2-chloro-3-methoxyphenol

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

Procedure: To a solution of 2-chloro-3-methoxyphenol (19.3 g) in 1,2-dichloroethane (150 mL) were added triethylamine (73.7 g), magnesium chloride (57.8 g) and paraformaldehyde (36.5 g), and the mixture was stirred at 70° C. for 4 hr under nitrogen atmosphere. The reaction mixture was poured into 1N hydrochloric acid, and the precipitate was removed by filtration, and washed with dichloromethane. The organic layer was washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (21.5 g). the precipitate was removed by filtration washed with dichloromethane The organic layer was washed with 1N hydrochloric acid and saturated brine dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an aqueous solution (100 mL) of potassium hydroxide (11.0 g) was added 2-chlorobenzene-1,3-diol (22.8 g). Then, dimethyl sulfate (19.9 g) was slowly added to the reaction mixture while keeping the reaction mixture at 10° C. to 20° C., and the mixture was stirred at 100° C. for 2 days. The reaction mixture was acidified with 2N hydrochloric acid, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (18.0 g). at 10° C. to 20° C. the mixture was extracted with dichloromethane The organic layer was dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether)

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

Procedure: 3-Chloroperoxybenzoic acid (760 mg, 4.396 mmol) was added portionwise to a solution of 2-Chloro-3-Methoxybenzaldehyde (500 mg, 2.931 mmol) in dichloromethane (12 ml) and the mixture was stirred for 3 hours at room temperature. Further 3-chloroperoxybenzoic acid (760 mg, 4.396 mmol) was added and mixture allowed to stir for 18 hrs. The solution was diluted with 12 ml dichloromethane and washed with saturated sodium sulphite solution (15 ml) and saturated sodium hydrogen carbonate solution (15 ml). The organic layer was dried over sodium sulphate and concentrated in vacuo to a yellow gum. The residue was dissolved in methanol (12 ml), triethylamine (0.05 ml) was added and the mixture stirred for 18 hours at room temperature. The solution was concentrated in vacuo, dissolved in diethyl ether (20 ml) and extracted with 1N sodium hydroxide (20 ml). The aqueous layer was acidified to pH1 by dropwise addition of 2N hydrochloric acid and extracted with diethyl ether (2×25 ml). These combined organic layers were dried over sodium sulphate and concentrated in vacuo to afford the title compound as a brown gum in 70% yield, 325 mg. to stir for 18 hrs washed with saturated sodium sulphite solution (15 ml) and saturated sodium hydrogen carbonate solution (15 ml) The organic layer was dried over sodium sulphate concentrated in vacuo to a yellow gum The residue was dissolved in methanol (12 ml) triethylamine (0.05 ml) was added the mixture stirred for 18 hours at room temperature The solution was concentrated in vacuo dissolved in diethyl ether (20 ml) extracted with 1N sodium hydroxide (20 ml) The aqueous layer was acidified to pH1 by dropwise addition of 2N hydrochloric acid extracted with diethyl ether (2×25 ml) These combined organic layers were dried over sodium sulphate concentrated in vacuo

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

Procedure: 3-Chloroperoxybenzoic acid (760 mg, 4.396 mmol) was added portionwise to a solution of 2-Chloro-3-Methoxybenzaldehyde (500 mg, 2.931 mmol) in dichloromethane (12 ml) and the mixture was stirred for 3 hours at room temperature. Further 3-chloroperoxybenzoic acid (760 mg, 4.396 mmol) was added and mixture allowed to stir for 18 hrs. The solution was diluted with 12 ml dichloromethane and washed with saturated sodium sulphite solution (15 ml) and saturated sodium hydrogen carbonate solution (15 ml). The organic layer was dried over sodium sulphate and concentrated in vacuo to a yellow gum. The residue was dissolved in methanol (12 ml), triethylamine (0.05 ml) was added and the mixture stirred for 18 hours at room temperature. The solution was concentrated in vacuo, dissolved in diethyl ether (20 ml) and extracted with 1N sodium hydroxide (20 ml). The aqueous layer was acidified to pH1 by dropwise addition of 2N hydrochloric acid and extracted with diethyl ether (2×25 ml). These combined organic layers were dried over sodium sulphate and concentrated in vacuo to afford the title compound as a brown gum in 70% yield, 325 mg. to stir for 18 hrs washed with saturated sodium sulphite solution (15 ml) and saturated sodium hydrogen carbonate solution (15 ml) The organic layer was dried over sodium sulphate concentrated in vacuo to a yellow gum The residue was dissolved in methanol (12 ml) triethylamine (0.05 ml) was added the mixture stirred for 18 hours at room temperature The solution was concentrated in vacuo dissolved in diethyl ether (20 ml) extracted with 1N sodium hydroxide (20 ml) The aqueous layer was acidified to pH1 by dropwise addition of 2N hydrochloric acid extracted with diethyl ether (2×25 ml) These combined organic layers were dried over sodium sulphate concentrated in vacuo

