While the size of the aircraft takes a few hours to get used to, I would say the most common difficulty is adapting to flying longhaul / international. Often you will find very good pilots( myself included), that have lots of experience in a certain areas, whether it be Europe, USA, Brazil, etc.... and when they start flying to China, New Zealand , Bangladesh, Kyrgyzstan, etc.....it is common to struggle with different rules, enormous language barriers, and other peculiarities.
I constantly hear guys say to me, " I don't know how you understood anything he said....I got nothing"
Its just a matter of time and operating experience but not something you will master in class