A novel TsCl-mediated domino sequence to expeditiously access quinolone-based antibiotics, such as ciprofloxacin, norfloxacin, pefloxacin, oxilinic acid, ivacaftor and the precursor of grepftfloxacin and ozenoxacin, starting from commercially available chromone-3-carboxaldehydes and amines, was developed. The total synthesis of these quinolone-based drugs via this sequence shortens the original seven/eight step synthesis to three/four steps with a high overall yield under environmentally benign conditions. The quinolone-based antibiotic drug analogues could also be efficiently synthesized by varying the starting materials and chemical reagents for discovering and developing new antibiotics.