Looks like you have a really nice space to work with. 21' is a very nice long room! I've got about as much space as you but for model trains, long is better than square.
From your previous work I assume you're doing modern or close to it. You've got an industrial area, a small town, and a city area. No nature areas? Ever consider doing double-decker or is that getting too crazy?
From the bulges at the end I assume you want the ability to loop trains, always a plus. I think you could have a really cool layout with 3 distinct scenes and it should be pretty easy to hide the loops at the ends and make the whole layout look like a proto-realistic point to point deal. Actually it looks like we have almost the exact same plan except that mine has an extra bend in it.
2' is about minimum for a return loop, it also is a good limit to put on reach for comfortable working. I wouldn't use anything less than a 12" radius curve, and since you need about an inch of space around the track if you bump your ends up to maybe 26-27" you'll have the space.
I'm sure people have lots of ideas, but we need an era, a location, and the sort of activities you want to be able to do on your layout. Or even the types/lengths of trains you want.