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The increasing complexity of multi-core architectures demands for a comprehensive evaluation of different solutions and alternatives at every stage of the design process, considering different aspects at the same time. Simulation frameworks are attractive tools to fulfil this requirement, due to their flexibility. Nevertheless, state-of-the-art simulation frameworks lack a joint analysis of power, performance, temperature profile and reliability projection at system-level, focusing only on a specific aspect. This paper presents a comprehensive estimation framework that jointly exploits these design metrics at system-level, considering processing cores, interconnect design and storage elements. We describe the framework in details, and provide a set of experiments that highlight its capability and flexibility, focusing on temperature and reliability analysis of multi-core architectures supported by Network-on-Chip interconnect.