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1
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2442642767
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For a general overview see: a
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For a general overview see: (a) Szallasi, A.; Appendino, G. J. Med. Chem. 2004, 47, 2717.
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J. Med. Chem
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Szallasi, A.1
Appendino, G.2
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3
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39049165772
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For disclosure of clinical development candidates see: a
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For disclosure of clinical development candidates see: (a) Lukin, K.; Hsu, M. C.; Chambournier, G.; Kotecki, B.; Venkatramani, C. J.; Leanna, M. R. Org. Process Res. Dev. 2007, 11, 578.
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Lukin, K.1
Hsu, M.C.2
Chambournier, G.3
Kotecki, B.4
Venkatramani, C.J.5
Leanna, M.R.6
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4
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33646677987
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(b) Rami, H. K.; Thompson, M.; Stemp, G.; Fell, S.; Jerman, J. C.; Stevens, A. J.; Smart, D.; Sargent, B.; Sanderson, D.; Randall, A. D.; Gunthorpe, M. J.; Davis, J. B. Bioorg. Med. Chem. Lett. 2006, 16, 3287.
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Rami, H.K.1
Thompson, M.2
Stemp, G.3
Fell, S.4
Jerman, J.C.5
Stevens, A.J.6
Smart, D.7
Sargent, B.8
Sanderson, D.9
Randall, A.D.10
Gunthorpe, M.J.11
Davis, J.B.12
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5
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34547573343
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(a) Norman, M. H.; Fotsch, C.; Doherty, E. M.; Bo, Y.; Chen, N.; Chakrabarti, P.; Gavva, N. R.; Nishimura, N.; Nixey, T.; Ognyanov, V.; Rzasa, R.; Stec, M.; Surapaneni, S.; Tamir, R.; Viswanadhan, V.; Zhu, J.; Treanor, J. S. J. Med. Chem. 2007, 50, 3497.
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J. Med. Chem
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Norman, M.H.1
Fotsch, C.2
Doherty, E.M.3
Bo, Y.4
Chen, N.5
Chakrabarti, P.6
Gavva, N.R.7
Nishimura, N.8
Nixey, T.9
Ognyanov, V.10
Rzasa, R.11
Stec, M.12
Surapaneni, S.13
Tamir, R.14
Viswanadhan, V.15
Zhu, J.16
Treanor, J.S.17
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6
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34547560453
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(b) Doherty, E. M.; Bannon, A. W.; Bo, Y.; Chen, N.; Dominguez, C.; Falsey, J.; Fotsch, C.; Gavva, N. R.; Katon, J.; Nixey, T.; Ognyanov, V.; Pettus, L.; Rzasa, R.; Stec, M.; Surapaneni, S.; Tamir, R.; Zhu, J.; Treanor, J. S.; Norman, M. H. J. Med. Chem. 2007, 50, 3515.
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J. Med. Chem
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Doherty, E.M.1
Bannon, A.W.2
Bo, Y.3
Chen, N.4
Dominguez, C.5
Falsey, J.6
Fotsch, C.7
Gavva, N.R.8
Katon, J.9
Nixey, T.10
Ognyanov, V.11
Pettus, L.12
Rzasa, R.13
Stec, M.14
Surapaneni, S.15
Tamir, R.16
Zhu, J.17
Treanor, J.S.18
Norman, M.H.19
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7
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34547556499
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(c) Wang, H.; Katon, J.; Balan, C.; Bannon, A. W.; Bernard, C.; Doherty, E. M.; Dominguez, C.; Gavva, N. R.; Gore, V.; Ma, V.; Nishimura, N.; Surapaneni, S.; Tang, P.; Tamir, R.; Thiel, O. R.; Treanor, J. S.; Norman, M. H. J. Med. Chem. 2007, 50, 3528.
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J. Med. Chem
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Wang, H.1
Katon, J.2
Balan, C.3
Bannon, A.W.4
Bernard, C.5
Doherty, E.M.6
Dominguez, C.7
Gavva, N.R.8
Gore, V.9
Ma, V.10
Nishimura, N.11
Surapaneni, S.12
Tang, P.13
Tamir, R.14
Thiel, O.R.15
Treanor, J.S.16
Norman, M.H.17
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8
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43449132863
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$424 for 25 g
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$424 for 25 g.
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11
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0001414642
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(c) Gupta, R. R.; Ojha, K. G.; Kalwania, G. S.; Kumar, M. Heterocycles 1980, 14, 1145.
