Seward was born in on May 16, 1801, in the small community of Florida, New York, in Orange County. He was the fourth son of Samuel Sweezy Seward and his wife Mary (Jennings) Seward. Samuel Seward was a wealthy landowner and slaveholder in New York State; slavery was not fully abolished in the state until 1827. Florida was located some 60 miles (97 km) north of New York City, west of the Hudson River, and was a small rural village of perhaps a dozen homes.

There were no primaries in 1860, no way to be certain how many delegates a candidate might receive. Nevertheless, going into the 1860 Republican National Convention in May in Chicago, Seward was seen as the overwhelming favorite. Others spoken of for the nomination included Ohio Governor Salmon P. Chase, former Missouri congressman Edward Bates, and former Illinois congressman Abraham Lincoln.  Seward stayed in Auburn during the convention; Weed was present on his behalf and worked to shore up Seward's support. He was amply supplied with money: business owners had eagerly given, expecting Seward to be the next president. Weed's reputation was not entirely positive; he was believed corrupt by some, and his association both helped and hurt Seward.  Enemies such as publisher and former Seward ally Horace Greeley cast doubts as to Seward's electability in the battleground states of Illinois, Indiana, Pennsylvania and New Jersey. Lincoln had worked hard to gain a reputation as a moderate in the party and hoped to be seen as a consensus second choice, who might be successful in those critical states, of which the Republicans had to win three to secure the election. Lincoln's men, led by his friend David Davis, were active on his behalf. As Lincoln had not been seen as a major candidate, his supporters had been able to influence the decision to hold the convention in his home state, and surrounded the New York delegation, pro-Seward, with Lincoln loyalists. They eventually were successful in gaining the support of the delegations from the other battleground states, boosting delegates' perceptions of Lincoln's electability. Although Lincoln and Seward shared many views, Lincoln, out of office since 1849, had not excited opposition as Seward had in the South and among Know Nothings. Lincoln's views on nativism, which he opposed, were not public.  On the first ballot, Seward had 173 1/2  votes to Lincoln's 102, with 233 needed to nominate. Pennsylvania shifted its vote to Lincoln on the second ballot, and Seward's lead was cut to 184 1/2  to 181. On the third, Lincoln had 231 1/2  to Seward's 180 after the roll call, but Ohio changed four votes from Chase to Lincoln, giving the Illinoian the nomination and starting a small stampede; the nomination was eventually made unanimous. When word reached Seward by telegraph, by the accounts of witnesses, he calmly remarked that Lincoln had some of the attributes needed to be president, and would certainly be elected.  Despite his public nonchalance, Seward was devastated by his convention loss, as were many of his supporters. The New Yorker was the best-known and most popular Republican, and his defeat shocked many in the North, who felt that Lincoln had been nominated through chicanery. Although Seward sent a letter stating Weed was not to blame, Seward's political manager took the defeat hard. Seward was initially inclined to retire from public life, but received many letters from supporters: distrustful of Lincoln, they urged Seward to remain involved in politics. On his way to Washington to return to Senate duties, he stopped in Albany to confer with Weed, who had gone to Lincoln's home in Springfield, Illinois to meet with the candidate, and had been very impressed at Lincoln's political understanding. At the Capitol, Seward received sympathy even from sectional foes such as Jefferson Davis.  Lincoln faced three major opponents. A split in the Democratic Party had led northerners to nominate Senator Douglas, while southerners chose Vice President John C. Breckinridge. The Constitutional Union Party, a new party consisting mostly of former Southern Whigs, selected former Tennessee senator John Bell. As Lincoln would not even be on the ballot in ten southern states, he needed to win almost every northern state to take the presidency. Douglas was said to be strong in Illinois and Indiana, and if he took those, the election might be thrown into the House of Representatives. Seward was urged to undertake a campaign tour of the Midwest in support of Lincoln and did so for five weeks in September and October, attracting huge crowds. He journeyed by rail and boat as far north as Saint Paul, Minnesota, into the border state of Missouri at St. Louis, and even to Kansas Territory, though it had no electoral votes to cast in the election. When the train passed through Springfield, Seward and Lincoln were introduced, with Lincoln appearing "embarrassed" and Seward "constrained". In his oratory, Seward spoke of the U.S. as a "tower of freedom", a Union that might even include Canada, Latin America, and Russian America.  New York was key to the election; a Lincoln loss there would deadlock the Electoral College. Soon after his return from his Midwest tour, Seward embarked on another, speaking to large crowds across the state of New York. At Weed's urging he went to New York City and gave a patriotic speech before a large crowd on November 3, only three days before the election. On Election Day, Lincoln carried most Northern states, while Breckinridge took the Deep South, Bell three border states, and Douglas won Missouri--the only state Seward campaigned in that Lincoln did not win. Lincoln was elected.  Lincoln faced the question of what to do about Fort Sumter in Charleston harbor, held by the Army against the will of South Carolinians, who had blockaded it. The fort's commander, Major Robert Anderson, had sent word that he would run out of supplies. Seward, backed by most of the Cabinet, recommended to Lincoln that an attempt to resupply Sumter would be provocative to the border states, that Lincoln hoped to keep from seceding. Seward hinted to the commissioners that had come to Washington on behalf of the Confederacy that Sumter would be surrendered. Lincoln was loath to give up Sumter, feeling it would only encourage the South in its insurgency.  With the Sumter issue unresolved, Seward sent Lincoln a memorandum on April 1, proposing various courses of action, including possibly declaring war on France and Spain if certain conditions were not met, and reinforcing the forts along the Gulf of Mexico. In any event, vigorous policies were needed and the president must either establish them himself or allow a Cabinet member to, with Seward making it clear he was willing to do it. Lincoln drafted a reply indicating that whatever policy was adopted, "I must do it", though he never sent it, but met with Seward instead, and what passed between them is not known. Seward's biographers make the point that the note was sent to a Lincoln who had not yet proved himself in office.  Lincoln decided on expeditions to try to relieve Sumter and Florida's Fort Pickens. Meanwhile, Seward was assuring Justice John Archibald Campbell, the intermediary with the Confederate commissioners that had come to Washington in an attempt to secure recognition, that no hostile action would be taken. Lincoln sent a notification to South Carolina's governor of the expedition, and on April 12, Charleston's batteries began firing on Sumter, beginning the Civil War.

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