ethyl benzoate

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:0.00; pressure:0.00; stir:

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

Procedure: To a solution of 2-methylthiazole (500 mg, 5.1 mmol) in anhydrous THF (10 mL) at −78° C. under nitrogen was added dropwise n-BuLi (2.5 mol/L, 2.0 mL), after being stirred at this temperature for 1 hour, a solution of ethyl benzoate (1.1 g, 7.3 mmol) in anhydrous THF (5 mL) was added, and the reaction mixture was stirred at room temperature overnight. When TLC (PE:EtOAc=7:1) indicated that the starting materials were consumed, water was added to quench the reaction, and the aqueous layer extracted with EtOAc (10 mL×3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by column chromatography (PE:EtOAc=15:1) to afford Intermediate 3 as a yellow oil (170 mg, yield: 17.0%). the reaction mixture was stirred at room temperature overnight were consumed water was added to quench the reaction the aqueous layer extracted with EtOAc (10 mL×3) The combined organic layer was washed with brine (10 mL) dried over Na2SO4 filtered concentrated purified by column chromatography (PE:EtOAc=15:1)

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

Procedure: 86 ml (86 mmoles) of 1.0 M sodium bis(trimethylsilyl)amide in tetrahydrofuran was added drop-wise by addition funnel to a solution of 6.03 g (43 mmoles) 4-methyl-2-(methylthio)pyrimidine and 6.46 g (43 mmoles) ethyl benzoate in 86 ml tetrahydrofuran under a nitrogen atmosphere. After 2 hours the reaction was quenched with saturated ammonium chloride solution. Most of the tetrahydrofuran was removed in vacuo. The residue was diluted with 400 ml ethyl acetate and 200 ml water. The organic layer was separated and washed 2×100 ml saturated sodium chloride solution, separated, dried over Na2SO4, filtered, and concentrated in vacuo to give 10.45 g (42.77 mmoles) of 2-[2-(methyl thio)pyrimidin-4-yl]-1-phenyle thanone as a viscous red-brown oil that solidified upon standing. MH+=244.9. After 2 hours the reaction was quenched with saturated ammonium chloride solution Most of the tetrahydrofuran was removed in vacuo The residue was diluted with 400 ml ethyl acetate and 200 ml water The organic layer was separated washed 2×100 ml saturated sodium chloride solution separated dried over Na2SO4 filtered concentrated in vacuo

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

Procedure: (4-{[(2-Chloro-pyridine-3-carbonyl)-amino]-methyl}-benzyl)-carbamic acid tert-butyl ester (12.0 g, 32.2 mmol) (see Preparation 7), 3-hydroxy-benzoic acid ethyl ester (6.42 g, 38.6 mmol) and caesium carbonate (15.7 g, 48.3 mmol) were stirred in dioxan (180 ml) at 70° C. under an atmosphere of nitrogen for 18 hours. Starting material remained, so a further aliquot of 3-hydroxy-benzoic acid ethyl ester (6.42 g, 38.6 mmol) and caesium carbonate (15.7 g, 48.3 mmol) were added along with dioxan (420 ml) and N,N-dimethylformamide (40 ml) and the reaction stirred at 70° C. for a further 22 hours. The solvent was then removed under reduced pressure, the residue partitioned between ethyl acetate (200 ml) and water (200 ml), and the organic layer separated. The organic layer was then washed with a saturated aqueous solution of sodium chloride (3-fold 100 ml), the solvent removed in vacuo and the residue purified by flash column chromatography on silica gel eluting with a solvent gradient of 0:100 changing to 50:50, by volume, ethyl acetate:hexane to give 3-{3-[4-tert-butoxycarbonylamino-methyl)-benzylcarbamoyl]-pyridin-2-yloxy}-benzoic acid ethyl ester (7.42 mg) as an off-white foam. The solvent was then removed under reduced pressure the residue partitioned between ethyl acetate (200 ml) and water (200 ml) the organic layer separated The organic layer was then washed with a saturated aqueous solution of sodium chloride (3-fold 100 ml) the solvent removed in vacuo the residue purified by flash column chromatography on silica gel eluting with a solvent gradient of 0:100 changing to 50:50, by volume, ethyl acetate

