Yeah, whenever I have to hit the up-key relatively late, the game is about to end. Occasionally I manage to salvage a 2048 even if I have to do that, but never a 4096 (though it's been close a couple of times, and "someday").
Strategy: Like others I want to build the big numbers to the bottom (though any edge will work as well, but as I played too much Tetris in my time...), and the biggest in a corner. The reason is clear. To build anything big, it is to your advantage to keep near same size numbers close to each other. The new tiles are small (2s and 4s), so they need to be kept far away from the largest ones. The further the game progresses the more rigid the rule of keeping the largest one in the corner becomes. So towards the end I do a bit of planning. If I hope to build, say a 256, to a particular spot on the third row (to couple it with the same number in the bottom row), then I try to plan ahead, and prepare 128, 64 and 32 on the third row, so that I can combine them with a 32 from further up. So in particular I try to avoid having larger numbers on top of smaller ones. After a major merger small numbers will appear in the bottom, and you need to build them up, too. Trying not to block access to them is a big part.
Whenever I have to hit the up-key late in the game (or am forced move the biggest tile away from the corner), it usually means that the end is near. Often this is a consequence of careless play (I play too fast), but occasionally the random number generator is unkind and fills the bottom three rows together with a fully empty top row. I still think that a bit of planning could avoid that more often than not, but I haven't built the skills to anticipate such an eventuality. That is something I should learn, but ... as Paul said ... I really should delete the bookmark.
