This paper presents a centralized and strategical approach for Unmanned aircraft systems Traffic Management (UTM) to design optimal 4D trajectories minimizing the total flight time of all vehicles over a given time window. Potential losses of pairwise separation between vehicles are modeled and solved. A 4D trajectory is modeled by choosing an horizontal path (with an associated nominal speed profile), a departure slot and a cruising flight level. The problem is formulated as a mixed-integer linear program. A two-step solution approach is proposed that takes into account operational requirements, such as late flight intention deposits, or static and dynamic geofences; and that is able to deal with very high traffic density (up to 6300 vehicles in an horizon of one hour). Experimental results show that it is possible, by delaying flights at the departure or modifying their 4D route (vertically or horizontally), to obtain Unmanned Aircraft Systems (UAS) flyable trajectories that avoid losses of separation and minimize the total flown time.