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As for 50 moves and repetition of positions - those would be pretty easy with three pieces on board.
Or four pieces.
When and how does it get prohibitive?
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The repetition of positions gets prohibitive already with just KRK if you want to cover all possible situations. If you're only interested in positions with no repeats under 9.2.3 you can simply ignore it because the tablebase generated play will not itself produce any repeats. For a weak solution of chess it's sufficient to consider only positions with ply count 0 under 9.3, which always occur first and can't have any repeats.
The 50 move rule will probably not cause tablebase generation to become prohibitive if it's not already without.The Syzygy tables already cover the 50 move rule, so it's only an issue if you want quickest mates (DTM50).
There are, up to 7 men, a tiny percentage of winning positions that need more than a 50 move rule. Up to 26 pieces you can expect that percentage to drop dramatically because the classifications become swamped with endgames that have a large mismatch in material which should lead to short phases in the mates. And the positions that do need more moves don't need anything like 100 times the space, even for DTM50 tablebases, because the variations in play fall into a few ranges of ply counts.
Touch move is dumber but it doesn't mess up the game as much. It's equivalent to a rule saying both the knights must face the same direction. The 50 move rule totally screws up the most interesting complex and beautiful aspects of the game. Imagine someone in a tournament avoiding getting into a winning endgame because it might not be won in 50 moves. Those amazing KRKKNN 250+ move endgames are just pure chess, no vague strategies or general principles, you just have to make the exact moves for hundreds of moves straight to force the win, pure geometry.
Also there's no evidence to suggest that the 50 move rule even speeds up games. A game could go over 5,300 moves with the rule, yet the longest chess game on record ever is like 260 moves. The longest world championship game was only 136 moves, would it really have been a big deal if these games were this long and violated the 50 move rule? I really want to see an argument of a classical game that would have gone on for 500-1000 if the 50 move rule wasn't enforced. Just one.