Using ChemAIRS, we explored synthetic pathways to AbbVie’s Surzetoclax (ABBV-453), a highly complex, next-generation BCL-2 inhibitor weighing nearly 1000 Da with multiple fused tricyclic and macrocyclic rings. In High-Risk Retrosynthesis mode, ChemAIRS showcased its ability to navigate this molecular complexity. Guided by human insight, the AI-driven retrosynthesis platform delivered a streamlined, convergent, and experimentally executable synthesis, highlighting the power of human-AI collaboration in modern drug discovery.