Mexican outfit Puebla surrendered the lead on two occasions as they were held to a 2-2 draw at home to Racing Club on Wednesday.
The Clausura 2015 Copa MX winners took the lead inside the opening minutes thanks to Argentine forward Matias Alustiza.
The lead was short-lived, however, with Gustavo Bou restoring parity just 10 minutes later.
Alustiza put Puebla back ahead via the penalty spot, but Ricardo Noir struck 16 minutes from time to silence the home support.
Racing now hold the advantage going into the second leg thanks to their two away goals, with a spot in Group 3 up for grabs alongside Boca Juniors, Bolivar and Deportivo Cali.
Jonathan Calleri scored on his Sao Paulo debut to earn a 1-1 draw away to Peruvian side Cesar Vallejo.
Vallejo took a surprise lead when Alejandro Hohberg scored inside the opening 20 minutes.
The home side took their one-goal advantage into the break but Calleri equalised with a delightful chip over goalkeeper Salomon Libman in the 66th minute.
The winner of the tie will advance to Group 1 and face River Plate, The Strongest and Trujillanos.