Free energy calculations for chemical reactions with a steep energy barrier require well defined reaction coordinates (RCs). However, when multiple parallel channels exist along selected RC, the application of conventional enhanced samplings is difficult to generate correct sampling within limited simulation time and thus cannot give correct prediction about the favorable pathways, the relative stability of multiple products or intermediates. Here, we implement the selective integrated tempering sampling (SITS) method with quantum mechanical and molecular mechanical (QM/MM) potential to investigate the chemical reactions in solution. The combined SITS-QM/MM scheme is used to identify possible reaction paths, intermediate and product states, and the free energy profiles for the different reaction paths. Two double proton transfer reactions were studied to validate the implemented method and simulation protocol, from which the independent and correlated proton transfer processes are identified in two representative systems, respectively. This protocol can be generalized to various kinds of chemical reactions for both academic studies and industry applications, such as in exploration and optimization of potential reactions in DNA encoded compound library and halogen or deuterium substitution of the hit discovery and lead optimization stages of drug design via providing a better understanding of the reaction mechanism along the designed chemical reaction pathways.