Name: 19741-14-1|4-(((2,4-Diaminopteridin-6-yl)methyl)(methyl)amino)benzoic acid|95%
Brand: Ambeed
SKU: A532297
Price: 140.0 USD
Availability: InStock
Rating: 94 (40 reviews)

1
[ 945-24-4 ]
[ 10541-83-0 ]
[ 19741-14-1 ]

Reference： [1]Journal of Organic Chemistry,2001,vol. 66,p. 5146 - 5154
[2]Journal of Medicinal Chemistry,1989,vol. 32,p. 2426 - 2431
[3]Journal of Medicinal Chemistry,2018,vol. 61,p. 3503 - 3515

2
[ 3783-61-7 ]
[ 19741-14-1 ]
[ 112113-88-9 ]

Yield	Reaction Conditions	Operation in experiment
53%	With diethyl cyanophosphonate; triethylamine In N,N-dimethyl-formamide for 96h; Ambient temperature;

Reference： [1]Rosowsky, Andre; Bader, Henry; Forsch, Ronald A.; Moran, Richard G.; Freisheim, James H. [Journal of Medicinal Chemistry, 1988, vol. 31, # 4, p. 763 - 768]

3
[ 3687-18-1 ]
[ 19741-14-1 ]
[ 113811-47-5 ]

Reference： [1]Journal of Medicinal Chemistry,1988,vol. 31,p. 1326 - 1331

4
[ 2942-58-7 ]
[ 19741-14-1 ]
[ 6234-01-1 ]
[ 79640-68-9 ]
[ 95485-10-2 ]
[ 95485-11-3 ]

Reference： [1]Journal of Medicinal Chemistry,1985,vol. 28,p. 660 - 667

5
[ 5070-13-3 ]
[ 19741-14-1 ]
[ 95485-01-1 ]

Yield	Reaction Conditions	Operation in experiment
86%	With triethylamine In N,N-dimethyl-formamide at 55℃; for 5h;

Reference： [1]Rosowsky; Freisheim; Moran; Solan; Bader; Wright; Radike-Smith [Journal of Medicinal Chemistry, 1986, vol. 29, # 5, p. 655 - 660]

6
[ 53838-27-0 ]
[ 19741-14-1 ]
[ 79640-68-9 ]

Reference： [1]Journal of Medicinal Chemistry,1981,vol. 24,p. 1450 - 1455

7
[ 79640-72-5 ]
[ 19741-14-1 ]
[ 79648-88-7 ]

Yield	Reaction Conditions	Operation in experiment
	With diethyl cyanophosphonate; triethylamine 1.) DMF, 80 deg C, 2 min, 2.) DMF, 80 deg C, 2 h; Yield given. Multistep reaction;
	With diethyl cyanophosphonate; N-ethyl-N,N-diisopropylamine 1.) DMF, 4 h, 2.) room temperature, 48 h; Multistep reaction;
	Stage #1: 4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoic acid With diethyl cyanophosphonate; triethylamine In N,N-dimethyl-formamide at 20℃; for 3h; Stage #2: L-glutamic acid 1-tert-butyl ester 5-methyl ester With triethylamine In N,N-dimethyl-formamide at 20℃; for 72h; Stage #3: With ammonia In dichloromethane; water	2; 9 To a solution of 9 (3.3 g, 10.1 mmol) in DMF (340 ml) was added Et3N (2.1 ml, 15.2 mmol) followed by diethylcyanophosphonate. (2.3 ml, 15.2 mmol). The reaction mixture was stirred at room temperature for 3 h. Et3N (2.1 ml, 15.1 mmol) and the glutamic acid diester (2.57 g, 10.1 mmol) were added to the reaction mixture and the reaction was stirred at room temperature for 72 h. The solvents were removed under reduced pressure. The residue was dissolved in CH2Cl2 and the organic layer was washed with 1% NH4OH (2×) and brine (2×). The organic layer was dried (MgSO4) and concentrated. The crude residue was purified by silica gel chromatography (7/7/1 CH2Cl2/acetone/methanol to 7/7/2 CH2Cl2/acetone/methanol) to give 10 (2.6 g).

