2-[(4-methoxyphenyl)methylamino]ethanol

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-chloro-6-oxo-1,6-dihydropyridine-2-carboxylic acid (1, 0.25 g, 1.44 mmol) in acetonitrile (10 mL), 2-((4-methoxybenzyl)amino)ethanol (2, 0.31 g, 1.73 mmol) followed by cesium carbonate (1.18 g, 3.61 mmol) and HATU (1.26 g, 3.32 mmol) were added and the reaction mixture was stirred at 50° C. for 16 h. The reaction mixture was diluted with water and the compound was extracted in ethyl acetate. The organic layer was washed with brine, separated, dried over sodium sulphate and concentrated under reduced pressure. The residue obtained was purified via column chromatography (silica, ethyl acetate/hexanes=60%) to afford 7-chloro-2-(4-methoxybenzyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6-(2H)-dione (3). Yield: 0.24 g, 52%; MS (ESI) m/z 319 [M+1]+. were added the compound was extracted in ethyl acetate The organic layer was washed with brine separated dried over sodium sulphate concentrated under reduced pressure The residue obtained was purified via column chromatography (silica, ethyl acetate/hexanes=60%)

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

Procedure: Acetic acid (ca. 150 ml) was added to a solution of p-anisaldehyde (58.2 g, 0.42 mol) and ethanolamine (152 ml, 2.52 mol) in methanol (1 L), to achieve a pH of 6. Sodium triacetoxyborohydride (100 g, 0.47 mol) was added portionwise, and once addition was complete, the mixture was stirred at room temperature for 72 hours. The mixture was concentrated under reduced pressure, basified using 1N sodium hydroxide solution and extracted with dichloromethane (10×300 ml). The combined extracts were evaporated and the crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (98:2 to 90:10) to afford the title compound, 42 g. 1H-NMR (CDCl3, 400 MHz) δ: 2.78 (t, 2H), 3.62 (t, 2H), 3.75 (m, 5H), 4.24 (s, 2H), 6.81 (d, 2H), 7.22 (d, 2H). LRMS: m/z (ES+) 182 [MH+]. once addition The mixture was concentrated under reduced pressure extracted with dichloromethane (10×300 ml) The combined extracts were evaporated the crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (98:2 to 90:10)

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

Procedure: To a solution of 3-bromo-6-fluoro-2-methylbenzoic acid (Cpd QQ, 4.8 g, 2.4 mmol), 2-[(4-methoxybenzyl)amino]ethanol (130a, 5.5 g, 23 mmol) and DIPEA (8 g, 62 mmol) in dry DMF (80 mL) was added HATU (12 g, 31 mmol). The mixture was stirred at room temperature for 14 hours. To the reaction mixture was added EtOAc (130 mL). The solution was washed with brine (4×60 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc, 2/1) to give 3-bromo-6-fluoro-N-(2-hydroxyethyl)-N-(4-methoxybenzyl)-2-methylbenzamide (130b, 4 g, 48.8%) as a colorless oil. The solution was washed with brine (4×60 mL) dried over Na2SO4 concentrated under vacuum The residue was purified by column chromatography (petroleum ether/EtOAc, 2/1)

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-methoxybenzaldehyde (10 g, 74 mmol), 2-aminoethanol (4.9 g, 81 mmol) and NaHCO3 (9.3 g, 110 mmol) in MeOH (100 mL) was refluxed for 3 hours. The reaction mixture was cooled to 15° C. To the mixture was added portionwise NaBH4 (3.3 g, 88 mmol) at 15° C. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give 2-[(4-methoxybenzyl)amino]ethanol (130a, 20 g) as a brown oil. was refluxed for 3 hours The reaction mixture was filtered the filtrate was concentrated under vacuum

