The esc key really doesnt cause that much trouble, although I would like my right click too, and being able to directly Fx between say, magic research and gem income would be nice too. I often forget it doesnt work and try it anyway.
But in general the UI is very easy to operate. I go around hitting r,b,t,e and shift clicking like nobody's business.
And the ctrl-1 through 9 to save order setups is really nice too.