the reality of in-room safes is that they only protect against theft by someone who isn't supposed to have access to your room. but at most places, the risk of some stranger coming from outside the hotel and into your room is very low. the real risk comes from hotel staff, who not only have unfettered access to your room, but have a long list of excuses for being there.

if the hotel has a thief, the safe is probably the first place they look for things to steal. remember, they don't want to spend too much time in the room, and they don't want to steal large items. for the thief, the ideal victim is someone who left a large amount of cash in the safe - just like the OP. because there is a strong chance that the guest either hasn't counted their cash, may assume they've miscounted when they check after the thief has come by, or may assume they must have spent it on something.

while most (hopefully!) thieves are independent operators, the cynic in me can't help suspecting that the hotel management is often in on the take. the cynic in me sometimes suspects the same of the local police in some places (or other thieves posing as police, to throw the guest off).