Carbon−hydrogen−oxygen symbiotic networks (CHOSYNs) provide a systematic multiscale framework for integrating multiple hydrocarbon processing plants. Earlier approaches have focused on high-level performance benchmarking using atomic and stoichiometric targeting techniques, which are subsequently detailed to identify the implementation strategies for allocation and processing. These sequential approaches are very powerful for the cases involving benchmarks that are independent of the system details (e.g., minimum usage of raw materials, minimum discharge of wastes, maximum revenue). For objectives involving detailed process information (e.g., capital cost minimization), there is a need to include the system details early enough in optimization. This paper proposes a systematic approach for incorporating detailed process simulations throughout the various stages of synthesizing a CHOSYN. The proposed approach involves the use of computer-aided process simulators and simultaneous optimization for synthesizing a CHOSYN. Critical data are generated and used at each design stage. For existing facilities, targeting uses the simulated data on available resources and sinks (e.g., flow rate, composition, pressure, and temperature). Process synthesis is used to generate a set of candidate new units and plants to be added, while detailed simulation is used to size these plants and identify the specific needs for flows and compositions. The proposed approach is implemented for a case study that involves five existing plants and a set of seven candidate plants that can induce symbiosis. The results show final configurations with the selection of new plants, the reduction of raw material, the allocation of internal and external sources, and the details of process information, capital and operating costs, and flow rate, pressure, and temperature of the exchangeable streams across the network.