A second referendum bothers me for more or less the same reason the first one did: it's simply the wrong decision to try and break up the UK, and both countries would be worse off because of it.
The "once in a generation" part doesn't bother me particularly, because it's legally and politically meaningless. Very often it's used as a threat, if anything: ie, it's meant along the lines of "if you do this there is no turning back." But democracies are always free to change their decisions; no electorate can ever be beholden to its predecessors, in the same way that no law can ever be passed in this country that cannot be overturned at any point in the future.