Abstract: A mechanochemical desymmetrization of symmetrical bisand tris-alkynes via a controlled 1,3-dipolar cycloaddition reaction with nitrile oxide dipoles has been developed. This convenient, efficient, and simple protocol allows access to 3,5-isoxazole-alkyne adducts from easily prepared or commercially available symmetrical bis-and tris-alkynes in moderate to excellent yield. The synthetic utility of 3,5isoxazole-alkyne was demonstrated by developing a route to access β-ketoenamine-alkyne derivatives and the synthesis of unsymmetrical bis-3,5-isoxazoles products in good to excellent yields.