ethyl 3-bromobenzoate

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

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

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

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

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium phosphate (1.38 g, 6.5 mmol), palladium(II) acetate (56 mg, 0.25 mmol), and (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-di-tert-butylphosphine (139 mg, 0.25 mmol) were combined in a microwave tube under nitrogen. Ethyl 3-bromobenzoate (1.145 g, 5 mmol) in dimethoxyethane (2 mL) and isopropylamine (385 mg, 6.5 mmol) in dimethoxyethane (2 mL) were added. The tube was filled with nitrogen again. The tube was then capped, and the reaction mixture was heated in a microwave oven (Biotage Initiator™ 2.0, 0 to 100 watts) with stirring at 160° C. for 70 minutes. Then dichloromethane was added, and the crude mixture was filtered. The filtrate was concentrated. The residue was purified by chromatography on silica gel (hexane/ethyl acetate=7:1) to give ethyl 3-(isopropylamino)benzoate. The tube was filled with nitrogen again The tube was then capped the reaction mixture was heated in a microwave oven (Biotage Initiator™ 2.0, 0 to 100 watts) the crude mixture was filtered The filtrate was concentrated The residue was purified by chromatography on silica gel (hexane/ethyl acetate=7:1)

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium phosphate (1.38 g, 6.5 mmol), palladium(II) acetate (56 mg, 0.25 mmol), and (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-di-tert-butylphosphine (139 mg, 0.25 mmol) were combined in a microwave tube under nitrogen. Ethyl 3-bromobenzoate (1.145 g, 5 mmol) in dimethoxyethane (2 mL) and isopropylamine (385 mg, 6.5 mmol) in dimethoxyethane (2 mL) were added. The tube was filled with nitrogen again. The tube was then capped, and the reaction mixture was heated in a microwave oven (Biotage Initiator™ 2.0, 0 to 100 watts) with stirring at 160° C. for 70 minutes. Then dichloromethane was added, and the crude mixture was filtered. The filtrate was concentrated. The residue was purified by chromatography on silica gel (hexane/ethyl acetate=7:1) to give ethyl 3-(isopropylamino)benzoate. The tube was filled with nitrogen again The tube was then capped the reaction mixture was heated in a microwave oven (Biotage Initiator™ 2.0, 0 to 100 watts) the crude mixture was filtered The filtrate was concentrated The residue was purified by chromatography on silica gel (hexane/ethyl acetate=7:1)

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1,2,3,4-tetrahydro-2,7-naphthyridine dihydrochloride (41.4 mg, 0.20 mmol), cesium carbonate (326 mg, 1.0 mmol), and triethylamine (0.056 mL, 0.40 mmol) in 2.0 mL dioxane was warmed until the amine starting material had dissolved. The reaction filtrate was transferred into another reaction vial and the following added: a spatula portion of cesium carbonate, ethyl 3-bromobenzoate (0.032 mL, 0.20 mmol), palladium acetate (2.2 mg, 0.01 mmol) plus catalytic Pd2(dba)3, and RAC-BINAP (6.2 mg, 0.01 mmol). The reaction was heated at 95° C. for 17 hours, filtered, and evaporated to an oil. The oil was chromatograph eluting with CHCl3/EtOAc to give the title compound as a light yellow oil (3.2 mg, 6%). 1H NMR (CDCl3) δ: 8.46 (s, 1H), 8.39 (d, J=5.0 Hz, 1H), 7.66 (dd, J=2.3, 1.5 Hz, 1H), 7.54 (dt, J=7.5, 1.2 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 7.16 (dd, J=8.4, 1.9 Hz, 1H), 7.12 (d, J=5.0 Hz, 1H), 4.46 (s, 2H), 4.39 (q, J=7.1 Hz, 2H), 3.62 (t, J=5.9 Hz, 2H), 3.01 (t, J=5.7 Hz, 2H), 1.38-1.44 (m, 3H). had dissolved following added filtered evaporated to an oil eluting with CHCl3/EtOAc

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

Procedure: This intermediate was prepared from ethyl 3-bromobenzoate and cyclobutylzinc bromide in two steps according to the preparation of 6-cyclopentyl-benzoic acid.

