This is a really picky part of the game.
The safe is behind a portrait in the Master bedroom. When Holmes has investigated everything both inside and outside the house, then Watson will shout out to him that the safe has been revealed. It will happen automatically -- the portrait will swing back. Very likely you won't even be in the room at the time, you'll just hear Watson's yell.
It's likely just one footprint or bloodstain that you've missed examining in close-up.
_________________________
"Bleat, Watson -- unmitigated bleat!" ~ Sherlock Holmes