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

Procedure: 3-Chloroperoxybenzoic acid (760 mg, 4.396 mmol) was added portionwise to a solution of 2-Chloro-3-Methoxybenzaldehyde (500 mg, 2.931 mmol) in dichloromethane (12 ml) and the mixture was stirred for 3 hours at room temperature. Further 3-chloroperoxybenzoic acid (760 mg, 4.396 mmol) was added and mixture allowed to stir for 18 hrs. The solution was diluted with 12 ml dichloromethane and washed with saturated sodium sulphite solution (15 ml) and saturated sodium hydrogen carbonate solution (15 ml). The organic layer was dried over sodium sulphate and concentrated in vacuo to a yellow gum. The residue was dissolved in methanol (12 ml), triethylamine (0.05 ml) was added and the mixture stirred for 18 hours at room temperature. The solution was concentrated in vacuo, dissolved in diethyl ether (20 ml) and extracted with 1N sodium hydroxide (20 ml). The aqueous layer was acidified to pH1 by dropwise addition of 2N hydrochloric acid and extracted with diethyl ether (2×25 ml). These combined organic layers were dried over sodium sulphate and concentrated in vacuo to afford the title compound as a brown gum in 70% yield, 325 mg. to stir for 18 hrs washed with saturated sodium sulphite solution (15 ml) and saturated sodium hydrogen carbonate solution (15 ml) The organic layer was dried over sodium sulphate concentrated in vacuo to a yellow gum The residue was dissolved in methanol (12 ml) triethylamine (0.05 ml) was added the mixture stirred for 18 hours at room temperature The solution was concentrated in vacuo dissolved in diethyl ether (20 ml) extracted with 1N sodium hydroxide (20 ml) The aqueous layer was acidified to pH1 by dropwise addition of 2N hydrochloric acid extracted with diethyl ether (2×25 ml) These combined organic layers were dried over sodium sulphate concentrated in vacuo

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

Procedure: 3-Chloroperoxybenzoic acid (760 mg, 4.396 mmol) was added portionwise to a solution of 2-Chloro-3-Methoxybenzaldehyde (500 mg, 2.931 mmol) in dichloromethane (12 ml) and the mixture was stirred for 3 hours at room temperature. Further 3-chloroperoxybenzoic acid (760 mg, 4.396 mmol) was added and mixture allowed to stir for 18 hrs. The solution was diluted with 12 ml dichloromethane and washed with saturated sodium sulphite solution (15 ml) and saturated sodium hydrogen carbonate solution (15 ml). The organic layer was dried over sodium sulphate and concentrated in vacuo to a yellow gum. The residue was dissolved in methanol (12 ml), triethylamine (0.05 ml) was added and the mixture stirred for 18 hours at room temperature. The solution was concentrated in vacuo, dissolved in diethyl ether (20 ml) and extracted with 1N sodium hydroxide (20 ml). The aqueous layer was acidified to pH1 by dropwise addition of 2N hydrochloric acid and extracted with diethyl ether (2×25 ml). These combined organic layers were dried over sodium sulphate and concentrated in vacuo to afford the title compound as a brown gum in 70% yield, 325 mg. to stir for 18 hrs washed with saturated sodium sulphite solution (15 ml) and saturated sodium hydrogen carbonate solution (15 ml) The organic layer was dried over sodium sulphate concentrated in vacuo to a yellow gum The residue was dissolved in methanol (12 ml) triethylamine (0.05 ml) was added the mixture stirred for 18 hours at room temperature The solution was concentrated in vacuo dissolved in diethyl ether (20 ml) extracted with 1N sodium hydroxide (20 ml) The aqueous layer was acidified to pH1 by dropwise addition of 2N hydrochloric acid extracted with diethyl ether (2×25 ml) These combined organic layers were dried over sodium sulphate concentrated in vacuo

