All reported yields are isolated yields. The mechanochemical conditions were compared to solutionbased conditions. Reported mechanochemical conditions allowed successful desymmetrization of the bis-alkyne (7h) to obtain 3,5isoxazole-alkyne adduct (9s) in 70 % yield and with a superior selectivity for (9s) over the symmetrical bis-3,5-isoxazole product only after 60 minutes of milling (Scheme 3). Performing the desymmetrization with larger volumes of mesitylene (η =45 µL/mg, 7 mL) yielded 3,5-isoxazole-alkyne adduct (9s) in 32 % yield, with poor selectivity after 16 h at room temperature. The described comparison emphasizes the impact of mechanochemistry in achieving unique reactivity modes to access unexplored chemical space with lower waste production. [a] 1 H-NMR Yield of 9s when the reaction is performed by η =45 µL/mg, 7 mL of mesitylene, for a detailed procedure, see section SI (PS3).