[Cl:1][CH2:2][C:3]#[N:4].S(=O)(=O)(O)O.O[C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][C:13]([NH:21][C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[O:23])([CH2:14]3)[CH2:12]1)[CH2:18]2.[OH-:30].[Na+]>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:4][C:15]12[CH2:20][CH:11]3[CH2:18][CH:17]([CH2:19][C:13]([NH:21][C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[O:23])([CH2:12]3)[CH2:14]1)[CH2:16]2)=[O:30]Chloroacetonitrile (2.0 mL, 32 mmol) was cooled to 0° C. Sulfuric acid (1.0 mL, 19 mmol) was added slowly at 0° C. After addition completed, the mixture was stirred at 0° C. for 5 minutes. Pyridine-2-carboxylic acid (3-hydroxy-adamantan-1-yl)-amide (0.42 g, 1.56 mmol, from step 1) was added in one portion and the mixture was stirred at rt overnight. The thick solution was poured into ice-water (10 mL). DCM (10 mL) was added. While the mixture was cooled with an ice-bath, the pH of the aqueous phase (top) was adjusted to 10-13 with 10 N aq. NaOH. The aqueous layer was extracted with DCM. The combined organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to afford 0.53 g (96.9%) of crude title compound, pyridine-2-carboxylic acid [3-(2-chloro-acetylamino)-adamantan-1-yl]-amide, as an oil, which became a colorless solid upon standing at room temperature. LC-MS (Gradient: acetonitrile in water, 20-85%, in 1.7 minutes with a cycle time of 2 min. Flow rate: 5.0 mL/min. Mobile phase additive: 30 mM of ammonium formate. Column: Inertsil® ODS, 50×4.6 mm, 3 μm particle size (GL Sciences, Tokyo, Japan)): Retention time: 1.08 min; purity (UV254): 100%; ESI-MS m/z: 348 (M+H)+. It was used in the next step without further purification.
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