A comprehensive computational study of the mechanism and stereoselectivity of the Diels-Alder (DA) reaction between 2,3-dimethylbuta-1,3-diene 1 and the dienophile 2, 5-(4-bromobenzylidene)-3-methyl-2-(trifluoromethyl)-3,5-dihydro-4H-imidazol-4-one. To rationalize the energetic and geometrical parameters controlling the cycloaddition, reaction profiles were analyzed using DFT at the M06-2X-D3/6–311G(d,p) level. The electron localization function (ELF) was topologically analyzed for the reactants and transition states to identify changes in electronic structure and bonding. The detailed energetic analyses reveal that the reaction goes through a concerted but asynchronous mechanism, and two stereoisomeric paths have been identified (TS1 and TS2). It is rationalized that the reaction is exothermic and exergonic, and that TS1 is the kinetically and thermodynamically favored pathway. In addition, the Bonding Evolution Theory (BET) analysis of the calculated potential energy surface along the Intrinsic Reaction Coordinate (IRC) of the preferred pathway identifies six independent stages that support the asynchronous binding of the two bimolecular partners, in which the C-C bond-generating stages are not strictly concerted. Non-covalent interaction (NCI) and independent gradient model Hirshfeld partition (IGMH) analyses were performed to visualize and quantify the weak attractive and repulsive interactions present in the transition states. They present unique molecular perspectives on the factors that control the stereoselectivity and stability of the cycloaddition products. In addition, molecular docking simulations were performed against the VEGFR2 tyrosine kinase domain to assess the biological potential of the obtained cycloadducts.