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22744449063
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(a) Augeri, D. J.; Robl, J. A.; Betebenner, D. A.; Magnin, D. R.; Khanna, A.; Robertson, J. G.; Wang, A.; Simpkins, L. M.; Taunk, P.; Huang, Q.; Han, S.-P.; Abboa-Offei, B.; Cap, M.; Xin, L.; Tao, L.; Tozzo, E.; Welzel, G. E.; Egan, D. M.; Marcinkeviciene, J.; Chang, S. Y.; Biller, S. A.; Kirby, M. S.; Parker, R. A.; Hammann, L. G. J. Med. Chem. 2005, 48, 5025-5037.
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more..
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8
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72449167164
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Int. Pub. Num. WO2004052850
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(a) Vu, T. C.; Brzozowski, D. B.; Fox, R.; Godfrey, J. D.; Hanson, R. L.; Kolotuchin, S. V.; Mazzullo, J. A.; Patel, R. N.; Wang, J.; Wong, K.; Yu, J.; Zhu, J.; Magnin, D. R.; Augeri, D. J.; Hamann, L. G. Methods and Compounds Producing Dipeptidyl Petidase IV Inhibitors and Intermediates Thereof. Int. Pub. Num. WO2004052850, 2004.
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9
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34547223622
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(b) Hanson, R. L.; Goldberg, S. L.; Brzozowski, D. B.; Tully, T. P.; Cazzulino, D.; Parker, W. L.; Lyngberg, O. K.; Vu, T. C.; Wong, M. K.; Patel, R. N. Adv. Synth. Catal. 2007, 349, 1369-1378.
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11
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13844281029
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12
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72449162312
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note
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The combined mother liquor and cake washes had <1000 ppm of IPMS on scale.
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13
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72449149890
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note
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Lab-scale gas evolution studies showed that no significant gas was evolved until after ∼15% of the MSA was added and that, if the MSA addition was spread over 1 h or longer, ∼90% of the reaction would occur during the acid charge. This allowed a high level of control over the evolution of carbon dioxide and isobutylene.
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14
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33745079610
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Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biol. Chem. 2006, 4, 2337-2347.
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Carey, J.S.1
Laffan, D.2
Thomson, C.3
Williams, M.T.4
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15
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72449170259
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note
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3-DMF, 2-chloro-4,6-dimethoxy-1,3,5-triazine, N,N2 -carbonyldiimidazole. Specifically, mixed anhydrides suffered from nonselective reactivity with amine 4.
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16
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72449178698
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note
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While kilogram quantities typically cost ∼$2000/kg, manufacturingscale quantities typically run an order of magnitude less at $100 to $200 per kg.
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17
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28944443142
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Dunn, P. J.; Hoffmann, W.; Kang, Y.; Mitchell, J. C.; Snowden, M. J. Org. Process Res. Dev. 2005, 9, 956-961.
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Snowden, M.J.5
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18
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72449176608
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note
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Potassium bicarbonate allowed for higher concentrations of salts than sodium bicarbonate and therefore reduced product loss to the aqueous layer. Though potassium carbonate washes were also effective, they were not chosen to avoid the possibility of epimerization during the subsequent distillation.
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19
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3743146459
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Anthoni, U.; Christensen, D.; Christophersen, C.; Nielsen, P. H. Acta Chem. Scand. 1995, 49, 203-6.
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21
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0001332244
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37049133381
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Clark, J. H.; Emsley, J. J. Chem. Soc., Dalton Trans. 1974, 11, 1125-9.
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23
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72449183368
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note
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LD 50: >2005 mg/kg (rat), cutaneous irritation: nonirritant (rabbit), ocular irritation: nonirritant (rabbit). See the MSDS at Seppic (Seppic, Inc., Fairfield, NJ).
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24
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72449155812
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note
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Epimerization of the nitrile stereogenic center was observed at pH >12 under warm, alcoholic conditions.
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25
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72449165153
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note
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The water solubility of the monohydrate is 19 mg/mL.
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27
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4243173684
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(a) Cypes, S. H.; Wenslow, R. M.; Thomas, S. M.; Chen, A. M.; Dorwart, J. G.; Corte, J. R.; Kaba, M. Org. Process Res. Dev. 2004, 8, 576-582.
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Horsley, L.H.1
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