3-ethoxyphenol

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

Procedure: A mixture of 1-[6-(2,6-diethyl-phenyl)-4-ethoxy-pyridin-3-yl]-butan-1-ol (67 mg, 0.20 mmol), 3-ethoxy-phenol (34 mg, 0.25 mmol), triphenylphosphine (65 mg, 0.25 mmol), and DEAD (36 mg, 0.25 mmol) in THF (1 mL) is stirred at room temperature overnight. Aqueous NH4Cl solution (5 mL) and hexane (10 mL) are added to the mixture, and the organic layer is separated. The organic layer is washed with NaHCO3 solution, brine, dried over Na2SO4, and concentrated. The residue is purified by PTLC to give 2-(2,6-diethyl-phenyl)-5-[1-(3-ethoxy-phenoxy)-butyl]-4-ethoxy-pyridine. 1H NMR (CDCl3) 8.55 (s, 1H), 7.27 (m, 1H), 7.07-7.14 (m, 3H), 6.73 (s, 1H), 6.43-6.49 (m, 3H), 5.57 (m, 1H), 4.13 (q, 2H), 3.95 (q, 2H), 2.56-2.37 (m, 4H), 1.85-2.05 (m, 2H), 1.40-1.60 (m, 5H), 1.37 (t, 3H), 0.96-1.08 (m, 9H). the organic layer is separated The organic layer is washed with NaHCO3 solution, brine dried over Na2SO4 concentrated The residue is purified by PTLC

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

Procedure: A mixture of 1-[6-(2,6-diethyl-phenyl)-4-ethoxy-pyridin-3-yl]-butan-1-ol (67 mg, 0.20 mmol), 3-ethoxy-phenol (34 mg, 0.25 mmol), triphenylphosphine (65 mg, 0.25 mmol), and DEAD (36 mg, 0.25 mmol) in THF (1 mL) is stirred at room temperature overnight. Aqueous NH4Cl solution (5 mL) and hexane (10 mL) are added to the mixture, and the organic layer is separated. The organic layer is washed with NaHCO3 solution, brine, dried over Na2SO4, and concentrated. The residue is purified by PTLC to give 2-(2,6-diethyl-phenyl)-5-[1-(3-ethoxy-phenoxy)-butyl]-4-ethoxy-pyridine. 1H NMR (CDCl3) 8.55 (s, 1H), 7.27 (m, 1H), 7.07-7.14 (m, 3H), 6.73 (s, 1H), 6.43-6.49 (m, 3H), 5.57 (m, 1H), 4.13 (q, 2H), 3.95 (q, 2H), 2.56-2.37 (m, 4H), 1.85-2.05 (m, 2H), 1.40-1.60 (m, 5H), 1.37 (t, 3H), 0.96-1.08 (m, 9H). the organic layer is separated The organic layer is washed with NaHCO3 solution, brine dried over Na2SO4 concentrated The residue is purified by PTLC

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

Procedure: To a mixture of 5-bromoveratraldehyde (245 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) in ethanol (2 ml) was added piperidine (0.1 ml, 1 mmol). The mixture was stirred at room temperature for 15 min, then 3-ethoxyphenol (138 mg, 1 mmol) was added and it was stirred overnight. The solvent was evaporated and the residue was purified by chromatography on silica gel (EtOAc/Hexane, 1:2) to yield the title compound. 1H NMR (CDCl3): 6.84-6.82 (m, 2H), 6.70 (s, 1H), 6.61-6.65 (m, 1H), 6.53 (s, 1H), 4.62 (m, 3H), 4.0 (q, J=6.0, 2H), 3.82 (s, 6H), 1.4 (t, J=6.0, 3H). it was stirred overnight The solvent was evaporated the residue was purified by chromatography on silica gel (EtOAc/Hexane, 1:2)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The two reactions were performed in parallel. Two microwave vials were set up in parallel. In a large 30 mL microwave vial, 3-(ethyloxy)phenol (2 times 1.25 g, 9.045 mmol) was dissolved in 6 mL of dimethylformamide. 1-Fluoro-4-nitrobenzene (2 times 1.28 g, 9.045 mmol) and potassium carbonate (2 times 3.75 g, 27.15 mmol) were added. The reaction mixture was heated under microwave irradiation during 1 hour at 120° C. The combined reaction mixtures were filtered. The filtrated solid was washed with dichloromethane. The volatiles were evaporated under vacuum. Some dichloromethane and brine were added to this crude. The compound was extracted with dichloromethane (2 times) and ethyl acetate (2 times). The combined organic phases were dried over sodium sulphate. This afforded the title compound (4 g). The combined reaction mixtures were filtered The filtrated solid was washed with dichloromethane The volatiles were evaporated under vacuum Some dichloromethane and brine were added to this crude The compound was extracted with dichloromethane (2 times) and ethyl acetate (2 times) The combined organic phases were dried over sodium sulphate