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-methoxybenzaldehyde (10 g, 74 mmol), 2-aminoethanol (4.9 g, 81 mmol) and NaHCO3 (9.3 g, 110 mmol) in MeOH (100 mL) was refluxed for 3 hours. The reaction mixture was cooled to 15° C. To the mixture was added portionwise NaBH4 (3.3 g, 88 mmol) at 15° C. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give 2-[(4-methoxybenzyl)amino]ethanol (130a, 20 g) as a brown oil. was refluxed for 3 hours The reaction mixture was filtered the filtrate was concentrated under vacuum

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 1 L round bottom flask is charged with 2-aminoethanol (29 g, 213 mmol), 4-methoxybenzaldehyde (39 g, 639 mmol), methanol (250 mL) and acetic acid (75 mL) under a nitrogen atmosphere. The contents were cooled to 0° C. and sodium triacetoxyborohydride (50 g, 234 mmol) was added over a 20 minute period. The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and partitioned between water (500 mL) and ethyl acetate (500 mL). The ethyl acetate layer was washed with 3N HCl (400 mL). The HCl layer is separated, cooled to 0° C., made basic using 6N NaOH and extracted with dichloromethane (2×100 mL). The dichloromethane layer was dried over sodium sulfate and concentrated under reduced pressure to yield the title compound a as an oil (20 g). 1H-NMR of the oil was consistent with the desired structure. concentrated under reduced pressure partitioned between water (500 mL) and ethyl acetate (500 mL) The ethyl acetate layer was washed with 3N HCl (400 mL) The HCl layer is separated cooled to 0° C. extracted with dichloromethane (2×100 mL) The dichloromethane layer was dried over sodium sulfate concentrated under reduced pressure

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

Procedure: Acetic acid (ca. 150 ml) was added to a solution of p-anisaldehyde (58.2 g, 0.42 mol) and ethanolamine (152 ml, 2.52 mol) in methanol (1L), to achieve a pH of 6. Sodium triacetoxyborohydride (100 g, 0.47 mol) was added portionwise, and once addition was complete, the mixture was stirred at room temperature for 72 hours. The mixture was concentrated under reduced pressure, basified using 1N sodium hydroxide solution and extracted with dichloromethane (10×300 ml). The combined extracts were evaporated and the crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (98:2 to 90:10) to afford the title compound, 42 g. 1H-NMR (CDCl3, 400 MHz) δ: 2.78 (t, 2H), 3.62 (t, 2H), 3.75 (m, 5H), 4.24 (s, 2H), 6.81 (d, 2H), 7.22 (d, 2H). LRMS: m/z (ES+) 182 [MH+]. once addition The mixture was concentrated under reduced pressure extracted with dichloromethane (10×300 ml) The combined extracts were evaporated the crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (98:2 to 90:10)

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

Procedure: Acetic acid (ca. 150 ml) was added to a solution of p-anisaldehyde (58.2 g, 0.42 mol) and ethanolamine (152 ml, 2.52 mol) in methanol (1L), to achieve a pH of 6. Sodium triacetoxyborohydride (100 g, 0.47 mol) was added portionwise, and once addition was complete, the mixture was stirred at room temperature for 72 hours. The mixture was concentrated under reduced pressure, basified using 1N sodium hydroxide solution and extracted with dichloromethane (10×300 ml). The combined extracts were evaporated and the crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (98:2 to 90:10) to afford the title compound, 42 g. 1H-NMR (CDCl3, 400 MHz) δ: 2.78 (t, 2H), 3.62 (t, 2H), 3.75 (m, 5H), 4.24 (s, 2H), 6.81 (d, 2H), 7.22 (d, 2H). LRMS: m/z (ES+) 182 [MH+]. once addition The mixture was concentrated under reduced pressure extracted with dichloromethane (10×300 ml) The combined extracts were evaporated the crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (98:2 to 90:10)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 1 L round bottom flask is charged with 2-aminoethanol (29 g, 213 mmol), 4-methoxybenzaldehyde (39 g, 639 mmol), methanol (250 mL) and acetic acid (75 mL) under a nitrogen atmosphere. The contents were cooled to 0° C. and sodium triacetoxyborohydride (50 g, 234 mmol) was added over a 20 minute period. The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and partitioned between water (500 mL) and ethyl acetate (500 mL). The ethyl acetate layer was washed with 3N HCl (400 mL). The HCl layer is separated, cooled to 0° C., made basic using 6N NaOH and extracted with dichloromethane (2×100 mL). The dichloromethane layer was dried over sodium sulfate and concentrated under reduced pressure to yield the title compound a as an oil (20 g). 1H-NMR of the oil was consistent with the desired structure. concentrated under reduced pressure partitioned between water (500 mL) and ethyl acetate (500 mL) The ethyl acetate layer was washed with 3N HCl (400 mL) The HCl layer is separated cooled to 0° C. extracted with dichloromethane (2×100 mL) The dichloromethane layer was dried over sodium sulfate concentrated under reduced pressure

