Integrating innovative design technologies with simulation of building use, for refurbishment, valorization, new construction, and operational management, is crucial to conceive responsive and intelligent spaces according to the dynamic needs of their occupants. Users’ presence, both humans and agents, must be integrated into the actual simulation models for evaluating and enhancing the ability of the designed spaces to host new uses and, eventually, to adapt itself accordingly. BIM enables – and is limited to – advanced simulations of building behaviors such as energy, structural, and acoustics, but lacks the ability to handle space use processes. This research focuses on the conceptual representation of the next generation of building models, which will be able to evolve the IFC standard by adding the AECO semantic values, with the occupant’s well-being as a central reference for analysis. This paper contributes to sketching a theoretical framework within which it is possible to compute the interaction between Users and Spaces according to the context in which the reciprocal behavior occurs. An innovative methodology is proposed based on a multilayer organization: (i) Object-based for project data automation (BIM); (ii) Ontology-based for semantic reasoning (IFC modular enhancement for inferences); (iii) Cognitive-based for comparing goals and exploring consequences /side effects of design choices (Semantics Engines/Agents). The implementation pipeline checks some crucial aspects of the integration feasibility to engineer design knowledge and reasoning, and illustrates the automation criticalities for providing the existing BIM system the semantics required to achieve the User/Space symbiosis goal-directed behavior simulation.