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The two reactions were performed in parallel. Two microwave vials were set up in parallel. In a large 30 mL microwave vial, 3-(ethyloxy)phenol (2 times 1.25 g, 9.045 mmol) was dissolved in 6 mL of dimethylformamide. 1-Fluoro-4-nitrobenzene (2 times 1.28 g, 9.045 mmol) and potassium carbonate (2 times 3.75 g, 27.15 mmol) were added. The reaction mixture was heated under microwave irradiation during 1 hour at 120° C. The combined reaction mixtures were filtered. The filtrated solid was washed with dichloromethane. The volatiles were evaporated under vacuum. Some dichloromethane and brine were added to this crude. The compound was extracted with dichloromethane (2 times) and ethyl acetate (2 times). The combined organic phases were dried over sodium sulphate. This afforded the title compound (4 g). The combined reaction mixtures were filtered The filtrated solid was washed with dichloromethane The volatiles were evaporated under vacuum Some dichloromethane and brine were added to this crude The compound was extracted with dichloromethane (2 times) and ethyl acetate (2 times) The combined organic phases were dried over sodium sulphate

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

Procedure: A 500 mL flask fitted with a stir-bar and septum with an Ar inlet was charged with 3-ethoxyphenol (20.4 g, 148 mmol), K2CO3 (28.5 g, 222 mmol), and DMF (250 mL). To the resultant solution was added ethyl bromoacetate (27.1 g, 18.0 mL, 162 mmol) and the mixture stirred overnight. The solids were filtered off and rinsed with EtOAc (500 mL). The filtrate was washed with saturated aqueous NH4Cl (2×250 mL), H2O (2×250 mL), and brine (200 mL), filtered through phase separation paper, and concentrated in vacuo to give 33.6 g of ethyl 3-ethoxyphenoxyacetate as a colorless oil (100%). 1H NMR (60 MHz, CDCl3): δ 7.2-6.9 (m, 1H), 6.6-6.3 (m, 3H), 4.6 (s, 2H), 4.2 (qt, 2H), 4.0 (qt, 2H), 1.4 (t, 3H), 1.3 (t, 3H) ppm. HPLC analysis (0:10:90 H2O:A1:MeOH) showed a purity of 98% with a retention time of 5.3 min. A 500 mL flask fitted with a stir-bar The solids were filtered off rinsed with EtOAc (500 mL) The filtrate was washed with saturated aqueous NH4Cl (2×250 mL), H2O (2×250 mL), and brine (200 mL) filtered through phase separation paper concentrated in vacuo

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

Procedure: A 500 mL flask fitted with a stir-bar and septum with an Ar inlet was charged with 3-ethoxyphenol (20.4 g, 148 mmol), K2CO3 (28.5 g, 222 mmol), and DMF (250 mL). To the resultant solution was added ethyl bromoacetate (27.1 g, 18.0 mL, 162 mmol) and the mixture stirred overnight. The solids were filtered off and rinsed with EtOAc (500 mL). The filtrate was washed with saturated aqueous NH4Cl (2×250 mL), H2O (2×250 mL), and brine (200 mL), filtered through phase separation paper, and concentrated in vacuo to give 33.6 g of ethyl 3-ethoxyphenoxyacetate as a colorless oil (100%). 1H NMR (60 MHz, CDCl3): δ 7.2-6.9 (m, 1H), 6.6-6.3 (m, 3H), 4.6 (s, 2H), 4.2 (qt, 2H), 4.0 (qt, 2H), 1.4 (t, 3H), 1.3 (t, 3H) ppm. HPLC analysis (0:10:90 H2O:A1:MeOH) showed a purity of 98% with a retention time of 5.3 min. A 500 mL flask fitted with a stir-bar The solids were filtered off rinsed with EtOAc (500 mL) The filtrate was washed with saturated aqueous NH4Cl (2×250 mL), H2O (2×250 mL), and brine (200 mL) filtered through phase separation paper concentrated in vacuo

