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The South Americans raced into a 3-1 lead at half time, with one of the most impressive performances witnessed in the recently renovated stadium, and Ireland simply hadn't enough to claw back the two goal deficit.
However, Ireland boss Giovanni Trapattoni will be quite pleased with the display from his youthful side - that boasted just 102 caps between the starting 11 - against the side ranked number seven in the world.
Having lost 2-0 to Estonia last Friday in torturous conditions, Uruguay coach Oscar Tabarez fielded a side capable of restoring pride, with nine of the players who started the World Cup semi-final last summer.
But it was two players that were missing from that game, captain Diego Lugano and youngster Abel Hernandez, along with Edinson Cavani, that found the net in a thrilling first half display of attacking ability.
Palermo's 20-year-old striker Hernandez impressed greatly in the opening half and he had the first chance for 'La Celeste', wonderfully controlling a Diego Forlan chip on his chest only to be prevented from scoring by the retreating Stephen Kelly, Ireland's captain for the night.
At the other end, Keith Fahey almost embarrassed Fernando Muslera in the Uruguayan goal, when his long range effort bounced just in front of the 'keeper, who could only watch as the ball ricocheted off him and just over the bar.
The opener came in the 12th minute, but it was far from a classic. Forlan's free kick was headed away by Fahey, but the ball deflected off Cavani's back and Lugano made no mistake, firing past Keiren Westwood.
Shane Long, Ireland's best player on the night, levelled the score three minutes later, winning the ball from Clark's long clearance, holding it up to feed Paul Green who moved the ball to Liam Lawrence on the right wing.
He checked, and with a sweet left foot cross, found Long, who had raced into the box and rose highest to head home his sixth international goal.
Despite the score, the visitors were clearly on top, and with Maxi Pereira given the freedom of Dublin, he roamed from the right wing across the field and fed Cavani with the perfect pass.
The Napoli hitman was ruthless, curling past Westwood into the far side-netting to regain the lead. Hernandez was terrorising the Irish defence and the man nicknamed 'The Jewel' eventually got his reward with five minutes to half time.
Liam Lawrence had his pocket picked on the halfway line and with Ireland's defence stretched Alvaro Pereira stormed forward and picked out the striker, who finished with a calm beyond his years.
Ireland were right back into the tie three minutes after the restart when Long's surge into the penalty box, and resultant pull-back, won a penalty after Martin Cacedes dived in and pulled down McCarthy.
Fahey made no mistake from the spot, thumping low and hard to Meslura's right. Long and Keogh continued to create opportunities for Ireland and after the latter's well struck shot was parried by Meslura into Long's path, the Reading striker just couldn't adjust his positioning quickly enough to get his shot on target.
Westwood, Shay Given's understudy in the Irish goal, showed his ability late on with a wonderful double save to keep Ireland in the tie, and despite a late half-chance from Keogh, Ireland simply couldn't undo the deficit from the first 45 minutes.