Goals to Gabriel and Alan Santos in the opening 10 minutes saw Santos stun Princesa Solimoes at the Arena Amazonia in Manaus.
Although the home side pulled a goal back just after half-time through Josinaldo Branco, Santos held on for a 2-1 win, ahead of their home leg on May 16.
In Sao Paulo on Wednesday, a penalty from captain and goalkeeper Rogerio Ceni capped off the home side's 3-0 victory over CRB in their second leg on Wednesday, as the Serie A club won 4-2 on aggregate.
The hosts took the lead in the 18th minute through Osvaldo, while Lucas doubled Sao Paulo's advantage five minutes after the break before Ceni converted his penalty in the 82nd.
Figueirense, the bottom side in Serie A, went down 2-1 to Serie B's fifth team Bragantino, while Bahia could only manage a scoreless draw at America Mineiro.
In other results, Londrina drew 3-3 at Gremio Barueri to win on away goals, a late penalty saw ASA win their first leg against Avai 3-2 and ABC drew with Atletico GO ahead of next week's second leg.
