Larger planes that need more passengers to justify service, as well as ones that can now fly longer distances nonstop, have changed airline economics.
During 1970 before it 747’d, Qantas served the following—You won’t likely see it serving these again:
During apartheid, South African Airways flights became impossible over most countries in Africa and Middle East. Hence its former service Athens to Lisbon. Taking off from Lisbon the airline could then fly all those Greek passengers over the Atlantic to South Africa.
I’ve flown some exotic airline routes that no longer exist:
Air France: Tehran > Delhi
Alitalia: Bangkok > Mumbai
Luxavia: Luxembourg > Johannesburg
Japan Airlines: Mexico City > Vancouver
Some other unusual routes that once operated include
Air Greenland: Baltimore > Kangerlussuaq
Air India: London > Montreal
Air India: London > New York City
Air France: Paris > Puerto Vallarta
Air Jamaica: Philadelphia > Toronto
Pakistan International: Barcelona > Chicago
Pakistan International: Manchester (UK) > New York City (until quite recently)
Qantas: San Francisco > Vancouver*
Royal Air Maroc: Montreal > New York City
Thai Airways International: Seattle > Toronto
*Qantas, I believe, still retains rights to fly this route. It has been doing so periodically. I once took it and again saved money, with excellent service.
In recent years, Delta has aggressively initiated new destinations such as Atlanta to Manaus, Fortaleza, and Recife (all in Brazil), and, as with these, abandoned them if demand wasn’t there.
Use weird airline routes when you can. You will often receive weird route prices!