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1.00 mL (6.24 mmol) ethyl 3-bromobenzoate was added 13.0 mL (6.50 mmol) 0.5 M cyclopentylzinc bromide solution in THF followed by 100 mg (0.137 mmol) 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) under argon atmosphere. The reaction mixture was stirred at 85° C. for 1.5 h, then diluted with water and stirred at RT for 12 h. The suspension was extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was filtered through Alox (EtOAC) and concentrated in vacuo. stirred at RT for 12 h The suspension was extracted with EtOAc The combined organic phases were dried over sodium sulfate filtered concentrated in vacuo The crude material was filtered through Alox (EtOAC) concentrated in vacuo

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

Procedure: (2,4-Dimethylphenyl)boronic acid (3.0 g, 20.0 mmol), ethyl 3-bromobenzoate (4.3 g, 18.8 mmol) and cesium carbonate (9.8 g, 30.0 mmol) were added to a mixture of ethanol (20 mL) and toluene (80 mL), and after argon substitution, tetrakis(triphenylphosphine)palladium(0) (0.30 g, 0.26 mmol) was added. The reaction mixture was stirred under an argon atmosphere at 70° C. for 18 hrs. The reaction mixture was cooled and insoluble material was filtered off through celite. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10) to give the title compound (5.0 g, yield 100%) as a colorless oil. The reaction mixture was cooled insoluble material was filtered off through celite The filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10)

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

Procedure: (2,4-Dimethylphenyl)boronic acid (3.0 g, 20.0 mmol), ethyl 3-bromobenzoate (4.3 g, 18.8 mmol) and cesium carbonate (9.8 g, 30.0 mmol) were added to a mixture of ethanol (20 mL) and toluene (80 mL), and after argon substitution, tetrakis(triphenylphosphine)palladium(0) (0.30 g, 0.26 mmol) was added. The reaction mixture was stirred under an argon atmosphere at 70° C. for 18 hrs. The reaction mixture was cooled and insoluble material was filtered off through celite. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10) to give the title compound (5.0 g, yield 100%) as a colorless oil. The reaction mixture was cooled insoluble material was filtered off through celite The filtrate was concentrated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10)

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1,2,3,4-tetrahydro-2,7-naphthyridine dihydrochloride (41.4 mg, 0.20 mmol), cesium carbonate (326 mg, 1.0 mmol), and triethylamine (0.056 mL, 0.40 mmol) in 2.0 mL dioxane was warmed until the amine starting material had dissolved. The reaction filtrate was transferred into another reaction vial and the following added: a spatula portion of cesium carbonate, ethyl 3-bromobenzoate (0.032 mL, 0.20 mmol), palladium acetate (2.2 mg, 0.01 mmol) plus catalytic Pd2(dba)3, and RAC-BINAP (6.2 mg, 0.01 mmol). The reaction was heated at 95° C. for 17 hours, filtered, and evaporated to an oil. The oil was chromatograph eluting with CHCl3/EtOAc to give the title compound as a light yellow oil (3.2 mg, 6%). 1H NMR (CDCl3) δ: 8.46 (s, 1H), 8.39 (d, J=5.0 Hz, 1H), 7.66 (dd, J=2.3, 1.5 Hz, 1H), 7.54 (dt, J=7.5, 1.2 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 7.16 (dd, J=8.4, 1.9 Hz, 1H), 7.12 (d, J=5.0 Hz, 1H), 4.46 (s, 2H), 4.39 (q, J=7.1 Hz, 2H), 3.62 (t, J=5.9 Hz, 2H), 3.01 (t, J=5.7 Hz, 2H), 1.38-1.44 (m, 3H). had dissolved following added filtered evaporated to an oil eluting with CHCl3/EtOAc