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

Procedure: 3-Chloroperoxybenzoic acid (760 mg, 4.396 mmol) was added portionwise to a solution of 2-Chloro-3-Methoxybenzaldehyde (500 mg, 2.931 mmol) in dichloromethane (12 ml) and the mixture was stirred for 3 hours at room temperature. Further 3-chloroperoxybenzoic acid (760 mg, 4.396 mmol) was added and mixture allowed to stir for 18 hrs. The solution was diluted with 12 ml dichloromethane and washed with saturated sodium sulphite solution (15 ml) and saturated sodium hydrogen carbonate solution (15 ml). The organic layer was dried over sodium sulphate and concentrated in vacuo to a yellow gum. The residue was dissolved in methanol (12 ml), triethylamine (0.05 ml) was added and the mixture stirred for 18 hours at room temperature. The solution was concentrated in vacuo, dissolved in diethyl ether (20 ml) and extracted with 1N sodium hydroxide (20 ml). The aqueous layer was acidified to pH1 by dropwise addition of 2N hydrochloric acid and extracted with diethyl ether (2×25 ml). These combined organic layers were dried over sodium sulphate and concentrated in vacuo to afford the title compound as a brown gum in 70% yield, 325 mg. to stir for 18 hrs washed with saturated sodium sulphite solution (15 ml) and saturated sodium hydrogen carbonate solution (15 ml) The organic layer was dried over sodium sulphate concentrated in vacuo to a yellow gum The residue was dissolved in methanol (12 ml) triethylamine (0.05 ml) was added the mixture stirred for 18 hours at room temperature The solution was concentrated in vacuo dissolved in diethyl ether (20 ml) extracted with 1N sodium hydroxide (20 ml) The aqueous layer was acidified to pH1 by dropwise addition of 2N hydrochloric acid extracted with diethyl ether (2×25 ml) These combined organic layers were dried over sodium sulphate concentrated in vacuo

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

Procedure: Using the method described in Example 126, Step 1,2-(4-iodo-6-oxo-6H-pyridazin-1-yl)-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (Intermediate 94) and 2-chloro-3-methoxy-phenol afforded 2-[4-(2-chloro-3-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide as a white solid as a mixture of diastereomers (42 mg, 77%); ES+-HRMS m/e calcd for C26H32N5O6Cl [M+H+] 546.2114 found 546.2114. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.78-0.97 (m, 6H), 1.24 (s, 3H), 1.30 (2×s, 3H), 1.45 (br. s., 1H), 1.69-1.87 (m, 1H), 2.05-2.25 (m, 1H), 3.73 (dd, J=8.5, 5.7 Hz, 1H), 3.92 (s, 3H), 4.00 (dd, J=8.5, 6.3 Hz, 1H), 4.04-4.19 (m, 2H), 4.35 (quin, J=5.8 Hz, 1H), 5.51 (dd, J=11.0, 4.1 Hz, 1H), 5.71 (d, J=2.7 Hz, 1H), 6.38 (d, J=2.4 Hz, 1H), 7.06 (d, J=8.2 Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 7.45 (t, J=8.2 Hz, 1H), 7.59 (s, 1H), 8.19 (d, J=2.7 Hz, 1H), 10.84 (s, 1H).

