The Wimbledon semi-finalist edged through 7-6 (7-5) 6-3 in fiercely hot conditions at Flushing Meadows.
And he was out of sorts when losing to Stanislas Wawrinka at Flushing Meadows.
The US Open at Flushing Meadows in New York gets under way on 31 August.
The Spaniard, 24, won a rain-interrupted final 6-4 5-7 6-4 6-2 at Flushing Meadows in New York.
Federer extended his unbeaten run at Flushing Meadows to 40 matches with a 7-6 (7-3) 7-5 7-5 win.
The 34-year-old - a former finalist at Flushing Meadows - went down 4-6 6-4 6-4 7-5 to Frenchman Santoro.
The world number two took the first-round encounter 7-5 6-3 7-5 in two hours 16 minutes at Flushing Meadows.
As long as Nadal and Federer and Serena and Andy Roddick are playing, people will flock to Flushing Meadows.
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That 2009 triumph was one of three she achieved at Flushing Meadows, while she also won the 2011 Australian Open.
As soon as you walk through the gates of Flushing Meadows you feel more like you are at a show.
Federer, who won a record 15th grand slam title at Wimbledon, is top seed at Flushing Meadows, the venue since 1978.
He will face either French 13th seed Richard Gasquet or U.S. collegiate champion Steve Johnson, who were playing later at Flushing Meadows.
Oudin will offer a tougher challenge than her first two opponents and is relishing the support she is getting at Flushing Meadows.
But his Flushing Meadows run marked the beginning of his demise rather than the start of his ascent up the men's rankings.
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Sampras' 14 Grand Slam singles wins are made up of seven Wimbledon titles, two Australian Open victories and five wins at Flushing Meadows.
Baseball woud be staged at the famous Yankee Stadium, tennis at Flushing Meadows, basketball at Madison Square Garden and the triathlon in Central Park.
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Fish, who had never gone beyond the second round at Flushing Meadows before this year, struggled with his serve against Monfils but volleyed superbly throughout.
She won 34 singles titles before retiring, including the US Open in 2005 when she defeated French hope Mary Pierce 6-3 6-1 at Flushing Meadows.
Like Murray, the Serbian is playing in his first tournament since Flushing Meadows, and wasted little time in beating Argentina's Carlos Berlocq in straight sets.
Williams, who is bidding to win the Flushing Meadows crown for the fourth time, will now meet former champion Clijsters in an eagerly awaited last four clash.
Murray has stuttered a little since landing his first major title at Flushing Meadows, wasting five match points before losing in the Shanghai Masters final to Serbian Novak Djokovic.
The match went up a level in a dramatic third set that saw Federer stretched as much as we have seen in the last three years at Flushing Meadows.
But since that dramatic five-set win over Roger Federer at Flushing Meadows, Del Potro has struggled with a wrist problem and won just two matches during the build-up to London.
But Federer was, if anything, even more impressive as he destroyed Robin Soderling 6-1 6-1 to set up the chance of revenge for that defeat by Djokovic at Flushing Meadows.
Williams will be defending champion at Flushing Meadows and said there was little for her to improve on before the final Grand Slam event of the year gets under way.
Since mid-summer she has claimed the Wimbledon and U.S. Open titles before coming out on top in the WTA Tour's finale, despite having not played since her Flushing Meadows triumph.
The world number nine said he must take a cautious approach in the build-up to a hectic two months to maintain any hopes of a Grand Slam challenge at Flushing Meadows.
But a surprise four-set defeat by Switzerland's Stanislas Wawrinka followed in the third round at Flushing Meadows, with the Briton beset by physical issues that he was unable to explain immediately afterwards.
Grass roots tennis will also see a boost in funding and Flushing Meadows in New York, which hosts the competition, will also be revamped, with a new Louis Armstrong Stadium and Grandstand.
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