4-chloro-2-methoxybenzaldehyde

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: In methylene chloride (80 ml) was dissolved (4-chloro-2-methoxyphenyl)methanol (3.69 g). Under ice cooling, molecular sieve 4A (4.57 g), N-methylmorpholine (2.81 g) and tetra-n-propylammonium perruthenate (420 mg) were added to the resulting solution, followed by stirring at room temperature for 2.5 hours. The reaction mixture was distilled under reduced pressure. The residue was subjected to chromatography on a silica gel column (hexane:ethyl acetate=9:1), whereby the title compound (3.07 g) was obtained as pale yellow oil. The reaction mixture was distilled under reduced pressure was obtained as pale yellow oil

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

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

Procedure: Toluene (3.5 mL) was added to a 3-necked flask and cooled to −60° C. n-BuLi (1.3 mL, 2.5M in hexanes) was added. A solution of 3-bromopyridine (0.3 mL, 3 mmol) in toluene (1.2 mL) was added dropwise to maintain internal temperature <−50° C. The resulting slurry was then stirred for 30 minutes at −60° C. THF (1.2 mL) was added dropwise, and the mixture was stirred for an additional 15 minutes. 4-Chloro-2-methoxy-benzaldehyde (561 mg, 3.3 mmol) was added and the mixture was allowed to warm to room temperature. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 7:3 hexanes/ethyl acetate to provide 201 mg (27%) of the title compound. MS (ESI) m/e 250 (M+H)+. was added to maintain internal temperature <−50° C the mixture was stirred for an additional 15 minutes to warm to room temperature The reaction was partitioned between ethyl acetate and water The organic layer was washed with brine dried (MgSO4) filtered concentrated under vacuum The residue was purified by flash column chromatography on silica gel with 7:3 hexanes/ethyl acetate

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

Procedure: Toluene (3.5 mL) was added to a 3-necked flask and cooled to −60° C. n-BuLi (1.3 mL, 2.5M in hexanes) was added. A solution of 3-bromopyridine (0.3 mL, 3 mmol) in toluene (1.2 mL) was added dropwise to maintain internal temperature <−50° C. The resulting slurry was then stirred for 30 minutes at −60° C. THF (1.2 mL) was added dropwise, and the mixture was stirred for an additional 15 minutes. 4-Chloro-2-methoxy-benzaldehyde (561 mg, 3.3 mmol) was added and the mixture was allowed to warm to room temperature. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 7:3 hexanes/ethyl acetate to provide 201 mg (27%) of the title compound. MS (ESI) m/e 250 (M+H)+. was added to maintain internal temperature <−50° C the mixture was stirred for an additional 15 minutes to warm to room temperature The reaction was partitioned between ethyl acetate and water The organic layer was washed with brine dried (MgSO4) filtered concentrated under vacuum The residue was purified by flash column chromatography on silica gel with 7:3 hexanes/ethyl acetate

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

Procedure: A solution of 4-bromo-2-trimethylsilanyl-thiazole (1.0 g, 4.23 mmol) in THF (8 mL) was cooled to −78° C. n-BuLi (1.68 mL, 2.5M in hexanes, 4.65 mmol) was added dropwise and the resulting solution was stirred at −78° C. for 30 minutes. A solution of 4-chloro-2-methoxy-benzaldehyde in THF (2 mL) was added to the reaction, followed by 30 minutes of stirring at −78° C. The reaction was then allowed to warm slowly to room temperature. 3M HCl (10 mL) was added and the reaction was stirred for 16 hours. The solution was then neutralized with Na2CO3 solution and partitioned between ethyl acetate and water. The combined organic layers were dried (MgSO4), filtered, and concentrated under vacuum. The residue was then purified by flash column chromatography on silica gel with 7:3 hexanes/ethyl acetate to provide 204 mg (19%) of the title compound. MS (ESI) m/e 256 (M+H)+, 1H NMR (DMSO-d6, 300 MHz): □ 8.92 (s, 1H), 7.61 (s, 1H), 7.51 (d, J=7.80 Hz, 1H), 7.03-7.07 (m, 2H), 6.30 (d, J=4.75 Hz, 1H), 6.19 (d, J=4.41 Hz, 1H), 3.81 (s, 3H). was added dropwise followed by 30 minutes of stirring at −78° C to warm slowly to room temperature the reaction was stirred for 16 hours partitioned between ethyl acetate and water The combined organic layers were dried (MgSO4) filtered concentrated under vacuum The residue was then purified by flash column chromatography on silica gel with 7:3 hexanes/ethyl acetate

