3-methoxy-2-(2-methylpropoxy)benzaldehyde

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

Procedure: A solution of methylamine (64 mL of a 2.0 M solution in MeOH, 128 mmol) was added to 2-isobutoxy-3-methoxybenzaldehyde (2.45 g, 11.9 mmol) and the solution was stirred for 18 h. The solution was concentrated under reduced pressure. The resulting clear oil was dissolved in EtOH (64 mL) and treated with NaBH4 (0.616 g, 16.3 mmol). After stirring for 7 h, the mixture was concentrated under reduced pressure and then dissolved in 1 N NaOH (57 mL). The mixture was extracted with Et2O (3×75 mL). The combined organics were washed with brine (2×100 mL), dried (Na2SO4) and concentrated to yield the title compound (2.43 g, 91%) as a light yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.01-6.88 (m, 3H), 3.76 (s, 3H), 3.63 (t, J=6.4 Hz, 3H), 2.25 (s, 3H), 2.00-1.93 (m, 1H), 1.84 (br s, 1H), 0.98 (d, J=6.6 Hz, 6H). The solution was concentrated under reduced pressure The resulting clear oil was dissolved in EtOH (64 mL) After stirring for 7 h the mixture was concentrated under reduced pressure dissolved in 1 N NaOH (57 mL) The mixture was extracted with Et2O (3×75 mL) The combined organics were washed with brine (2×100 mL) dried (Na2SO4) concentrated

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

Procedure: A solution of 2-hydroxy-3-methoxybenzaldehyde (4.00 g, 26.2 mmol) in DMF (50 mL) was treated with K2CO3 (8.00 g, 57.9 mmol) followed by iodoisobutane (4.53 mL, 39.4 mmol). The resulting slurry was stirred for at ambient temperature for 18 h. Additional DMF (70 mL) was added to help aid stirring, and the mixture was heated to 40° C. for 18 h. Additional iodoisobutane (2.26 mL, 19.7 mmol) was added and the mixture was stirred at ambient temperature for 48 h. The reaction was quenched with H2O (100 mL) and the mixture was extracted with EtOAc (3×100 mL). The combined organics were washed with H2O (2×100 mL) and brine (2×100 mL), dried (Na2SO4) and concentrated to an orange oil. Purification by column chromatography (silica gel, hexanes/EtOAc, 90:10) gave the title compound (2.46 g, 62%) as a clear oil: 1H NMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.36 (dd, J=7.9, 1.7 Hz, 1H), 7.27 (dd, J=7.8, 1.7 Hz, 1H), 7.19 (dt, J=7.8, 0.6 Hz, 1H), 3.85 (m, 5H), 2.09-2.00 (m, 1H), 0.99 (d, J=6.7 Hz, 6H). stirring the mixture was heated to 40° C. for 18 h the mixture was stirred at ambient temperature for 48 h The reaction was quenched with H2O (100 mL) the mixture was extracted with EtOAc (3×100 mL) The combined organics were washed with H2O (2×100 mL) and brine (2×100 mL) dried (Na2SO4) concentrated to an orange oil Purification by column chromatography (silica gel, hexanes/EtOAc, 90:10)

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

Procedure: This compound was prepared as described in Intermediate 1 by the reaction of 2-isobutoxy-3-methoxybenzaldehyde (1.328 g, 5.984 mmol) with 5-ethyloxycarbonylimidazo[2,1-b][1,3]thiazol-6-yl-methyl(triphenyl)phosphonium bromide (3.0 g, 5.440 mmol) in the presence of sodium hydride (0.23 g, 5.984 mmol) in anhydrous DMSO (15 mL) to give 1.50 g of product as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.07 (d, J=6.9 Hz, 6H), 1.47 (t, J=6.9 Hz, 3H), 2.12-2.23 (m, 1H), 3.75 (d, J=6.6 Hz, 2H), 3.86 (s, 3H), 4.40-4.49 (m, 2H), 6.85 (d, J=7.8 Hz, 1H), 6.90 (d, J=4.5 Hz, 1H), 7.05 (t, J=7.8 Hz, 1H), 7.28-7.33 (m, 1H), 7.76 (d, J=16.2 Hz, 1H), 8.03 (d, J=16.2 Hz, 1H), 8.07-8.11 (m, 1H); APCI-MS (m/z) 399.09 (M−H)−. This compound was prepared

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

Procedure: The title compound was synthesized by condensation of Intermediate 15 (350 mg, 1.071 mmol) with 2-isobutoxy-3-methoxybenzaldehyde (312 mg, 1.516 mmol) in the presence of sodium ethoxide (146 mg, 2.147 mmol) in ethanol (15 ml) according to the procedure of Example 24 to give 187 mg of the desired product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 0.90-0.99 (m, 6H), 1.80-1.86 (m, 1H), 3.58-3.65 (m, 2H), 3.77 (s, 3H), 6.85-6.93 (m, 2H), 6.99-7.06 (m, 2H), 7.40-7.50 (m, 5H), 7.96-8.02 (m, 1H), 8.09-8.14 (m, 1H); ESI-MS (m/z) 517.18 (M+H)+.

