If you're looking for the single place in NYC to position yourself for maximum access to the rest of the city, Union Square is the place for you.  

You can get to the upper east or west sides, the financial district, Brooklyn, Queens, the Bronx, the airports.  

It's only one of two Manhattan streets that has a cross-town subway, the miraculous L train, which is probably responsible for the resurgance of Williamsburg, which is a single stop from Manhattan and just three stops from the magic of Union Square. (The other cross-town street is 42nd.) 

On a walk today I happened by an entrance to the subway that tells the story.