I think that it depends on how much you want to spend.
There are some nice hotels in mid-town, (Westin, Hilton, Sheraton, etc). You will find cheaper hotels in Upper-West side as well as Lower-west side. But be careful, some of these cheap hotels are not that good. Rooms may be very small, and sometimes the location is not the best. Hotels.com is a good way to see prices and room availability.
Not sure how long you plan to spend in NYC, but I would definitely spend one day in Downtown. You have to see Battery Park, Pier 17, SoHo, China Town, Tribeca, Washington Square, etc. They are all amazing places, and trust me one day won't be enough. If there weather is good, I would recommend to walk to the Brooklyn and back via Brooklyn Bridge. It provides with nice view on the city.
I would recommend to visit midtown, by going to Empire State Building (visit the terrace and be there early as it takes long time to get up), than follow Fifth Ave, up. You will see Rockefeller Center, the St. Patrick's Cathedral, one of many Trump Towers (but this one has really nice inside waterfall with nice restaurant/cafe and it is a good bathroom stop.
) Walk up until the Apple Store, than take Central Park South towards Columbus Circle (go left, towards west/NJ). BTW,there are few pricey hotels there as well with a nice view on the Central Park. When you get to Columbus Circle, take your gf inside. This is an amazing spot, and there is Sephora as well! Girls like that store!
There is more to do in Columbus Circle than just Sephora. Really nice place!
Than I would walk down the Broadway all the way to the Time Square. To be honest after so much walking you will be happy to go to the hotel.
Besides your normal tourist attractions, I would definitely visit UN, you don't have to go for the tour, but it may be nice to see it once in the lifetime. Definitely visit the Metropolitan Museum of Arts, a MUST! If you get lucky, there is a terrace and the views out from there are simply fantastic! You will easily spend a day in there. It is a really huge museum.
If you want to, i would suggest to take a tourist bus tour of the city, but if you want to travel to Downtown or around the city, definitely use the Subway. It is fast and safe in the Manhattan. Sometimes Taxi is hard to get, especially during rush hour and Friday afternoon.
There is so much to do in the City, musicals (well.....they are on strike now, but I hope that this well end relatively soon
), there are nice shopping places (Pier 17, Columbus Circle, plus many stores along Fifth Ave, Sixth Ave and Broadway, and a plenty in SoHo.) and there are some really nice restaurants. There is very good stake house, Del Frisco's (http://www.delfriscos.com/newyork/). Not the cheapest stake house, but it is THE BEST stake house.
I am sure that I missed lots of other nice attractions, but as you can see there is a lot of to do in the Midtown and Downtown, but I would definitely choose a hotel in midtown, as it is close to many attractions.