A new approach to arylated 2-trifluoromethylquinolines based on novel regioselective Suzuki-Miyaura coupling reactions has been developed. Moreover, site-selective, chemo-selective amination reactions were performed. The new 2-trifluoromethylquinoline derivatives were tested as potential NPPs inhibitors and evaluated for their potential to inhibit two families of ecto-nucleotidases, i.e. NPPs and nucleoside triphosphate diphosphohydrolases (NTPDases). Several derivatives were active on a nanomolecular concentration. The results were validated based on docking studies to study the active binding site of the molecules.