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

Procedure: A solution of 4-bromo-2-trimethylsilanyl-thiazole (1.0 g, 4.23 mmol) in THF (8 mL) was cooled to −78° C. n-BuLi (1.68 mL, 2.5M in hexanes, 4.65 mmol) was added dropwise and the resulting solution was stirred at −78° C. for 30 minutes. A solution of 4-chloro-2-methoxy-benzaldehyde in THF (2 mL) was added to the reaction, followed by 30 minutes of stirring at −78° C. The reaction was then allowed to warm slowly to room temperature. 3M HCl (10 mL) was added and the reaction was stirred for 16 hours. The solution was then neutralized with Na2CO3 solution and partitioned between ethyl acetate and water. The combined organic layers were dried (MgSO4), filtered, and concentrated under vacuum. The residue was then purified by flash column chromatography on silica gel with 7:3 hexanes/ethyl acetate to provide 204 mg (19%) of the title compound. MS (ESI) m/e 256 (M+H)+, 1H NMR (DMSO-d6, 300 MHz): □ 8.92 (s, 1H), 7.61 (s, 1H), 7.51 (d, J=7.80 Hz, 1H), 7.03-7.07 (m, 2H), 6.30 (d, J=4.75 Hz, 1H), 6.19 (d, J=4.41 Hz, 1H), 3.81 (s, 3H). was added dropwise followed by 30 minutes of stirring at −78° C to warm slowly to room temperature the reaction was stirred for 16 hours partitioned between ethyl acetate and water The combined organic layers were dried (MgSO4) filtered concentrated under vacuum The residue was then purified by flash column chromatography on silica gel with 7:3 hexanes/ethyl acetate

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

Procedure: 4-Chloro-2-methoxy-benzaldehyde (0.54 g, 3.2 mmol) in 10 mL of THF was treated with 3.0 M EtMgBr (2 mL, 6.0 mmol) at room temperature. The solution was stirred for 1 hour and quenched with MeOH. The solution was poured into water, treated 10 mL of 10% HCl, extracted with EtOAc several times. The combined organic layers were washed brine, dried (MgSO4), filtered, and concentrated. The residue was diluted with CH2Cl2, treated with PCC (1.33 g, 6.4 mmol) for 2 hours. The reaction mixture was filtered through a pack of silica gel to give 0.42 g of the title compound. MS (DCI) m/e 199 (M+H)+. quenched with MeOH The solution was poured into water treated 10 mL of 10% HCl extracted with EtOAc several times The combined organic layers were washed brine dried (MgSO4) filtered concentrated The residue was diluted with CH2Cl2 The reaction mixture was filtered through a pack of silica gel

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

Procedure: 4-Chloro-2-methoxy-benzaldehyde (0.54 g, 3.2 mmol) in 10 mL of THF was treated with 3.0 M EtMgBr (2 mL, 6.0 mmol) at room temperature. The solution was stirred for 1 hour and quenched with MeOH. The solution was poured into water, treated 10 mL of 10% HCl, extracted with EtOAc several times. The combined organic layers were washed brine, dried (MgSO4), filtered, and concentrated. The residue was diluted with CH2Cl2, treated with PCC (1.33 g, 6.4 mmol) for 2 hours. The reaction mixture was filtered through a pack of silica gel to give 0.42 g of the title compound. MS (DCI) m/e 199 (M+H)+. quenched with MeOH The solution was poured into water treated 10 mL of 10% HCl extracted with EtOAc several times The combined organic layers were washed brine dried (MgSO4) filtered concentrated The residue was diluted with CH2Cl2 The reaction mixture was filtered through a pack of silica gel

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

Procedure: 4-Chloro-2-methoxybenzaldehyde (250 mg, 1.47 mmol) was diluted with nitromethane (556 μL, 10.3 mmol) followed by the addition of methylamine hydrochloride (59.4 mg, 0.879 mmol) and sodium acetate (72.1 mg, 0.879 mmol). After stirring for 12 hours, the reaction was loaded directly onto a biotage 25 cartridge and eluted with 5% ethyl acetate/hexanes to yield (E)-4-chloro-2-methoxy-1-(2-nitrovinyl)benzene (245 mg, 1.15 mmol, 78.3% yield). eluted with 5% ethyl acetate/hexanes

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chloro-2-Fluorobenzaldehyde (300 mg, 1.89 mmol) was diluted with NaOMe (3784 μL, 1.89 mmol) (solution in methanol), heated to 50° C. and stirred for 3 hours. The reaction was concentrated in half and loaded directly onto a biotage 25 cartridge eluting with 5% ethyl acetate/hexanes to yield 4-chloro-2-methoxybenzaldehyde (250 mg, 1.47 mmol, 77.5% yield). The reaction was concentrated in half eluting with 5% ethyl acetate/hexanes