 18 h. The reaction mixture was cooled RT and poured into chilled aqueous 1N HCl solution (1500 mL), the resulting precipitate was filtered and washed with petroleum ether 60-80 and dried in vacuo to obtain (E)-3-(4-fluoro-2-methylphenyl)acrylic acid (18 g, 69%) as an off white solid. The reaction mixture was cooled RT poured the resulting precipitate was filtered washed with petroleum ether 60-80 dried in vacuo

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

Procedure: Dissolved 5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carbonitrile (58 mg) in 4 mL ethanol and added 0.250 mmol of 4-fluoro-2-methylbenzaldehyde followed by a single drop of piperidine. This solution was then heated to 85° C. for 17 hrs, then the ethanol was evaporated and the resulting product was scraped from the reaction vessels. The powder was then resuspended in 4 mL of MeOH and 3 eq. of sodium borohydride was added and left stirring overnight at room temperature. Then MeOH was then evaporated and the product C29 was scraped and collected. (50 mg) the ethanol was evaporated the resulting product was scraped from the reaction vessels left Then MeOH was then evaporated collected

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 100.89 g of aluminum chloride (mol. Wt. 133.34; 756.6 mmol) and about 503.54 g of 3-fluorotoluene (mol. Wt. 110.13; 4,572 mmol) were charged to a 2 liter Parry -brand 4522 stainless steel reaction vessel. To this mixture was added 5 drops of concentrated HCl. The vessel was sealed, heated to 60° C., and purged three times with carbon monoxide with the pressure of the vessel increased to 200 psi for each purging. After the third purge, the vessel was vented and a final introduction of CO was made at a pressure of about 200 psi, the pressure at which the reaction was maintained for the total reaction time of about 17 hours (the reaction temperature was maintained at 60° C. for the duration as well). Once the reaction was complete, the resultant mixture (exhibiting a dark orange color) was poured into about 500 mL of ice water (which turned the solution a yellow color), to which was added 500 mL of cyclohexane. The top, organic layer was removed and washed three times with water using a separatory funnel and dried over magnesium sulfate. The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 3-fluorotoluene, and left about 79.65 g of a benzaldehyde mixture consisting of 4-fluoro-2-methylbenzaldehyde (88.4%) and 2-fluoro-4-methylbenzaldehyde (11.6%) (mol. Wt. 138.14; 576.6 mmol; yield of approximately 76.2%). The vessel was sealed purged three times with carbon monoxide with the pressure of the vessel increased to 200 psi for each purging After the third purge the pressure at which the reaction was maintained for the total reaction time of about 17 hours (the reaction temperature was maintained at 60° C. for the duration as well) was poured into about 500 mL of ice water (which was added 500 mL of cyclohexane The top, organic layer was removed washed three times with water using a separatory funnel dried over magnesium sulfate The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 3-fluorotoluene left about 79.65 g of a benzaldehyde mixture

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 100.89 g of aluminum chloride (mol. Wt. 133.34; 756.6 mmol) and about 503.54 g of 3-fluorotoluene (mol. Wt. 110.13; 4,572 mmol) were charged to a 2 liter Parr®-brand 4522 stainless steel reaction vessel. To this mixture was added 5 drops of concentrated HCl. The vessel was sealed, heated to 60° C., and purged three times with carbon monoxide with the pressure of the vessel increased to 200 psi for each purging. After the third purge, the vessel was vented and a final introduction of CO was made at a pressure of about 200 psi, the pressure at which the reaction was maintained for the total reaction time of about 17 hours (the reaction temperature was maintained at 60° C. for the duration as well). Once the reaction was complete, the resultant mixture (exhibiting a dark orange color) was poured into about 500 mL of ice water (which turned the solution a yellow color), to which was added 500 mL of cyclohexane. The top, organic layer was removed and washed three times with water using a separatory funnel and dried over magnesium sulfate. The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 3-fluorotoluene, and left about 79.65 g of a benzaldehyde mixture consisting of 4-fluoro-2-methylbenzaldehyde (88.4%) and 2-fluoro-4-methylbenzaldehyde (11.6%) (mol. Wt. 138.14; 576.6 mmol; yield of approximately 76.2%). The vessel was sealed purged three times with carbon monoxide with the pressure of the vessel increased to 200 psi for each purging After the third purge the pressure at which the reaction was maintained for the total reaction time of about 17 hours (the reaction temperature was maintained at 60° C. for the duration as well) was poured into about 500 mL of ice water (which was added 500 mL of cyclohexane The top, organic layer was removed washed three times with water using a separatory funnel dried over magnesium sulfate The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 3-fluorotoluene left about 79.65 g of a benzaldehyde mixture

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

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

Procedure: A -78° C. solution of 2-fluoro-5-bromotoluene (25.764 gm, 136.3 mmol) in THF (200 ml) was treated with n-BuLi (2.5M in hexane, 60 ml, 150 mmol) over a 12-minute period. After stirring for one hour, the cloudy white mixture was treated with neat dimethylformamide (30 ml, 28.3 gm, 387 mmol) over a two-minute period. Stirring continued for an additional hour. The mixture was then quenched with saturated NH4Cl, warmed to room temperature, and made acidic with 10% HCl. The mixture was extracted with Et2O and the ether extract was washed with H2O and brine, then dried (Na2SO4), filtered, and stripped. The dark residue was distilled (bp 55° C. @1 mm) to give the title compound (16.286 gm, 86%). Stirring continued for an additional hour The mixture was then quenched with saturated NH4Cl The mixture was extracted with Et2O the ether extract was washed with H2O and brine dried (Na2SO4) filtered The dark residue was distilled (bp 55° C. @1 mm)