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Channeling those frustrations into the second set, he took another early lead only to find himself at three games apiece when another backhand landed beyond the baseline. On the brink of an epic meltdown, Medvedev capitalized on a patchy bit of play from Davidovich Fokina, who broke himself from 40-15 up with a slew of unforced errors.
Medvedev shook off three missed set points—two on his serve with bold forehand misses—to tap into a vein of solid serving and level the match as Davidovich Fokina earned a code violation for an audible obscenity.
Break points continued to abound for Medvedev early in the decider; he converted his fourth of the set with a backhand putaway and reeled off 13 of the next 15 points to earn a commanding 5-1 advantage.
Though Davidovich Fokina managed a late hold, it only briefly postponed the inevitable as Medvedev moved to match point and wrapped up the win with an ace.
In the end, it was all love for the emotional Russian, who wrote "Love clay :)" on the camera following the milestone win.
"I probably will say it even if I win Roland Garros, one moment probably when Rafa retires, maybe it will be just a little bit easier. I will still like other surfaces more, but it's only my opinion, so I don't pretend to have the truthful opinion."
Up next for Medvedev is No. 16 seed Cristian Garin, who knocked out Dominik Koepfer in straight sets earlier in the day.
The round of 16 took shape on Wednesday with top seeds Medvedev and Rafael Nadal leading the way. Monte Carlo champion Stefanos Tsitsipas made a winning debut in Madrid; the No. 4 seed eased past the prodigal Benoit Paire, 6-1, 6-2. The Frenchman snapped a seven-match losing streak but Tsitsipas ultimately advanced with little issue to book an intriguing third-round clash with Norway's Casper Ruud.
An emerging threat on clay, Ruud is fresh off back-to-back semifinal finishes in Monte Carlo and Munich, and backed up an impressive upset of No. 15 seed Félix Auger-Aliassime with an equally decisive victory against Yoshihito Nishioka, 6-1, 6-2.
American John Isner earned an encounter with No. 6 seed Andrey Rublev after saving a match point to survive Roberto Bautista Agut, 6-4, 6-7 (4), 7-6 (6), while Monte Carlo semifinalist Daniel Evans maintained his momentum with a 6-7 (5), 6-4, 6-2 win over John Millman. Evans will next face No. 5 seed Alexander Zverev, who eased past former Madrid finalist Kei Nishikori, 6-3, 6-2.