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

Procedure: A mixture of 1-[6-(2,6-diethyl-phenyl)-4-ethoxy-pyridin-3-yl]-butan-1-ol (67 mg, 0.20 mmol), 3-ethoxy-phenol (34 mg, 0.25 mmol), triphenylphosphine (65 mg, 0.25 mmol), and DEAD (36 mg, 0.25 mmol) in THF (1 mL) is stirred at room temperature overnight. Aqueous NH4Cl solution (5 mL) and hexane (10 mL) are added to the mixture, and the organic layer is separated. The organic layer is washed with NaHCO3 solution, brine, dried over Na2SO4, and concentrated. The residue is purified by PTLC to give 2-(2,6-diethyl-phenyl)-5-[1-(3-ethoxy-phenoxy)-butyl]-4-ethoxy-pyridine. 1H NMR (CDCl3) 8.55 (s, 1H), 7.27 (m, 1H), 7.07-7.14 (m, 3H), 6.73 (s, 1H), 6.43-6.49 (m, 3H), 5.57 (m, 1H), 4.13 (q, 2H), 3.95 (q, 2H), 2.56-2.37 (m, 4H), 1.85-2.05 (m, 2H), 1.40-1.60 (m, 5H), 1.37 (t, 3H), 0.96-1.08 (m, 9H). the organic layer is separated The organic layer is washed with NaHCO3 solution, brine dried over Na2SO4 concentrated The residue is purified by PTLC

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To solution of methyl 5-chloro-2,4-difluorobenzoate (25.9 mg, 0.125 mmol) and 3-ethoxyphenol (17.3 mg, 0.125 mmol) in dimethyl formamide (0.5 mL) was added cesium carbonate (82 mg, 0.25 mmol), the mixture was shaken at 120° C. for 16 hours, filtered and evaporated in vacuo. Water (1 mL) was added and extracted with ethyl acetate (3×1 mL), the combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was dissolved in THF (0.7 mL) and to this solution was added a 1M aqueous solution of lithium hydroxide (0.7 mL) and the mixture was shaken at 30° C. for 16 hours. The reaction mixture was evaporated in vacuo, a 1M aqueous solution of hydrochloric acid (0.7 mL) was added and extracted with ethyl acetate (3×1 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and evaporated in vacuo. To this residue was added methanesulfonamide (28.6 mg, 0.300 mmol) and a solution of 4-dimethylaminopyridine (24.4 mg, 0.200 mmol) and EDCl (38.3 mg, 0.200 mmol) in dichloromethane (1 mL), the solution was shaken at 30° C. for 16 hours and evaporated in vacuo. The crude product was purified on a HPLC column (Sepax BR-C18 100*21.2 mm*5 μm, acetonitrile-water (0.1% trifluoroacetic acid) gradient to yield 6.2 mg (16 μmol) 5-chloro-4-(3-ethoxyphenoxy)-2-fluoro-N-(methylsulfonyl)benzamide. filtered evaporated in vacuo Water (1 mL) was added extracted with ethyl acetate (3×1 mL) the combined organic layers were dried over sodium sulphate filtered evaporated in vacuo The residue was dissolved in THF (0.7 mL) and to this solution was added a 1M aqueous solution of lithium hydroxide (0.7 mL) the mixture was shaken at 30° C. for 16 hours The reaction mixture was evaporated in vacuo a 1M aqueous solution of hydrochloric acid (0.7 mL) was added extracted with ethyl acetate (3×1 mL) The combined organic layers were dried over anhydrous sodium sulphate filtered evaporated in vacuo evaporated in vacuo The crude product was purified on a HPLC column (Sepax

