Organic synthesis plays a fundamental role in medicinal chemistry, allowing the obtainment of compounds with desired pharmacological properties. In this context, new synthesis methods are continuously being explored to improve the efficiency and sustainability of these processes, such as the use of ultrasound. In this work, the synthesis and structural characterization by Nuclear Magnetic Resonance and Ultrasound of 2-nitrochalcone derivatives substituted with electron-withdrawing (fluoro) and electron-donating (methoxy) groups in the three isomeric positions of the B ring are presented, using both a conventional method and a non-conventional ultrasound-assisted method. The results show that both methodologies are effective for the obtainment of these compounds, but the conventional method presents some additional advantages in the case of these nitrochalcones, such as shorter reaction times and better reaction yields. Chalcones and their derivatives are of great interest in medicinal chemistry due to their broad spectrum of biological activities, including anti-inflammatory, antioxidant, antitumor, and antimicrobial properties. The strategic introduction of specific substituents can modulate and improve these pharmacological properties. This study contributes to the development of more efficient synthesis methods for the obtainment of compounds with potential pharmacological activity, highlighting the importance of organic synthesis in the search for new drugs and therapies. The findings presented in this work can serve as a basis for future research in the field of medicinal chemistry, where organic synthesis plays a crucial role in the identification and optimization of new drug candidates.