Blue Square North side Northwich suffered a 3-1 defeat to League Two strugglers Lincoln in the FA Cup second-round clash at the Victoria Stadium.
Two goals in 15 minutes from Jamie Clarke ended Northwich's hopes after Matthew Bailey had cancelled out Chris Fagan's 18th-minute opener early in the second half.
Amongst the all-league clashes, the game of the day involved MK Dons and Exeter, the latter taking a 3-1 lead midway through the second half, but Paul Ince's side produced a stunning comeback to secure their place in the third-round draw, Jermaine Easter poaching the winner in a 4-3 victory in the 86th minute.
Notts County came from behind to beat League Two leaders Bournemouth 2-1, with Lee Hughes and Craig Westcarr on the scoresheet in the second half after Brett Pitman had given the Cherries a first-half lead at Dean Court.
Colchester, third in League One, had to wait until the 94th minute to crack League Two Hereford courtesy of John-Joe O'Toole's second goal for the club following his loan move from Watford.
League One Huddersfield also beat League Two opposition in Port Vale courtesy of Nathan Clarke's 12th-minute effort.
Gillingham beat Burton Albion 1-0 with Curtis Weston scoring the only goal in the 69th minute at the Priestfield Stadium.
After taking a 3-0 lead, Southampton survived a late rally against Northampton at Sixfields Stadium as the home side pulled back two goals late on.
League One's bottom club Tranmere will need a replay to overcome Aldershot after being held to a goalless draw at Prenton Park.
Brentford edged past Walsall 1-0 at Griffin Park in an all-League One affair courtesy of Leon Legge's 13th-minute winner and League Two rivals Accrington and Barnet will have to replay after their 2-2 draw - John O'Flynn scoring a 95th-minute penalty for the Bees to send them back to Underhill.
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