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To solution of methyl 5-chloro-2,4-difluorobenzoate (25.9 mg, 0.125 mmol) and 3-ethoxyphenol (17.3 mg, 0.125 mmol) in dimethyl formamide (0.5 mL) was added cesium carbonate (82 mg, 0.25 mmol), the mixture was shaken at 120° C. for 16 hours, filtered and evaporated in vacuo. Water (1 mL) was added and extracted with ethyl acetate (3×1 mL), the combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was dissolved in THF (0.7 mL) and to this solution was added a 1M aqueous solution of lithium hydroxide (0.7 mL) and the mixture was shaken at 30° C. for 16 hours. The reaction mixture was evaporated in vacuo, a 1M aqueous solution of hydrochloric acid (0.7 mL) was added and extracted with ethyl acetate (3×1 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and evaporated in vacuo. To this residue was added methanesulfonamide (28.6 mg, 0.300 mmol) and a solution of 4-dimethylaminopyridine (24.4 mg, 0.200 mmol) and EDCl (38.3 mg, 0.200 mmol) in dichloromethane (1 mL), the solution was shaken at 30° C. for 16 hours and evaporated in vacuo. The crude product was purified on a HPLC column (Sepax BR-C18 100*21.2 mm*5 μm, acetonitrile-water (0.1% trifluoroacetic acid) gradient to yield 6.2 mg (16 μmol) 5-chloro-4-(3-ethoxyphenoxy)-2-fluoro-N-(methylsulfonyl)benzamide. filtered evaporated in vacuo Water (1 mL) was added extracted with ethyl acetate (3×1 mL) the combined organic layers were dried over sodium sulphate filtered evaporated in vacuo The residue was dissolved in THF (0.7 mL) and to this solution was added a 1M aqueous solution of lithium hydroxide (0.7 mL) the mixture was shaken at 30° C. for 16 hours The reaction mixture was evaporated in vacuo a 1M aqueous solution of hydrochloric acid (0.7 mL) was added extracted with ethyl acetate (3×1 mL) The combined organic layers were dried over anhydrous sodium sulphate filtered evaporated in vacuo evaporated in vacuo The crude product was purified on a HPLC column (Sepax

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To solution of methyl 5-chloro-2,4-difluorobenzoate (25.9 mg, 0.125 mmol) and 3-ethoxyphenol (17.3 mg, 0.125 mmol) in dimethyl formamide (0.5 mL) was added cesium carbonate (82 mg, 0.25 mmol), the mixture was shaken at 120° C. for 16 hours, filtered and evaporated in vacuo. Water (1 mL) was added and extracted with ethyl acetate (3×1 mL), the combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was dissolved in THF (0.7 mL) and to this solution was added a 1M aqueous solution of lithium hydroxide (0.7 mL) and the mixture was shaken at 30° C. for 16 hours. The reaction mixture was evaporated in vacuo, a 1M aqueous solution of hydrochloric acid (0.7 mL) was added and extracted with ethyl acetate (3×1 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and evaporated in vacuo. To this residue was added methanesulfonamide (28.6 mg, 0.300 mmol) and a solution of 4-dimethylaminopyridine (24.4 mg, 0.200 mmol) and EDCl (38.3 mg, 0.200 mmol) in dichloromethane (1 mL), the solution was shaken at 30° C. for 16 hours and evaporated in vacuo. The crude product was purified on a HPLC column (Sepax BR-C18 100*21.2 mm*5 μm, acetonitrile-water (0.1% trifluoroacetic acid) gradient to yield 6.2 mg (16 μmol) 5-chloro-4-(3-ethoxyphenoxy)-2-fluoro-N-(methylsulfonyl)benzamide. filtered evaporated in vacuo Water (1 mL) was added extracted with ethyl acetate (3×1 mL) the combined organic layers were dried over sodium sulphate filtered evaporated in vacuo The residue was dissolved in THF (0.7 mL) and to this solution was added a 1M aqueous solution of lithium hydroxide (0.7 mL) the mixture was shaken at 30° C. for 16 hours The reaction mixture was evaporated in vacuo a 1M aqueous solution of hydrochloric acid (0.7 mL) was added extracted with ethyl acetate (3×1 mL) The combined organic layers were dried over anhydrous sodium sulphate filtered evaporated in vacuo evaporated in vacuo The crude product was purified on a HPLC column (Sepax

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

Procedure: A solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-cyano-3-methyl-2-(methylsulfonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidine-3-yl}carbamate (110 mg), 3-ethoxyphenol (31 μl) and potassium carbonate (39 mg) in N,N-dimethylformamide (2 ml) was stirred at 50° C. for 1 hour. After the reaction solution was allowed to cool, a saturated aqueous ammonium chloride solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to obtain the title compound (86 mg) as a white solid. to cool followed by extraction with ethyl acetate The organic layer was washed with water a saturated aqueous sodium chloride solution, dried over sodium sulfate filtered the filtrate was concentrated under reduced pressure The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1)