Reference： [1]Rosowsky, Andre; Forsch, Ronald; Uren, Jack; Wick, Michael [Journal of Medicinal Chemistry, 1981, vol. 24, # 12, p. 1450 - 1455]
[2]Kralovec; Spencer; Blair; Mammen; Singh; Ghose [Journal of Medicinal Chemistry, 1989, vol. 32, # 11, p. 2426 - 2431]
[3]Davey, Ross A.; Davey, Mary W.; Cullen, Karen V.; Wells, Xanthe E.; Francis, Craig L.; Williams, Hua-Ming; Yang, Qi; Moghaddam, Minoo J.; Widmer, Fred; Whittaker, Robert G. [British Journal of Pharmacology, 2002, vol. 137, # 8, p. 1280 - 1286]
[4]Current Patent Assignee: AGGENIX - US7230101, 2007, B1 Location in patent: Page/Page column 60-61; 79-80

8
[ 19741-14-1 ]
[ 6234-01-1 ]
[ 79640-68-9 ]
[ 95485-10-2 ]
[ 95485-11-3 ]

Reference： [1]Journal of Medicinal Chemistry,1985,vol. 28,p. 660 - 667

9
[ 19741-14-1 ]
[ 5722-16-7 ]
[ 113976-31-1 ]

Yield	Reaction Conditions	Operation in experiment
52%	With diethyl cyanophosphonate; triethylamine In N,N-dimethyl-formamide for 76h; Ambient temperature;

Reference： [1]Rosowsky; Bader; Kohler; Freisheim; Moran [Journal of Medicinal Chemistry, 1988, vol. 31, # 7, p. 1338 - 1344]

10
[ 19741-14-1 ]
[ 13650-49-2 ]
[ 96846-16-1 ]

Reference： [1]Journal of Medicinal Chemistry,1986,vol. 29,p. 655 - 660

11
[ 19741-14-1 ]
[ 89106-10-5 ]
[ 89106-05-8 ]

Yield	Reaction Conditions	Operation in experiment
94%	With triethylamine; diethyl dicarbonate In N,N-dimethyl-formamide for 72h; Ambient temperature;
	With diethyl cyanophosphonate; triethylamine 1.) DMF, overnight, RT, 2.) DMF, RT, 3 d; Yield given. Multistep reaction;

Reference： [1]Forsch, Ronald A.; Rosowsky, Andre [Journal of Organic Chemistry, 1984, vol. 49, # 7, p. 1305 - 1309]
[2]Rosowsky, Andre; Forsh, Ronald A.; Freisheim, James H.; Galivan, John; Wick, Michael [Journal of Medicinal Chemistry, 1984, vol. 27, # 7, p. 888 - 893]

12
[ 19741-14-1 ]
[ 74536-29-1 ]
[ 100484-54-6 ]

Reference： [1]Journal of Medicinal Chemistry,1986,vol. 29,p. 655 - 660

13
[ 19741-14-1 ]
[ 108-23-6 ]
[ 407616-56-2 ]

Yield	Reaction Conditions	Operation in experiment
0.31 g	With triethylamine In N,N-dimethyl-formamide for 0.5h; Ambient temperature;
	With triethylamine In N,N-dimethyl-formamide for 0.25h; Ambient temperature;

Reference： [1]Rosowsky, Andre; Yu, Cheng-Sein; Uren, Jack; Lazarus, Herbert; Wick, Michael [Journal of Medicinal Chemistry, 1981, vol. 24, # 5, p. 559 - 567]
[2]Rosowsky, A.; Yu, C.-S. [Journal of Medicinal Chemistry, 1983, vol. 26, # 10, p. 1448 - 1452]

14
[ 19741-14-1 ]
[ 13288-57-8 ]
[ 83399-36-4 ]

Reference： [1]Journal of Medicinal Chemistry,1983,vol. 26,p. 111 - 113

15
[ 19741-14-1 ]
[ 112113-86-7 ]
[ 112113-85-6 ]

Yield	Reaction Conditions	Operation in experiment
47%	With diethyl cyanophosphonate; triethylamine In N,N-dimethyl-formamide for 40h; Ambient temperature;

Reference： [1]Rosowsky, Andre; Bader, Henry; Forsch, Ronald A.; Moran, Richard G.; Freisheim, James H. [Journal of Medicinal Chemistry, 1988, vol. 31, # 4, p. 763 - 768]

16
[ 19741-14-1 ]
[ 5686-32-8 ]
[ 113976-32-2 ]

Yield	Reaction Conditions	Operation in experiment
62%	With diethyl cyanophosphonate; triethylamine In N,N-dimethyl-formamide for 76h; Ambient temperature;

