Polyethylene glycol-400 (PEG-400) was developed as an efficient and eco-friendly reaction medium for the synthesis of new isoxazolyl pyrido[2,3-d]pyrimidines I [Ar' = Ph, 2-furanyl, 2-methylphenyl, etc.; Ar = Ph, 2-thienyl, 3-pyridinyl, etc.] from isoxazolyl cyanoacetamide synthon compounds II [Ar = Ph, 2-thienyl, 3-pyridinyl, etc.].Compound II were employed with various aromatic aldehydes and malononitrile in the presence of triethylamine (Et3N) afforded the corresponding dihydropyridines III at room temperature by using PEG-400 as a solvent medium as well as catalyst.The compounds III on treatment with thiourea in the presence of PEG-400 at 90°C gave the target compounds I in good to excellent yields.The newly synthesized compounds I and III and were characterized by IR, 1H NMR, 13C NMR and HRMS anal.The target compounds I was screened for their anti-inflammatory and analgesic activities.Among the tested compounds, the compounds I [Ar' = Ph, Ar = 2-furanyl, 2-thienyl, 3-pyridinyl; Ar' = 2-thienyl, 2-furanyl, Ar = phenyl; Ar' = Ar = 2-thienyl] showed significant anti-inflammatory and potent analgesic activities as that of reference drugs.The advantages of this protocol were operational simplicity, catalyst free, environmental safety, wide substrate scope, good yields and PEG-400 was recovered and reused.Most significant of all, this protocol is green.