Molecule optimization is a critical step in drug development to improve the desired properties of drug candidates through chemical modification. We have developed a novel deep generative model, Modof, over molecular graphs for molecule optimization. Modof modifies a given molecule through the prediction of a single site of disconnection at the molecule and the removal and/or addition of fragments at that site. A pipeline of multiple, identical Modof models is implemented into Modof-pipe to modify an input molecule at multiple disconnection sites. Here we show that Modof-pipe is able to retain major molecular scaffolds, allow controls over intermediate optimization steps and better constrain molecule similarities. Modof-pipe outperforms the state-of-the-art methods on benchmark datasets. Without molecular similarity constraints, Modof-pipe achieves 81.2% improvement in the octanol–water partition coefficient, penalized by synthetic accessibility and ring size, and 51.2%, 25.6% and 9.2% improvement if the optimized molecules are at least 0.2, 0.4 and 0.6 similar to those before optimization, respectively. Modof-pipe is further enhanced into Modof-pipem to allow modification of one molecule to multiple optimized ones. Modof-pipem achieves additional performance improvement, at least 17.8% better than Modof-pipe.