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(1980)
Heterocycles
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Gupta, R.R.1
Ojha, K.G.2
Kalwania, G.S.3
Kumar, M.4
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15
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43449090842
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Identified by LC/MS analysis
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Identified by LC/MS analysis.
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16
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43449089010
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The intermediates in this proposed mechanism were not observed directly
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The intermediates in this proposed mechanism were not observed directly.
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19
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0013644525
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(c) Butler, A. R.; Glidewell, C.; Liles, D. S. Acta Crystallogr., Sect. B 1978, 34, 3241.
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(1978)
Acta Crystallogr., Sect. B
, vol.34
, pp. 3241
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Butler, A.R.1
Glidewell, C.2
Liles, D.S.3
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20
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0142227938
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Jordan, A. D.; Lou, C.; Reitz, A. B. J. Org. Chem. 2003, 68, 8693.
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(2003)
J. Org. Chem
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, pp. 8693
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Jordan, A.D.1
Lou, C.2
Reitz, A.B.3
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22
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43449120837
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The following conditions were used: acetic anhydride, triethylamine, ethyl acetate, rt
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The following conditions were used: acetic anhydride, triethylamine, ethyl acetate, rt.
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23
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0034605453
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An enantioselective hydroamination for a leading reference see: Kawatsura, M, Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 9546. of 4-fluorostyrene with piperazine also appears feasible, but this option was not explored due to the relatively high price of the starting material
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An enantioselective hydroamination (for a leading reference see: Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 9546. of 4-fluorostyrene with piperazine also appears feasible, but this option was not explored due to the relatively high price of the starting material.
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24
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10344253344
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For examples on related substrates see: a
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For examples on related substrates see: (a) Arink, A. M.; Kronenburg, C. M. P.; Jastrzebski, J. T. B. H.; Lutz, M.; Spek, A. W.; Gossage, R. A.; van Koten, G. J. Am. Chem. Soc. 2004, 126, 16249.
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(2004)
J. Am. Chem. Soc
, vol.126
, pp. 16249
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Arink, A.M.1
Kronenburg, C.M.P.2
Jastrzebski, J.T.B.H.3
Lutz, M.4
Spek, A.W.5
Gossage, R.A.6
van Koten, G.7
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25
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0035846070
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(b) Tagat, J. R.; Steensma, R. W.; McCombie, S. T. W.; Nazareno, D. V.; Lin, S.-I.; Neustadt, B. R.; Cox, K.; Xu, S.; Wojcik, L.; Murray, M. G.; Vantuno, N.; Baroudy, B. M.; Strizki, J. M. J. Med. Chem. 2001, 44, 3343.
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(2001)
J. Med. Chem
, vol.44
, pp. 3343
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Tagat, J.R.1
Steensma, R.W.2
McCombie, S.T.W.3
Nazareno, D.V.4
Lin, S.-I.5
Neustadt, B.R.6
Cox, K.7
Xu, S.8
Wojcik, L.9
Murray, M.G.10
Vantuno, N.11
Baroudy, B.M.12
Strizki, J.M.13
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26
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0000627594
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The obtained result was slightly inferior to results reported in the literature but no detailed optimization of this reaction was carried out at this point. For a reference see: Mathre, D. J, Thompson, A. S, Douglas, A. W, Hoogsten, K, Carroll, J. D, Gorley, E. Q, Grabowski, E. J. J. J. Org. Chem. 1993, 58, 2880
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The obtained result was slightly inferior to results reported in the literature but no detailed optimization of this reaction was carried out at this point. For a reference see: Mathre, D. J.; Thompson, A. S.; Douglas, A. W.; Hoogsten, K.; Carroll, J. D.; Gorley, E. Q.; Grabowski, E. J. J. J. Org. Chem. 1993, 58, 2880.
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6344246095
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Barnett, C. J.; Huff, B.; Kobierski, M. E.; Letourneau, M.; Wilson, T. M. J. Org. Chem. 2004, 69, 7653.
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(2004)
J. Org. Chem
, vol.69
, pp. 7653
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Barnett, C.J.1
Huff, B.2
Kobierski, M.E.3
Letourneau, M.4
Wilson, T.M.5
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29
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0001015969
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Murahashi, S.-I.; Kondo, K.; Hakata, T. Tetrahedron Lett. 1982, 23, 229.
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(1982)
Tetrahedron Lett
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, pp. 229
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Murahashi, S.-I.1
Kondo, K.2
Hakata, T.3
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30
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0032568913
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Abbenhuis, R. A.T.M.; Boersma, J.; van Koten, G. J. Org. Chem. 1998, 63, 4282.
