2-(3-hydroxyphenyl)acetonitrile

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

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

Procedure: To a solution of (3-hydroxyphenyl)acetonitrile (75.0 g, 0.56 mol) in toluene (750 mL) was added paraformaldehyde (84.0 g, 2.80 mol) and toluene-4-sulfonic acid monohydrate (10.7 g, 56.0 mmol) at room temperature. The reaction mixture was heated at reflux for 40 minutes. Toluene was removed by evaporation. Water (150 mL) and ethyl acetate (150 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was separated by preparative HPLC to give 2-(4H-benzo[d][1,3]dioxin-7-yl)acetonitrile (4.7 g, 5%). 1H NMR (300 MHz, CDCl3) δ 6.85-6.98 (m, 3H), 5.25 (d, J=3.0 Hz, 2H), 4.89 (s, 2H), 3.69 (s, 2H). The reaction mixture was heated at reflux for 40 minutes Toluene was removed by evaporation Water (150 mL) and ethyl acetate (150 mL) were added The organic layer was separated the aqueous layer was extracted with ethyl acetate The combined organics were washed with brine dried over anhydrous Na2SO4 evaporated under vacuum The residue was separated by preparative HPLC

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

Procedure: To a solution of (3-methoxyphenyl)acetonitrile (150 g, 1.03 mol) in CH2Cl2 (1000 mL) was added BBr3 (774 g, 3.09 mol) dropwise at −70° C. The mixture was stirred and warmed to room temperature slowly. Water (300 mL) was added at 0° C. The resulting mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under vacuum. The crude residue was purified by column (Petroleum Ether/EtOAc 10:1) to give (3-hydroxyphenyl)acetonitrile (75.0 g, 55%). 1H NMR (CDCl3, 300 MHz) δ 7.18-7.24 (m, 1H), 6.79-6.84 (m, 3H), 3.69 (s, 2H). The resulting mixture was extracted with CH2Cl2 The combined organic layers were dried over anhydrous Na2SO4 filtered evaporated under vacuum The crude residue was purified by column (Petroleum Ether/EtOAc 10:1)

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

Procedure: A solution of 2-(3-Hydroxyphenyl)acetonitrile (Step A, 5 g, 37 mmol) and diisopropyl azodicarboxylate (DIAD, 3.38 g, 16.7 mmol) in dry THF (20 ml) was added drop wise to a solution of 2,6-Dimethylbenzyl alcohol (2.25 g, 16.5 mmol) and triphenylphosphine (TPP, 4.3 g, 16.4 mmol) in THF (30 ml) at 0° C. under argon. The reaction mixture was stirred at room temperature for 16 hours or until all the starting material is consumed. Silica gel (25 g) was added to the mixture, solvents were removed under reduced pressure, loaded on silica gel column and eluted with methylene chloride:hexane (1:1) to give light yellow crystalline solid. is consumed Silica gel (25 g) was added to the mixture, solvents were removed under reduced pressure eluted with methylene chloride:hexane (1:1) to give light yellow crystalline solid

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

Procedure: To a solution of 2-(3-Methoxyphenyl)acetonitrile (3.6 g, 25.4 mmol) in dry methylene chloride (20 ml) was added BBr3 (55 ml, 1M in CH2Cl2, 55 mmol) at −78° C. under argon atmosphere. The reaction mixture was warmed to ambient temperature for 48 hours, quenched by crushed ice, and extracted with methylene chloride. The organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (CH2Cl2: ethyl acetate 4:1) to give the title compound as oil. quenched by crushed ice extracted with methylene chloride The organic layer was dried over Na2SO4 filtered concentrated purified by flash chromatography on a silica gel column (CH2Cl2: ethyl acetate 4:1)

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

Procedure: To a solution of 14.0 g (0.105 mol) of 3-hydroxyphenylacetonitrile in 500 ml of acetone were added 25.9 g (0.105 mol) of 4-chloromethyl-2-phenylthiazole hydrochloride and 34.2 g (0.105 mol) of cesium carbonate and 1 g of potassium iodide and the slurry is heated to reflux for 20 hours. The mixture is filtered and the solution is concentrated in vacuo to obtain crystals. Recrystallization from ethyl acetate gives 14.0 g (43%) crystals, m.p. 108°-110° C. The product is used without further purification in subsequent reactions. the slurry is heated to reflux for 20 hours The mixture is filtered the solution is concentrated in vacuo to obtain crystals Recrystallization from ethyl acetate