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

Procedure: Benzamidine hydrochloride (3.9 g, 24.9 mmol) was dissolved in a minimal amount of H2O (10 mL), to this was added sodium hydroxide pellets (1.0 g, 24.9 mmol, 1 eq.) dissolved in H2O (2 mL), followed by ethylbenzoate (4.53 mL, 26.1 mmol, 1.05 eq.). Ethanol was then added until a clear solution was obtained. The reaction mixture was then allowed to stir at room temperature overnight yielding a thick suspension, which was then filtered to give a white solid. After washing with diethyl ether to remove unreacted/excess β-ketoester the solid was dried in vacuo to give 57% of the desired product. 1H NMR δ (DMSO-d6): 8.31-8.18 (m, 5H, Ar), 7.60-7.54 (m, 5H, Ar), 6.92 (s, 1H, Ar). was obtained yielding a thick suspension, which was then filtered to give a white solid After washing with diethyl ether to remove unreacted/excess β-ketoester the solid was dried in vacuo

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

Procedure: Benzamidine hydrochloride (3.9 g, 24.9 mmol) was dissolved in a minimal amount of H2O (10 mL), to this was added sodium hydroxide pellets (1.0 g, 24.9 mmol, 1 eq.) dissolved in H2O (2 mL), followed by ethylbenzoate (4.53 mL, 26.1 mmol, 1.05 eq.). Ethanol was then added until a clear solution was obtained. The reaction mixture was then allowed to stir at room temperature overnight yielding a thick suspension, which was then filtered to give a white solid. After washing with diethyl ether to remove unreacted/excess β-ketoester the solid was dried in vacuo to give 57% of the desired product. 1H NMR δ (DMSO-d6): 8.31-8.18 (m, 5H, Ar), 7.60-7.54 (m, 5H, Ar), 6.92 (s, 1H, Ar). was obtained yielding a thick suspension, which was then filtered to give a white solid After washing with diethyl ether to remove unreacted/excess β-ketoester the solid was dried in vacuo

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

Procedure: To a solution of 2-methylpyridine (9.31 g) in tetrahydrofuran (200 ml) was added a 1.5M hexane solution of n-butyllithium (73.3 ml) at -20° C. The resulting solution was stirred for 30 minutes at room temperature and added to a solution of ethyl benzoate (15.02 g) in tetrahydrofuran (100 ml) at -60° C. After stirring for 2 hours at -60° C., acetic acid (15 ml) was added and the resulting mixture was allowed to warm to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water. The aqueous layer was reextracted with ethyl acetate and the combined extracts were washed with water, 10% aqueous solution of sodium hydrogen carbonate, and saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate extracts were filtered and evaporated. The residue (20.5 g) was chromatographed on silica gel (Merck 70-230 mesh, 308 g) eluting with chloroform to give 2-pyridylmethyl phenyl ketone ( 10.86 g) as an oil. After stirring for 2 hours at -60° C. to warm to room temperature concentrated in vacuo The residue was dissolved in ethyl acetate washed with water the combined extracts were washed with water, 10% aqueous solution of sodium hydrogen carbonate, and saturated aqueous sodium chloride After drying over magnesium sulfate the ethyl acetate extracts were filtered evaporated The residue (20.5 g) was chromatographed on silica gel (Merck 70-230 mesh, 308 g) eluting with chloroform

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

Procedure: To a solution of 2-methylpyridine (9.31 g) in tetrahydrofuran (200 ml) was added a 1.5M hexane solution of n-butyllithium (73.3 ml) at -20° C. The resulting solution was stirred for 30 minutes at room temperature and added to a solution of ethyl benzoate (15.02 g) in tetrahydrofuran (100 ml) at -60° C. After stirring for 2 hours at -60° C., acetic acid (15 ml) was added and the resulting mixture was allowed to warm to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water. The aqueous layer was reextracted with ethyl acetate and the combined extracts were washed with water, 10% aqueous solution of sodium hydrogen carbonate, and saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate extracts were filtered and evaporated. The residue (20.5 g) was chromatographed on silica gel (Merck 70-230 mesh, 308 g) eluting with chloroform to give 2-pyridylmethyl phenyl ketone ( 10.86 g) as an oil. After stirring for 2 hours at -60° C. to warm to room temperature concentrated in vacuo The residue was dissolved in ethyl acetate washed with water the combined extracts were washed with water, 10% aqueous solution of sodium hydrogen carbonate, and saturated aqueous sodium chloride After drying over magnesium sulfate the ethyl acetate extracts were filtered evaporated The residue (20.5 g) was chromatographed on silica gel (Merck 70-230 mesh, 308 g) eluting with chloroform