There are some airports where you can transfer from a domestic airline to one of its international partners without going through security twice. Others require a change of terminals and another trip through security. This is something worth taking into consideration as you consider possibly combining a domestic and an international flight. The specifics will depend on which airline(s) you choose.

In my experience, the most competitive fares to Asia are out of LAX, due to the large Asian immigrant populations. The downside of LAX is that transferring from a U.S. domestic airline to a foreign airline (for better service all around) is that most international flights are out of the international terminal.

As far as Tokyo is concerned, two days is not long enough. It's a huge and potentially confusing city, with a glitzy modern surface and hidden treasures on the side streets. When I go to a strange foreign city, I do the ultra touristy thing and take a bus tour the first day. (With Japan's aging population, there are more accommodations for people with mobility issues than ever before.) Then I make a note about what places I want to explore independently. I've used this successfully in Seoul, Busan, Taipei, Reykjavik, Edinburgh, and Dublin.