Hashim Amla helped South Africa pile on the runs to leave England facing what would be a record-breaking chase in the second Test at Trent Bridge on Sunday.
South Africa set England 474 to win after declaring their second innings on 343 for nine late on the third day.
The most made by any side to win in the fourth innings of a Test is the West Indies' 418 for seven against Australia at St John's, Antigua, in 2002/03.
England were left with a tricky four overs to bat before stumps.
South Africa nearly had a wicket with the very first ball when Alastair Cook was given out lbw to Morne Morkel.
But Cook immediately reviewed umpire Paul Reiffel's decision and, with replays indicating the ball would have gone over the stumps, the former Australia paceman's verdict was overturned.
Cook and fellow left-handed opener Keaton Jennings both survived to be nought not out at the close, with England one for none courtesy of a lone leg bye.
Earlier Amla, so often a thorn in England's side, made 87 -- his second fifty of the match.
Opener Dean Elgar (80) and returning captain Faf du Plessis (63) also among the runs as the Proteas, 1-0 behind in this four-match series with a 211-run defeat in the first Test at Lord's last week, cemented their already strong position in this match.
South Africa resumed on 75 for one.
Elgar was 38 not out and Amla 23 not out, with England in desperate need of early wickets if after some bad batting Saturday saw them concede a first-innings lead of 130.
Stuart Broad, on his Nottinghamshire home ground, then produced an excellent delivery to Amla, on 25, which carried to wicket-keeper Jonny Bairstow.
England appealed half-heartedly and then decided against reviewing Australian umpire Simon Fry's not out decision, only for replays to indicate there had been an edge.
Elgar had a reprieve on 55 when a thick edge off Broad flew high to gully where James Anderson, diving to his left, so nearly held a spectacular catch.
England eventually had a breakthrough when the painstaking Elgar took his eye off a Ben Stokes bouncer and tamely mis-hooked to Anderson at backward square leg.
England bowled tightly either side of lunch but with South Africa in command and so much time left in the game, their batsmen had no need to take undue risks.
Amla and du Plessis were largely content to pick off the loose ball.
But closing in on what would have been his 27th Test century and seventh against England, Amla -- who made 78 in the first innings -- fell 13 short this time around.
Trying to whip left-arm spinner Liam Dawson, whom he'd earlier hit for a straight six to complete his fifty, Amla was struck on the pad.
Reiffel rejected the lbw appeal but England's review was successful and Amla -- who made South Africa's Test record 311 not out against England at The Oval in 2012 -- was out.
It was the end of a near five-hour innings of 180 balls including 14 fours and that lone six.
Du Plessis, who did not play at Lord's following the birth of his first child, saw his patient vigil of 128 balls, including nine fours, end when he was lbw to Stokes with the new ball.
But with early cloud cover having given way to sunny blue skies, Philander kept the runs coming with two slog-sweep sixes off successive deliveries from Moeen Ali during his entertaining 42.
The off-spinner, who took four for 78, eventually caught and bowled Philander to prompt du Plessis's declaration.