When I've had success and fun, it's been abusing short runways with long-range aircraft that should not in normal circumstances fly there. Santa Ana (SNA), Chicago Midway (MDW), and Toronto City Centre (YTZ) come to mind.
You can fly B777-200s, A350-800s, and even B747-400Ds out of the first two for decent range, and even though jets are banned at YTZ in real life, the A319NEO can make it to Europe from there.
I've noticed a bunch of issues logged and topics posing questions around being unable to fly certain routes even though the aircraft have available hours and the runways are long enough.
If you're in a non-Open world, you have to follow the political restrictions built into the game. AE has a page specifically on this - be sure to read it over!