I think the Monon railroad in central Indiana, specifically the section from Monon to Indianpolis would be an awesome route to play on. It is short enough to create in a reasonable amount of time with enough detail, about 60 miles, but includes a good mixture of "high speed" running and scenic, hilly, and challenging terrain. Many high bridges over scenic valleys and lakes, and plenty of flatland cornfields. Plenty of small towns with tiny industries to switch, large grain suppliers and a special midwestern Americana charm that people far and near could enjoy. The Monon railroad is also extremely unique as far as equipment goes, F3's, BL2's, Alco's, and U-Boats. Semaphore signals were prevalent in the diesel era, up until abandonment. Really any leg of the Monon during any era would be a treat. All 4 legs of the railroad were less than 100 miles, and being a class l it was quite busy in it's day. Today, only one leg of the Monon is still in use, much of the original lines have been abandoned and torn up during the CSX era, so being able to run this line with detail of TSW would truly be a treat for any American Railfan. The "Hoosier Line" would truly be a unique railroad to include that would be drastically different from anything any railroad simulator has ever done. Plenty of info to be found at Monon.org
This is the TS forum, though I must admit, it'd be bloody fantastic to see the Monon or any of those old fallen flags be raised on the pole of either Train Sim Classic or Train Sim World, or even both.