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

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

Procedure: To a solution of 14.0 g (0.105 mol) of 3-hydroxyphenylacetonitrile in 500 ml of acetone were added 25.9 g (0.105 mol) of 4-chloromethyl-2-phenylthiazole hydrochloride and 34.2 g (0.105 mol) of cesium carbonate and 1 g of potassium iodide and the slurry is heated to reflux for 20 hours. The mixture is filtered and the solution is concentrated in vacuo to obtain crystals. Recrystallization from ethyl acetate gives 14.0 g (43%) crystals, m.p. 108°-110° C. The product is used without further purification in subsequent reactions. the slurry is heated to reflux for 20 hours The mixture is filtered the solution is concentrated in vacuo to obtain crystals Recrystallization from ethyl acetate

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

Procedure: To a solution of (3-hydroxyphenyl)acetonitrile (75.0 g, 0.56 mol) in toluene (750 mL) was added paraformaldehyde (84.0 g, 2.80 mol) and toluene-4-sulfonic acid monohydrate (10.7 g, 56.0 mmol) at room temperature. The reaction mixture was heated at reflux for 40 minutes. Toluene was removed by evaporation. Water (150 mL) and ethyl acetate (150 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was separated by preparative HPLC to give 2-(4H-benzo[d][1,3]dioxin-7-yl)acetonitrile (4.7 g, 5%). 1H NMR (300 MHz, CDCl3) δ 6.85-6.98 (m, 3 H), 5.25 (d, J=3.0 Hz, 2 H), 4.89 (s, 2 H), 3.69 (s, 2 H). The reaction mixture was heated at reflux for 40 minutes Toluene was removed by evaporation Water (150 mL) and ethyl acetate (150 mL) were added The organic layer was separated the aqueous layer was extracted with ethyl acetate The combined organics were washed with brine dried over anhydrous Na2SO4 evaporated under vacuum The residue was separated by preparative HPLC

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

Procedure: To a solution of (3-methoxyphenyl)acetonitrile (150 g, 1.03 mol) in CH2Cl2 (1000 mL) was added BBr3 (774 g, 3.09 mol) dropwise at −70° C. The mixture was stirred and warmed to room temperature slowly. Water (300 mL) was added at 0° C. The resulting mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under vacuum. The crude residue was purified by column (Petroleum Ether/EtOAc 10:1) to give (3-hydroxyphenyl)acetonitrile (75.0 g, 55%). 1H NMR (CDCl3, 300 MHz) δ 7.18-7.24 (m, 1 H), 6.79-6.84 (m, 3 H), 3.69 (s, 2 H). The resulting mixture was extracted with CH2Cl2 The combined organic layers were dried over anhydrous Na2SO4 filtered evaporated under vacuum The crude residue was purified by column (Petroleum Ether/EtOAc 10:1)

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

Procedure: To a solution of (3-methoxyphenyl)acetonitrile (150 g, 1.03 mol) in CH2Cl2 (1000 mL) was added BBr3 (774 g, 3.09 mol) dropwise at −70° C. The mixture was stirred and warmed to room temperature slowly. Water (300 mL) was added at 0° C. The resulting mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated under vacuum. The crude residue was purified by column (Petroleum Ether/EtOAc 10:1) to give (3-hydroxyphenyl)acetonitrile (75.0 g, 55%). 1H NMR (CDCl3, 300 MHz) δ 7.18-7.24 (m, 1 H), 6.79-6.84 (m, 3 H), 3.69 (s, 2 H). The resulting mixture was extracted with CH2Cl2 The combined organic layers were dried over anhydrous Na2SO4 filtered evaporated under vacuum The crude residue was purified by column (Petroleum Ether/EtOAc 10:1)

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

Procedure: To a solution of (3-hydroxyphenyl)acetonitrile (75.0 g, 0.56 mol) in toluene (750 mL) was added paraformaldehyde (84.0 g, 2.80 mol) and toluene-4-sulfonic acid monohydrate (10.7 g, 56.0 mmol) at room temperature. The reaction mixture was heated at reflux for 40 minutes. Toluene was removed by evaporation. Water (150 mL) and ethyl acetate (150 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was separated by preparative HPLC to give 2-(4H-benzo[d][1,3]dioxin-7-yl)acetonitrile (4.7 g, 5%). 1H NMR (300 MHz, CDCl3) δ 6.85-6.98 (m, 3 H), 5.25 (d, J=3.0 Hz, 2 H), 4.89 (s, 2 H), 3.69 (s, 2 H). The reaction mixture was heated at reflux for 40 minutes Toluene was removed by evaporation Water (150 mL) and ethyl acetate (150 mL) were added The organic layer was separated the aqueous layer was extracted with ethyl acetate The combined organics were washed with brine dried over anhydrous Na2SO4 evaporated under vacuum The residue was separated by preparative HPLC