Distillation columns with side reactors (SRCs) can be effectively employed to improve selectivity by manipulating the composition profiles of reactants and products inside the reaction zone. However, for the complex interaction between reaction and separation, it is difficult to simulate and optimize a SRC process. An independent reaction amount is introduced in simulating the SRC process to decouple the reaction kinetics from the mathematic models. Based on the concept of independent reaction amount, a systematic design approach, employing the Powell method, is developed to seek the internal synergistic effects between reaction and separation. The proposed optimum design methodology is demonstrated in a case study of benzyl chloride production. The effects of the design parameters, such as the number of separation stages, the stages between each reactor and the number of reactors on the process performance, are well-investigated. In addition, the effect of vapor boilup rate on the reaction capability is studied. Results demonstrate that, for the given vapor boilup rate, insufficient separation leads to a poor system performance, while excessive stages or reactors will not be beneficial toward improving reaction capability. Besides, by increasing the vapor boilup rate, the system performance can be improved obviously. The optimum configuration and the optimum match between separation and reaction can be achieved through the design approach.