I ride from 3rd Ave & 46th to WTC a few times a month in the evening, and the smoothest / fastest / least-hairy route I've found is:

Lex south
L on 22nd
R on 3rd Ave > Bowery

That takes you right to the Manhattan Bridge.

The stretch on Lex next to Grand Central is usually thick with cars, but once you get through that it flows pretty well.