One of the biggest issues players have with the mission is that "Big Smoke's aim sucks", and while somewhat true, he is not entirely at fault. I mean, he's peak human after all, it can't be all on him. Usually people say this because they're waaay too close to the train, you gotta go to the right more and then Smoke is able to actually target them accurately. This is the easiest way of doing the mission.

Another more fun way of completing the mission is just jumping on the train from a higher platform. When you get on the Sanchez with Smoke, pass the train, keep to the left of the tracks, and once the tracks veer to the left, drive onto the bridge arch and onto the building. Wait for the train to come by and then drive on top of the train. Then Big Smoke will proceed to kill the Vagos with no problem. Alternatively you could just run them over.

A more obscure way of doing it is to kill the train's driver. Drive way in front of the train and get out any gun (preferably the sniper rifle), aim at the window and blast him. He'll die, the train stops, and then the bastards can't go anywhere and you can kill them easily.