Your wife and matey are unlikely to end up on the wrong side of town – unless they fall asleep on the subway and end up in the Bronx or Upper Harlem! Conjures up images of the first chapter of Bonfire of the Vanities
I lived in Manhattan for a number of years. It is a a lot safer than London IMO and probably most UK cities, I and would happily walk around the streets all day and all night.
Personally, I wouldn't bother with an organized guide. It is an easy city to navigate and all the obvious tourist places are very easy to find and get to/from etc. Just get a decent guidebook.
In terms of places to eat, then New York has literally 1000's of good neighborhood restaurants in all the major residential parts of the city, which is pretty much everywhere in NYC.
Remember New Yorkers (or rather Manhattan folk) eat out several nights a week. Any place that is bustling with locals is always a good place to start.
The only places I would not look to eat at are around Times Square / Broadway. I expect there are some very decent places (pre Theatre Broadway dinners etc), but this is definitely where perhaps most of the tourist hotels are concentrated.