Serena Williams and Ekaterina Makarova sprinted into the semi-finals of the U.S. Open on Wednesday, while world number one Novak Djokovic and marathon man Kei Nishikori were forced to take the long road into the last four.

Having already played the longest match of the tournament in the fourth round, a bruising four-hour 19-minute battle with Canadian Milos Raonic, Nishikori had enough left in the tank to get past third seed Stan Wawrinka 3-6 7-5 7-6 (7) 6-7 (5) 6-4 in a four-hour 15-minute test of wills to become the first Japanese man into the last four of a grand slam in 81 years.

Bidding to reach the Flushing Meadows final for a fifth straight year, Djokovic did not need five sets to tame a valiant Andy Murray 7-6 (1) 6-7 (1) 6-2 6-4 but the big Serb did have to dig deep to see off his longtime rival who was in obvious distress at the end of what had been a wildly enthralling stadium court encounter.

While Murray and Djokovic battled their way through a 73 minute opening set, 32-year-old Williams needed just 63 minutes in total on a sultry evening to breeze past Italian Flavia Pennetta 6-3 6-2 and become the oldest player to reach the last four at Flushing Meadows since Martina Navratilova in 1991.

Russian left-hander Makarova, who will take on Williams for a spot in Sunday's final, made her best mark in grand slam singles by outslugging Victoria Azarenka, the U.S. Open runner-up the last two years, 6-4 6-2 in a snappy 87 minutes.

While the day presented plenty of intriguing matchups it was the late night clash under the Arthur Ashe Stadium floodlights between Murray and Djokovic, in a rematch of the 2012 final won by the Scotsman, that was always going to be the showstopper.

The pair delivered on the promise, combining for some stunning long rallies until Murray struggled with his movement near the end and required a hot compress for his back midway through the fourth set.

But he produced arguably his best tennis since having back surgery 11 months ago and gave the top seed a real scare.

"I think we played a very physical match in the first two hours," Djokovic said. "I am very glad to get through to another semi-final.

"We both gave our best. At times, the tennis was not that nice, we made a lot of unforced errors but that's due to a very physical battle we had in the first two sets.

"I knew coming into the match that he was going to go for his shots and the one who was the most aggressive would win. I am glad I managed to stay fit in the end and pull through."

UNBELIEVABLE FEELING

Next up for Djokovic will be the tireless Nishikori who is turning into the Flushing Meadows ironman having clocked up eight hours and 34 over his last two matches.

Nishikori arrived at sun-bathed Arthur Ashe Stadium looking fresh despite having played the latest finishing match ever at the U.S. Open a day earlier, when he walked off court on Tuesday morning at 2:26 a.m. local time.

"I don't know how I finished the game, but I'm happy," an exhausted Nishikori, who had a medical timeout in the third set to have his right foot taped, told the Arthur Ashe Stadium crowd.

"I feel amazing. I'm very happy to come to my first semi. I hope I can recover again and hopefully I can play 100 percent tennis next round."

Williams sleepwalked through the start of her quarter-final with Pennetta as the 11th seeded Italian broke twice on the way to a shock 3-0 lead.

But the 17-time grand slam winner awoke from her slumber, storming through the next six games and romping to an easy win.

"It feels so special to be back in the semi-finals for the first time this year," Williams, yet to lose more than three games in any set this championship, told the Arthur Ashe Stadium crowd.

"It's an unbelievable feeling. I'm so happy to have done it here."