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

Procedure: Using the method described in Example 126, Step 1,2-(4-iodo-6-oxo-6H-pyridazin-1-yl)-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (Intermediate 94) and 2-chloro-3-methoxy-phenol afforded 2-[4-(2-chloro-3-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide as a white solid as a mixture of diastereomers (42 mg, 77%); ES+-HRMS m/e calcd for C26H32N5O6Cl [M+H+] 546.2114 found 546.2114. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.78-0.97 (m, 6H), 1.24 (s, 3H), 1.30 (2×s, 3H), 1.45 (br. s., 1H), 1.69-1.87 (m, 1H), 2.05-2.25 (m, 1H), 3.73 (dd, J=8.5, 5.7 Hz, 1H), 3.92 (s, 3H), 4.00 (dd, J=8.5, 6.3 Hz, 1H), 4.04-4.19 (m, 2H), 4.35 (quin, J=5.8 Hz, 1H), 5.51 (dd, J=11.0, 4.1 Hz, 1H), 5.71 (d, J=2.7 Hz, 1H), 6.38 (d, J=2.4 Hz, 1H), 7.06 (d, J=8.2 Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 7.45 (t, J=8.2 Hz, 1H), 7.59 (s, 1H), 8.19 (d, J=2.7 Hz, 1H), 10.84 (s, 1H).

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

Procedure: To a solution of 2-chloro-3-methoxyphenol (19.3 g) in 1,2-dichloroethane (150 mL) were added triethylamine (73.7 g), magnesium chloride (57.8 g) and paraformaldehyde (36.5 g), and the mixture was stirred at 70° C. for 4 hr under nitrogen atmosphere. The reaction mixture was poured into 1N hydrochloric acid, and the precipitate was removed by filtration, and washed with dichloromethane. The organic layer was washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (21.5 g). the precipitate was removed by filtration washed with dichloromethane The organic layer was washed with 1N hydrochloric acid and saturated brine dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an aqueous solution (100 mL) of potassium hydroxide (11.0 g) was added 2-chlorobenzene-1,3-diol (22.8 g). Then, dimethyl sulfate (19.9 g) was slowly added to the reaction mixture while keeping the reaction mixture at 10° C. to 20° C., and the mixture was stirred at 100° C. for 2 days. The reaction mixture was acidified with 2N hydrochloric acid, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (18.0 g). at 10° C. to 20° C. the mixture was extracted with dichloromethane The organic layer was dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether)

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

Procedure: 3-Chloroperoxybenzoic acid (760 mg, 4.396 mmol) was added portionwise to a solution of 2-Chloro-3-Methoxybenzaldehyde (500 mg, 2.931 mmol) in dichloromethane (12 ml) and the mixture was stirred for 3 hours at room temperature. Further 3-chloroperoxybenzoic acid (760 mg, 4.396 mmol) was added and mixture allowed to stir for 18 hrs. The solution was diluted with 12 ml dichloromethane and washed with saturated sodium sulphite solution (15 ml) and saturated sodium hydrogen carbonate solution (15 ml). The organic layer was dried over sodium sulphate and concentrated in vacuo to a yellow gum. The residue was dissolved in methanol (12 ml), triethylamine (0.05 ml) was added and the mixture stirred for 18 hours at room temperature. The solution was concentrated in vacuo, dissolved in diethyl ether (20 ml) and extracted with 1N sodium hydroxide (20 ml). The aqueous layer was acidified to pH1 by dropwise addition of 2N hydrochloric acid and extracted with diethyl ether (2×25 ml). These combined organic layers were dried over sodium sulphate and concentrated in vacuo to afford the title compound as a brown gum in 70% yield, 325 mg. to stir for 18 hrs washed with saturated sodium sulphite solution (15 ml) and saturated sodium hydrogen carbonate solution (15 ml) The organic layer was dried over sodium sulphate concentrated in vacuo to a yellow gum The residue was dissolved in methanol (12 ml) triethylamine (0.05 ml) was added the mixture stirred for 18 hours at room temperature The solution was concentrated in vacuo dissolved in diethyl ether (20 ml) extracted with 1N sodium hydroxide (20 ml) The aqueous layer was acidified to pH1 by dropwise addition of 2N hydrochloric acid extracted with diethyl ether (2×25 ml) These combined organic layers were dried over sodium sulphate concentrated in vacuo