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With these two clubs having reached the last four in the 2020 edition of this tournament, it was perceived that they would cruise through to the knockout stages once again.
However, with both teams already suffering defeat at the hands of Barcelona SC, Santos and Boca Juniors need to perform strongly during the second half of Group C.
Having gotten revenge on Santos in the reverse fixture on April 28, Boca find themselves in the better position, but they can ill-afford another setback on Tuesday.
The Argentine giants would have been satisfied with a point at Barcelona on matchday three, but they ultimately succumbed to a second-half effort from Carlos Garces.
Although Santos started with two defeats in a row, their ruthless 5-0 win against The Strongest has given them momentum ahead of playing host to their rivals.
The response was necessary for Fernando Diniz with his squad having gone four matches without a victory in the Paulista A1.
While changes to the team have been made for that competition, Diniz will want more players to follow in the footsteps of youngster Kaio Jorge, who netted twice in the 3-2 defeat at Palmieras.
At a time when Santos have had problems in the cup, Boca lost out to Patronato in the league on Saturday, leaving them nine points adrift of early pacesetters Velez Sarsfield.