Novel and promising thiophenone derivatives were synthesised by regioselective ring opening of activated thiomalic acid anhydrides, with a variety of active methylene nucleophiles via a C-acylation/cyclisation process involving an S–C bond formation. This regioselective approach could be moreover established by X-ray diffraction structure analysis. The thiolactone ring can act as valuable synthetic scaffold for the preparation of natural and synthetic compounds with important biological and pharmacological activities.