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(1998)
J. Org. Chem
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Abbenhuis, R.A.T.M.1
Boersma, J.2
van Koten, G.3
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31
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6444231812
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Fujita, K.; Fujii, T.; Yamguchi, R. Org. Lett. 2004, 6, 3525.
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Org. Lett
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Fujita, K.1
Fujii, T.2
Yamguchi, R.3
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32
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0032568913
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A ruthenium-catalyzed synthesis of piperazines was reported earlier (Abbenhuis, R. A. T. M.; Boersma, J.; van Koten, G. J. Org. Chem. 1998, 63, 4282. ) but elevated temperatures of 180 °C were necessary. The successful examples (yields 7-34%) were limited to cyclization with anilines. No products were obtained when primary aliphatic amines were used in the reaction.
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A ruthenium-catalyzed synthesis of piperazines was reported earlier (Abbenhuis, R. A. T. M.; Boersma, J.; van Koten, G. J. Org. Chem. 1998, 63, 4282. ) but elevated temperatures of 180 °C were necessary. The successful examples (yields 7-34%) were limited to cyclization with anilines. No products were obtained when primary aliphatic amines were used in the reaction.
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34
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33845375188
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Shvo, Y.; Czarkie, D.; Rahamim, Y. J. Am. Chem. Soc. 1986, 108, 7400.
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J. Am. Chem. Soc
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Shvo, Y.1
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Choi, J. H.; Kim, Y. H.; Nam, S. H.; Shin, S. T.; Kim, M.-J.; Park, J. Angew. Chem., Int. Ed. 2002, 41, 2373.
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Choi, J.H.1
Kim, Y.H.2
Nam, S.H.3
Shin, S.T.4
Kim, M.-J.5
Park, J.6
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36
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(a) Opalka, C. J.; D'Ambra, T. E.; Facoone, J. J.; Bpdson, G.; Cossement, E. Synthesis 1995, 766.
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Synthesis
, pp. 766
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Opalka, C.J.1
D'Ambra, T.E.2
Facoone, J.J.3
Bpdson, G.4
Cossement, E.5
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0037016979
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(b) Pflum, D. A.; Krishnamurthy, D.; Zhengxu, H.; Senanayke, S. A. Tetrahedron Lett. 2002, 43, 923.
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Tetrahedron Lett
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(c) Bazzicalupi, C.; Bencini, A.; Fust, V.; Micheloni, M.; Paoletti, P.; Valtancoli, B. J. Org. Chem. 1994, 59, 7508.
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Paoletti, P.5
Valtancoli, B.6
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39
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0035924183
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Ksander, G. M.; deJesus, R.; Yuan, A.; Fink, C.; Moskal, M.; Carlson, E.; Kukkola, P.; Bilci, N.; Wallace, E.; Neubert, A.; Feldman, D.; Mogelesky, T.; Poirier, K.; Jeune, M.; Steele, R.; Wasvery, J.; Stephan, Z.; Cahill, E.; Webb, R.; Navarette, A.; Lee, W.; Gibson, J.; Alexander, N.; Sharif, H.; Hospattankar, A. J. Med. Chem. 2001, 44, 4677.
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Ksander, G.M.1
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Yuan, A.3
Fink, C.4
Moskal, M.5
Carlson, E.6
Kukkola, P.7
Bilci, N.8
Wallace, E.9
Neubert, A.10
Feldman, D.11
Mogelesky, T.12
Poirier, K.13
Jeune, M.14
Steele, R.15
Wasvery, J.16
Stephan, Z.17
Cahill, E.18
Webb, R.19
Navarette, A.20
Lee, W.21
Gibson, J.22
Alexander, N.23
Sharif, H.24
Hospattankar, A.25
more..
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43449129334
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The equimolar amounts for the starting materials are based on stoichiometry calculation not accounting for the potency of the starting materials. It was later discovered that the starting material 2 often only has potency wt/wt , of 90-95, which then de facto leads to use of excess 4,6-dichloropyrimidine in the coupling reaction
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The equimolar amounts for the starting materials are based on stoichiometry calculation not accounting for the potency of the starting materials. It was later discovered that the starting material 2 often only has potency (wt/wt %) of 90-95%, which then de facto leads to use of excess 4,6-dichloropyrimidine in the coupling reaction.
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43449096514
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An additional suspension in ethanol/water, followed by filtration was needed to reduce the content of DMF in the API ∼4000 ppm in the crude material
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An additional suspension in ethanol/water, followed by filtration was needed to reduce the content of DMF in the API (∼4000 ppm in the crude material).
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