In the present work, a combination of experimental and density functional theory (DFT) investigation of the (3+2) cycloaddition reactions of diazopropane with chalcone derivatives was reported. All calculations were performed using several DFT approaches (B3LYP, M06, M06-2X) and 6-311+G(d, p) basis set. Based on the NMR, MS analyses and IRC calculations, the pyrazole derivatives are the kinetic adducts over the oxadiazoles. The use of two equivalents of diazopropane leads to thermodynamical products. A molecular docking analysis was performed to investigate the efficiency of the obtained products against selected drug targets in anti-Alzheimer ligand-receptor interactions. We revealed that the ligands selected were bound mainly to the catalytic (CAS) and peripheral (PAS) anionic sites of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors, respectively. The selected ligands 1, 3, 4 and P14 may act as the best inhibitors against Alzheimer’s disease (AD).