Macrolide antibiotics represent a group of natural or semi-synthetic compounds consisting of a macrocyclic lactone ring connected to one or more deoxysugars. They are ofen used in the treatment and prevention of various infectious diseases. On the other hand, due to their broad spectrum of biological activity, isoxazole plays a significant role in drug design. As a result of years of research on compounds containing the isoxazole ring, numerous corresponding drugs have found their way to the market. This paper describes the synthesis of new macrolide-isoxazole conjugates. Four classes of macrolide-isoxazole conjugates were prepared through a four-step synthesis and their antibacterial activity tests are underway. In the first step of synthesis, By Michael's addition of 9-deoxo-9a-aza-9a-homoerythromycin A to acrylonitrile, 9a-N-(2-cyanoethyl)-9-deoxo-9a-aza-9a-homoerythromycin A (1) was prepared. By its catalytic reduction in the second step, in a hydrogen atmosphere with PtO2, 9a-N-(3-aminopropyl)-9-deoxo-9a-aza-9a-homoerythromycin A (2) was prepared. In the next step, derivatives of macrolide with isoxazole (3–5) were prepared by amidation of 2 with the appropriate isoxazole-5-carboxylic acid, using HATU or T3P as acid activators and DIPEA or TEA as bases. In the final step of synthesis, decladinosyl derivatives (6–8) were prepared by hydrolysis of compounds 3–5. The third class of derivatives (9–11) was prepared from the previously prepared 4''-O-(3-aminopropyl)-9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, using the appropriate isoxazole-5-carboxylic acid with HATU and DIPEA. The fourth class of macrolide-isoxazole conjugates (12–14) was prepared by amidation of 9a-N-(3-aminopropyl)-9-deoxo-9a-aza-9a-3-O-decladinosyl-5-O-dedesosaminyl-9a-homoerythromycin A with the appropriate isoxazole-5-carboxylic acid with HATU and DIPEA. The structures of all newly prepared compounds were confirmed by 1H- and 13C-NMR spectroscopy.