Reference： [1]Rosowsky; Bader; Kohler; Freisheim; Moran [Journal of Medicinal Chemistry, 1988, vol. 31, # 7, p. 1338 - 1344]

17
[ 19741-14-1 ]
[ 5686-31-7 ]
[ 113976-33-3 ]

Yield	Reaction Conditions	Operation in experiment
60%	With diethyl cyanophosphonate; triethylamine In N,N-dimethyl-formamide for 76h; Ambient temperature;

Reference： [1]Rosowsky; Bader; Kohler; Freisheim; Moran [Journal of Medicinal Chemistry, 1988, vol. 31, # 7, p. 1338 - 1344]

19
[ 19741-14-1 ]
[ 113976-44-6 ]
[ 113976-35-5 ]

Yield	Reaction Conditions	Operation in experiment
57%	With diethyl cyanophosphonate; triethylamine In N,N-dimethyl-formamide for 76h; Ambient temperature;

Reference： [1]Rosowsky; Bader; Kohler; Freisheim; Moran [Journal of Medicinal Chemistry, 1988, vol. 31, # 7, p. 1338 - 1344]

20
[ 19741-14-1 ]
[ 543-27-1 ]
[ 56892-71-8 ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine In dimethyl sulfoxide; N,N-dimethyl-formamide at 0℃; for 30h;
	With triethylamine In N,N-dimethyl-formamide 1.) 0 deg C, 90 min, 2.) 25 deg C, 30 min;
	With 4-methyl-morpholine In various solvent(s) at 0℃; for 0.333333h;

Reference： [1]Abraham; Nair; Kisliuk; Gaumont; Galivan [Journal of Medicinal Chemistry, 1990, vol. 33, # 2, p. 711 - 717]
[2]Abraham; McGuire; Galivan; Nimec; Kisliuk; Gaumont; Nair [Journal of Medicinal Chemistry, 1991, vol. 34, # 1, p. 222 - 227]
[3]Kempton, Robert J.; Black, Angelique M.; Anstead, Gregory M.; Kumar, A. Ashok; Blankenship, Dale T.; Freisheim, James H. [Journal of Medicinal Chemistry, 1982, vol. 25, # 4, p. 475 - 477]

21
γ-tert-butyl α-methyl N-(4-amino-4-deoxy-N¹⁰-methylpteroyl)-4-cyanoglutamate [ No CAS ]
[ 19741-14-1 ]
N-(4-amino-4-deoxy-N¹⁰-methylpteroyl)-4-carbamoylglutamic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 45% 2: 26%	With hydrogen bromide; acetic acid at 25℃; for 24h;

Reference： [1]Rosowsky; Bader; Freisheim [Journal of Medicinal Chemistry, 1991, vol. 34, # 1, p. 203 - 208]

22
[ 7532-09-4 ]
[ 19741-14-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium acetate; zinc(II) chloride at 37℃;
96%	With hydrogenchloride; Tris buffer; zinc(II) chloride In water at 38℃; for 48h;

Reference： [1]Rosowsky; Wright; Ginty; Uren [Journal of Medicinal Chemistry, 1982, vol. 25, # 8, p. 960 - 964]
[2]Luo, Jin; Smith, Michael D.; Lantrip, Douglas A.; Wang, Susan; Fuchs [Journal of the American Chemical Society, 1997, vol. 119, # 42, p. 10004 - 10013]

23
[ 59-05-2 ]
[ 19741-14-1 ]

Reference： [1]Agricultural and Biological Chemistry,1983,vol. 47,p. 1847 - 1852
[2]Phosphorus, Sulfur and Silicon and the Related Elements,2003,vol. 178,p. 17 - 32
[3]Combinatorial Chemistry and High Throughput Screening,2015,vol. 18,p. 723 - 734

24
[ 19741-14-1 ]
[ 56892-87-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	With diphenylphosphoranyl azide; triethylamine In dimethyl sulfoxide at 20℃; for 48h;
83%	With diphenylphosphoranyl azide; triethylamine In dimethyl sulfoxide for 20h;
83%	With triethylamine In tetrahydrofuran; dimethyl sulfoxide	11 4-[[(2,4-Diamino-6pteridinyl)methyl]methylamino]benzoyl azide 29: EXAMPLE 11 4-[[(2,4-Diamino-6pteridinyl)methyl]methylamino]benzoyl azide 29: A solution of 56 (100 mg, 0.31 mmol), diphenyllphosphoryl azide (0.13 mL 0.46 mmol), and Et3N (0.09 mL, 0.62 mmol) in DMSO (5 mL) was stirred for 20 h. THF (10 mL) was then added and the precipitate was filtered to give 29 (92 mg, 83%). 1H-NMR is the same as that reported in the literature.