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-chloro-6-oxo-1,6-dihydropyridine-2-carboxylic acid (1, 0.25 g, 1.44 mmol) in acetonitrile (10 mL), 2-((4-methoxybenzyl)amino)ethanol (2, 0.31 g, 1.73 mmol) followed by cesium carbonate (1.18 g, 3.61 mmol) and HATU (1.26 g, 3.32 mmol) were added and the reaction mixture was stirred at 50° C. for 16 h. The reaction mixture was diluted with water and the compound was extracted in ethyl acetate. The organic layer was washed with brine, separated, dried over sodium sulphate and concentrated under reduced pressure. The residue obtained was purified via column chromatography (silica, ethyl acetate/hexanes=60%) to afford 7-chloro-2-(4-methoxybenzyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6-(2H)-dione (3). Yield: 0.24 g, 52%; MS (ESI) m/z 319 [M+1]+. were added the compound was extracted in ethyl acetate The organic layer was washed with brine separated dried over sodium sulphate concentrated under reduced pressure The residue obtained was purified via column chromatography (silica, ethyl acetate/hexanes=60%)

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

Procedure: Acetic acid (ca. 150 ml) was added to a solution of p-anisaldehyde (58.2 g, 0.42 mol) and ethanolamine (152 ml, 2.52 mol) in methanol (1 L), to achieve a pH of 6. Sodium triacetoxyborohydride (100 g, 0.47 mol) was added portionwise, and once addition was complete, the mixture was stirred at room temperature for 72 hours. The mixture was concentrated under reduced pressure, basified using 1N sodium hydroxide solution and extracted with dichloromethane (10×300 ml). The combined extracts were evaporated and the crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (98:2 to 90:10) to afford the title compound, 42 g. 1H-NMR (CDCl3, 400 MHz) δ: 2.78 (t, 2H), 3.62 (t, 2H), 3.75 (m, 5H), 4.24 (s, 2H), 6.81 (d, 2H), 7.22 (d, 2H). LRMS: m/z (ES+) 182 [MH+]. once addition The mixture was concentrated under reduced pressure extracted with dichloromethane (10×300 ml) The combined extracts were evaporated the crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol (98:2 to 90:10)

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

Procedure: To a solution of 3-bromo-6-fluoro-2-methylbenzoic acid (Cpd QQ, 4.8 g, 2.4 mmol), 2-[(4-methoxybenzyl)amino]ethanol (130a, 5.5 g, 23 mmol) and DIPEA (8 g, 62 mmol) in dry DMF (80 mL) was added HATU (12 g, 31 mmol). The mixture was stirred at room temperature for 14 hours. To the reaction mixture was added EtOAc (130 mL). The solution was washed with brine (4×60 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc, 2/1) to give 3-bromo-6-fluoro-N-(2-hydroxyethyl)-N-(4-methoxybenzyl)-2-methylbenzamide (130b, 4 g, 48.8%) as a colorless oil. The solution was washed with brine (4×60 mL) dried over Na2SO4 concentrated under vacuum The residue was purified by column chromatography (petroleum ether/EtOAc, 2/1)