We don't live in Chicago, but would use it as our starting point due to the rail connections. The biggest obstacle as I see it is the travel times, but I feel like it's still within a doable range, as we don't mind sleeping on the train. So our idea of "reasonable distance" might be questionable lol.
As far as destinations, we are interested in visiting Philadelphia, DC, NYC, and maybe Boston, which all have decent transit networks and a downtown core where we could book hotels near train stations, etc. We also aren't afraid of using buses in cities we don't live in, and a certain degree of transit trial and error to get around.
Some destinations are likely going to require some uber trips or other creative solutions to get around, like Niagara Falls and Cincinnati. And I have some family near Albany NY who we'd probably go to stay with for a bit, and would depend on them driving us around in the area. But aside from that, the east coast cities I'd really like to hit seem like they are the closest we could approximate to the sort of trip we wish we could take. It just seems counterproductive to take a plane to Europe to then take trains around.
That's a great and compelling case for Pittsburgh, and I think it will fit in great to the map I'm working on for this trip! Thank you for the recommendation