N,N'-diphenylpropanediamide

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

Procedure: To the cold solution of malonic anhydride, prepared as above, was added aniline (700 μl, 6 equivalents). The reaction mixture was allowed to warm to room temperature. It was then extracted with 5 ml saturated aqueous NaHCO3, and the aqueous extract was washed with 5 ml ether, acidified with H2SO4, and extracted with 3-4-ml portions of ether. The ether extracts were combined and dried over Na2SO4, and the ether was removed under reduced pressure, to leave a residue of malonanilide (mp 127°-130° C., 180 mg, 72% isolated yield, based on diketone). It was then extracted with 5 ml saturated aqueous NaHCO3 the aqueous extract was washed with 5 ml ether extracted with 3-4-ml portions of ether dried over Na2SO4 the ether was removed under reduced pressure

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

Procedure: To a solution of malondianilide (102 mg, 0.40 mmol) in THF (2 mL) was added of NaH (16.3 mg, 60% wt. dispersion in mineral oil, 0.41 mmol). After 10 min, the malonate salt solution was added to a solution of 2-methanesulfonyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (100 mg, 0.367 mmol) in THF/DMF (2/0.5 mL). After 1 h, the reaction was quenched with sat. NH4Cl and extracted with EtOAc. The organic layer was washed with brine (1×), dried over MgSO4, filtered, and concentrated. The residue was triturated with EtOAc and H2O, and the solid was filtered.: ESIMS calcd 447 (W+H), found 447 M++H). After 1 h the reaction was quenched with sat. NH4Cl extracted with EtOAc The organic layer was washed with brine (1×) dried over MgSO4 filtered concentrated The residue was triturated with EtOAc and H2O the solid was filtered

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of NaH (32 mg, 60% wt. dispersion in mineral oil, 0.80 mmol) in DMF (0.5 mL) at room temperature was added malondianilide (169 mg, 0.67 mmol). The solution was stirred for 20 min and a solution of methyl 6-fluoronicotinate (129 mg, 0.62 mmol) in DMF (1 mL) was added. The reaction mixture was heated to 100° C. for 1 h, cooled to room temperature, and diluted with CH2Cl2 and water. The aqueous phase was extracted with CH2Cl2 (3×) and the combined extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by reverse phase HPLC (40% to 90% MeCN in water) gave methyl 6-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]nicotinate (66 mg, TFA salt, 21%) as a white solid: ESIMS calcd 390.1 (M++H), found 390.1 (M++H). cooled to room temperature The aqueous phase was extracted with CH2Cl2 (3×) the combined extracts were washed with brine (1×) dried over MgSO4 filtered concentrated Purification by reverse phase HPLC (40% to 90% MeCN in water)

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

Procedure: To a mixture of tert-butyl 4-bromobenzoate (7.349 g, 28.6 mmol), malondianilide (6.01 g, 23.7 mmol), and K3PO4 (15.15 g, 71 mmol) was added Pd2(dba)3 (996 mg, 1.09 mmol), toluene (50 mL), and P(tert-Bu)3 (1.08 mL, 4.35 mmol). The reaction mixture was degassed and heated to 70° C. for 16 h, additional Pd[P(tert-Bu)3]2 was added and the reaction was heated to 80° C. After 24 h, the reaction mixture was diluted with ethyl acetate, washed with water (1×), brine (1×), dried over MgSO4, and concentrated. tert-Butyl 4-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]benzoate was used without further purification: ESIMS calcd 431.2 (M++H), found 431.1 (M++H). The reaction mixture was degassed additional Pd[P(tert-Bu)3]2 was added the reaction was heated to 80° C the reaction mixture was diluted with ethyl acetate washed with water (1×), brine (1×) dried over MgSO4 concentrated tert-Butyl 4-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]benzoate was used without further purification

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

Procedure: To the cold solution of malonic anhydride, prepared as above, was added aniline (700 μl, 6 equivalents). The reaction mixture was allowed to warm to room temperature. It was then extracted with 5 ml saturated aqueous NaHCO3, and the aqueous extract was washed with 5 ml ether, acidified with H2SO4, and extracted with 3 4-ml portions of ether. The ether extracts were combined and dried over Na2SO4, and the ether was removed under reduced pressure, to leave a residue of malonanilide (mp 127°-130° C., 180 mg, 72% isolated yield, based on diketene). It was then extracted with 5 ml saturated aqueous NaHCO3 the aqueous extract was washed with 5 ml ether extracted with 3 4-ml portions of ether dried over Na2SO4 the ether was removed under reduced pressure