Pyridooxazine-tetrahydroisoquinoline derivatives were designed and synthesized for MDR modulating activity. Pyridooxazin-2-one scaffolds were constructed in a one-pot annulation of N-substituted-2-chloroacetamides with 2-bromo-3-hydroxy pyridine via Smiles rearrangement. The Pictet-Spengler cyclization to form tetrahydroisoquinoline ring afforded target compounds in 17-37% overall yields. Some of these compounds exhibited multidrug resistance (MDR) reversing activity.