Best reliability calls for a completely reuseable single stage launcher

Alas, SSTO fuel fraction is prohibitive. 2STO typically uses 1/3 the
propellant for a given payload, although vehicle empty weights are higher.

separating two vehicles at high speed in the atmosphere is not simple.

Shuttle does it every mission - SRBs from ET, ET from Orbiter.

Series staging is terrible because you take off without the second stage engines running, and thus without knowing whether they will start and run correctly.

Agreed

In any case there's little reason to use multiple different engine designs in one vehicle.

Servicing a single engine type is cheaper, if all other things are equal.
4 on the booster and 1 on the Orbiter would support a single engine core,
with differing bell arrangements.