LaLiga leader Atletico Madrid became the highest profile victim of a giant-killing act when it was knocked out of the Copa del Rey by third-tier side Cornella.
A seventh-minute goal from Cornella defender Adrian Jimenez on Wednesday knocked Atletico out of the tournament at an early stage for the second year in succession, reports Xinhua news agency.
Atletico coach Diego Simeone fielded a strong side which included B-team defender Ricard Sanchez, who blotted his copybook when he was sent off for two yellow cards in the 63rd minute.
Granada needed extra-time and a 116th minute winner from Darwin Machis to get past Cultural Leon, who, like Cornella, also play in Segunda B.
Marc Roviola put Cultural ahead after three minutes, and it looked as Atletico's conquerors from last season were set to produce another upset, but Jorge Molina equalised in the 19th minute.
The remaining 70 minutes of regulation time failed to produce any further goals, and Machis scored his winner after an error from home keeper Andoni Zubiaurre.
Levante striker Sergio Leon scored twice to rescue his side from an upset against third-tier Portugalete in one of the two midday kick-offs.
Leon put Levante ahead from close range in the 29th minute and scored a 93rd minute header to avoid extra-time after Mario Musy had headed Portugalete level from a free-kick just before the hour.
In the other midday game, Elche beat fellow third-tier side La Nucia 1-0 thanks to Lucas Boye's goal at the start of the second half.
Real Betis had to come back after conceding an early goal to Multivera in Pamplona. Javier Brinon opened the scoring for the home side in the fourth minute, but defenders Joan Miranda and Emerson turned the score around before half-time and Juanmi sealed the win on the hour.
Finally Osasuna moved into the next round with an easy 3-0 win in Olot with goals from Oir, Ante Budimir and Kike Barja, while Alaves also progressed thanks to Luis Rioja's 75th minute winner away to Deportivo La Coruna.
Tuesday's games had seen Ibiza surprise Celta Vigo, while Granada defeated Getafe.