The proposed desymmetrization allows for a modular synthesis of unsymmetrical bis-3,5-isoxazoles (Table ) under solvent-free conditions. We observed that the conditions for desymmetrization (Scheme 1) and previously reported conditions were ineffective for adding a second 3,5-isoxazole moiety. The reaction was insensitive to electronic properties of reactants as coupling of solid 3,5-isoxazole-alkyne with EWG (9a) or EDG (9e) with either hydroxyimidoyl chlorides bearing EWG or EDG did not yield the corresponding product and only starting material was recovered. Using alkyl 3,5-isoxazole-alkyne adduct (9t-u) demonstrated a improvement in the reaction performance, presumably due to more efficient mixing of the reagents independently of their physical state. . Liquid 3,5-isoxazole-alkyne adduct (9t) and sterically bulky hydroxyimidoyl chlorides with catalytic amounts of CuI and mesitylene liquid additive did not form the desired unsymmetrical bis-3,5-isoxazole alkyne (10a) (Table ). Improvements in the yield were observed when using less bulky substituents. Synthesis of unsymmetrical bis-3,5-isoxazole (10b) was obtained only in moderate yields due to the competing formation of furoxans. Using aromatic hydroxyimidoyl chlorides improves the yield of the reaction. Synthesis of unsymmetrical bis-3,5-isoxazoles (10c-f) was obtained in excellent yields independent of the electronic character of the substituent and their physical state. This is likely due to a faster coupling between the aromatic hydroxyimidoyl chlorides and alkyl terminal alkyne (9t-u) compared with the dimerization to form furoxans (Table ). In conclusion, we developed the first mechanochemical desymmetrization strategy for bis-and tris-alkynes to form 3,5isoxazole-alkyne adducts without using a large excess of either starting material and by a controlled 1,3-dipolar cycloaddition. The reported conditions were applicable for a range of aromatic and alkyl bis-and tris-alkyne. Late-stage reduction of the 3,5isoxazole moiety was achieved in high yield and selectivity, allowing a concise route to β-ketoenamine-alkyne derivatives. Furthermore, the mechanochemical desymmetrization allowed access to unsymmetrical bis-3,5-isoxazole from alkyl 3,5isoxazole-alkyne adducts (9t-u) in excellent yields. We believe this protocol can provide efficient access to more intricately functionalized poly-isoxazoles, boron-enaminoketonate, and facilitate the synthesis of natural products.