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

Procedure: The title compound was prepared by condensation of Intermediate 5 (400 mg, 1.289 mmol) with 2-isobutoxy-3-methoxybenzaldehyde (400 mg, 1.922 mmol) in presence of sodium ethoxide (175 mg, 2.578 mmol) in ethanol (15 ml) according to the procedure described in Example 24 to give 285 mg of the desired product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 0.93 (d, J=3.6 Hz, 6H), 1.72 (br s, 1H), 3.58 (br s, 2H), 3.77 (s, 3H), 6.91-7.00 (m, 4H), 7.53-7.58 (m, 3H), 7.78-7.84 (m, 2H), 8.00 (br s, 1H), 8.12 (d, J=15.3 Hz, 1H); ESI-MS (m/z) 501.24 (M+H)+.

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

Procedure: The title compound was prepared by the reaction of Intermediate 4 (350 mg, 1.325 mmol) with 2-isobutoxy-3-methoxybenzaldehyde (409 mg, 1.961 mmol) in presence of sodium ethoxide (178 mg, 2.264 mmol) according to the procedure described in Example 9 to give 270 mg of the desired product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 1.85 (d, J=3.9 Hz, 4H), 2.03 (d, J=7.8 Hz, 3H), 3.77 (s, 3H), 3.83 (d, J=6.3 Hz, 2H), 6.84 (d, J=15.6 Hz, 1H), 6.95-7.00 (m, 3H), 7.50-7.58 (m, 3H), 7.92-8.04 (m, 3H), 8.14 (d, J=15.3 Hz, 1H); ESI-MS (m/z) 470.45 (M+H)+.

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

Procedure: Step 2 intermediate from Intermediate 19 (1.2 g, 2.412 mmol) was reacted with NaH (60% dispersion in mineral oil, 105 mg, 2.610) and 2-isobutoxy-3-methoxybenzaldehyde (546 mg, 2.412 mmol) in dry DMSO (10 ml) according to the procedure outlined in Intermediate 2, Step 3 to yield 5.5 g of the desired compound as a white solid; 1H NMR (300 MHz, CDCl3) δ 1.03 (d, J=6.6 Hz, 6H), 1.98-2.06 (m, 1H), 3.68 (d, J=6.6 Hz, 2H), 3.79 (s, 3H), 6.30 (s, 1H), 6.98-7.16 (m, 3H), 7.30-7.33 (m, 1H), 8.05 (d, J=16.2 Hz, 1H), 8.23 (s, 1H).

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

Procedure: A solution of methylamine (64 mL of a 2.0 M solution in MeOH, 128 mmol) was added to 2-isobutoxy-3-methoxybenzaldehyde (2.45 g, 11.9 mmol) and the solution was stirred for 18 h. The solution was concentrated under reduced pressure. The resulting clear oil was dissolved in EtOH (64 mL) and treated with NaBH4 (0.616 g, 16.3 mmol). After stirring for 7 h, the mixture was concentrated under reduced pressure and then dissolved in 1 N NaOH (57 mL). The mixture was extracted with Et2O (3×75 mL). The combined organics were washed with brine (2×100 mL), dried (Na2SO4) and concentrated to yield the title compound (2.43 g, 91%) as a light yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.01-6.88 (m, 3H), 3.76 (s, 3H), 3.63 (t, J=6.4 Hz, 3H), 2.25 (s, 3H), 2.00-1.93 (m, 1H), 1.84 (br s, 1H), 0.98 (d, J=6.6 Hz, 6H). The solution was concentrated under reduced pressure The resulting clear oil was dissolved in EtOH (64 mL) After stirring for 7 h the mixture was concentrated under reduced pressure dissolved in 1 N NaOH (57 mL) The mixture was extracted with Et2O (3×75 mL) The combined organics were washed with brine (2×100 mL) dried (Na2SO4) concentrated

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

Procedure: A solution of 2-hydroxy-3-methoxybenzaldehyde (4.00 g, 26.2 mmol) in DMF (50 mL) was treated with K2CO3 (8.00 g, 57.9 mmol) followed by iodoisobutane (4.53 mL, 39.4 mmol). The resulting slurry was stirred for at ambient temperature for 18 h. Additional DMF (70 mL) was added to help aid stirring, and the mixture was heated to 40° C. for 18 h. Additional iodoisobutane (2.26 mL, 19.7 mmol) was added and the mixture was stirred at ambient temperature for 48 h. The reaction was quenched with H2O (100 mL) and the mixture was extracted with EtOAc (3×100 mL). The combined organics were washed with H2O (2×100 mL) and brine (2×100 mL), dried (Na2SO4) and concentrated to an orange oil. Purification by column chromatography (silica gel, hexanes/EtOAc, 90:10) gave the title compound (2.46 g, 62%) as a clear oil: 1H NMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.36 (dd, J=7.9, 1.7 Hz, 1H), 7.27 (dd, J=7.8, 1.7 Hz, 1H), 7.19 (dt, J=7.8, 0.6 Hz, 1H), 3.85 (m, 5H), 2.09-2.00 (m, 1H), 0.99 (d, J=6.7 Hz, 6H). stirring the mixture was heated to 40° C. for 18 h the mixture was stirred at ambient temperature for 48 h The reaction was quenched with H2O (100 mL) the mixture was extracted with EtOAc (3×100 mL) The combined organics were washed with H2O (2×100 mL) and brine (2×100 mL) dried (Na2SO4) concentrated to an orange oil Purification by column chromatography (silica gel, hexanes/EtOAc, 90:10)