Midfielder Jadson opened the scoring for Sao Paulo against the defending champions just five minutes into the match at the Pacaembu Stadium, then playmaker Lucas added to the lead in the 22nd and striker Luis Fabiano closed the first-half scoring seven minutes later.
Defender Rafael Toloi scored from a free kick in the 65th and Jadson netted again off a breakaway in the 77th.
The Brazilian club won the first leg 2-0 in Chile last week.
A three time Copa Libertadores champion, Sao Paulo will likely face Argentina's Independiente or Chile's Universidad Catolica, which drew 2-2 in the first leg in Argentina.
Their return game is Thursday in Chile.
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