Several Lewis and Bronsted acid catalysts were tested for the synthesis of some targeted diamides with anticancer activity from dicarboxylic acids and amines under the same reaction condition. Among those catalysts, Nb2O5 showed the highest catalytic activity to the corresponding diamides. Nb2O5 shows water- and base-tolerant properties for which it gives the highest yield of the synthesized products. Here, we present a novel and sustainable method for the direct synthesis of diamides with anticancer activity using a reusable heterogeneous catalyst Nb2O5. A molecular docking study was performed for all of the synthesized compounds with various therapeutical targets of cancer and found that the human epidermal growth factor receptor (HER2) has shown a significant dock score for our synthesized products. After obtaining the best pose from molecular docking, the complex is used for molecular dynamics study by running simulations for 10 ns. The root-mean-square deviations (RMSDs) of α carbon atoms of all systems are analyzed to detect their stability. This method is effective for the direct synthesis of diamides as anticancer agents from dicarboxylic acids and amines using Nb2O5 as a base-tolerant heterogeneous catalyst.