2-(bromomethyl)benzaldehyde

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

Procedure: Into a 50-mL round-bottom flask, was placed a solution of 2-(bromomethyl)benzaldehyde (150 mg, 0.75 mmol, 1.00 equiv) in CH3CN (25 mL). 2-[1-(Propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-ol (150 mg, 0.74 mmol, 1.00 equiv), potassium carbonate (210 mg, 1.52 mmol, 2.00 equiv), and KI (40 mg, 0.30 equiv) were added to the reaction. The resulting solution was heated to reflux for 6 h, and then it was cooled to rt. The resulting solution was diluted with 20 mL of H2O, and then it was extracted with 3×20 mL of ethyl acetate. The combined organic layers were washed with 1×30 mL of brine and concentrated under vacuum. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm, mobile phase, water with 0.05% TFA and MeCN (38.0% MeCN up to 55.0% in 8 min); Detector, nm. This provided 98.6 mg (41%) of 2-[([2-[1-(propan-2-yl)-1H-pyrazol-5-yl]pyridin-3-yl]oxy)methyl]benzaldehyde as a light yellow solid; 1HNMR (300 MHz, CDCl3, ppm): 10.01 (s, 1H), 8.43 (m, 1H), 7.88 (m, 1H), 7.86 (m, 1H), 7.61-7.79 (m, 6H), 6.61 (d, J=2.1 Hz, 1H), 5.60 (s, 2H), 4.69-4.78 (m, 1H), 1.46 (d, J=6.6 Hz, 6H); (ES, m/z): 322 [M+1]+. Into a 50-mL round-bottom flask, was placed The resulting solution was heated to reflux for 6 h it was extracted with 3×20 mL of ethyl acetate The combined organic layers were washed with 1×30 mL of brine concentrated under vacuum The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010)

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

Procedure: 2-Bromomethyl-benzaldehyde (11 g, 55.26 mmol) in acetonitrile (132 ml) was added to a solution of (4-Hydroxy-3-iodo-phenyl)-acetic acid methyl ester (16.06 g, 55 mmol), K2CO3 (8.36 g, 60.50 mmol) and Nal (2.07 g, 13.80 mmol) in acetonitrile (88 ml). The mixture was heated to reflux temperature and was stirred at this temperature for 3 hours. Once the mixture cooled down to room temperature, it was filtered and was then concentrated to dryness to obtain a residue that was diluted in toluene (212 ml) and then it was washed with NaOH 0.05N. Once the layers had separated, the aqueous layer was washed with toluene (100 ml) again and the organic layers were washed with water (2×100 ml, 1×50 ml), were concentrated to dryness to obtain a residue, which was then diluted with a mixture of acetone-water at 30° C. Then the mixture was cooled until 20-22° C. The solid formed was filtered to obtain 18 g (80%) of [4-(2-Formyl-benzyloxy)-3-iodo-phenyl]-acetic acid methyl ester (98%HPLC). The mixture was heated to reflux temperature it was filtered was then concentrated to dryness to obtain a residue that it was washed with NaOH 0.05N Once the layers had separated the aqueous layer was washed with toluene (100 ml) again the organic layers were washed with water (2×100 ml, 1×50 ml) were concentrated to dryness to obtain a residue, which Then the mixture was cooled until 20-22° C The solid formed was filtered