Reference： [1]Valiaeva; Bartley; Konno; Coward [Journal of Organic Chemistry, 2001, vol. 66, # 15, p. 5146 - 5154]
[2]Luo, Jin; Smith, Michael D.; Lantrip, Douglas A.; Wang, Susan; Fuchs [Journal of the American Chemical Society, 1997, vol. 119, # 42, p. 10004 - 10013]
[3]Current Patent Assignee: PURDUE UNIVERSITY SYSTEM - US6291673, 2001, B1

25
[ 45120-30-7 ]
[ 19741-14-1 ]
[ 79640-70-3 ]

Yield	Reaction Conditions	Operation in experiment
59%		To a solution of pteroic acid 6 (771 mg, 2.37 mmol, 95% purity) in anhydrous DMF (20 mL), PyBOP (1.55 g, 2.98 mmol) and triethylamine (2.52 mL, 19.0 mmol) were added and the turbid reaction mixture was stirred 2 h at 20 C. H-Glu-OtBu was added and the turbid mixture was stirred for another 22 h. Then, 0.5 M NaOH (20 mL) was added and the aqueous phase was washed with a solution of CH2CI2and EtOAc (1:4, 1 x 50 mL) then neutralized with 1 M HCI and concentrated. The crude was taken up in DMF (20 mL) and precipitate was removed by filtration. The filtrate was purified by preparative HPLC (eluent system 1) to give the title compound as an orange solid (681 mg, 59%). 1H NMR (400 MHz, DMSO-d5) delta 12.17 (br. s, 1H), 9.24 (br. s, 1H), 9.04 (br. s, 1H), 8.72 (s, 1H), 8.56 (br. s, 1H), 8.21 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 9.0 Hz, 2H), 7.35 (br. s, 1H), 6.82 (d, J = 9.0 Hz, 2H), 4.87 (s, 2H), 4.29 (ddd, J = 9.7, 7.5, 5.2 Hz, 1H), 3.25 (s, 3H), 2.32 (t, J = 7.5 Hz, 2H), 2.06 - 1.96 (m, 1H), 1.90 (ddt, J = 14.1, 9.3, 7.2 Hz, 1H), 1.39 (s, 9H). 13C NMR (101 MHz, DMSO-d5) delta 173.9, 171.5, 166.4, 162.8 (2C), 155.9, 151.2, 150.7, 148.8, 129.0, 122.3, 121.4, 111.2, 80.5, 54.9, 52.5, 40.2, 30.4, 27.7, 26.0; m.p.: > 154 C (decomposition); IR (neat) cm"1: 3342, 3118, 2976, 2931, 1716, 1639, 1601, 1506, 1364, 1152, 832.
46%	With potassium carbonate; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In dimethyl sulfoxide;Inert atmosphere;	The compound 13 was allowed to react with triphenylphosphine dibromide in DMA to obtain a compound 14.The compound 14 was dissolved in DMA under nitrogen gas stream, and then the compound 15 and DIEA were addedand reacted to obtain a compound 16 (yield: 69%). Subsequently, the compound 16 and the compound 17 were dissolvedin DMSO under nitrogen gas stream, and condensation reaction was performed with a BOP reagent to obtain a compound18 (yield: 46%). Subsequently, the compound 18 and the compound 19 were dissolved in DMA under nitrogen gasstream, and condensation reaction was performed with HATU to obtain a compound 20 (yield: 69%). Then, the compound20 was dissolved in dichloromethane, and deprotection was performed with TFA to obtain a compound 21 (MTX-NH2).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 2872 - 2875
[2]Patent: US9402911,2016,B2 .Location in patent: Page/Page column 48
[3]Australian Journal of Chemistry,2002,vol. 55,p. 635 - 645
[4]Patent: WO2018/37119,2018,A1 .Location in patent: Page/Page column 16-17
[5]Patent: EP3312273,2018,A1 .Location in patent: Paragraph 0163; 0165
[6]Journal of the American Chemical Society,2017,vol. 139,p. 16822 - 16829
[7]Tetrahedron Letters,2011,vol. 52,p. 1411 - 1414
[8]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 3152 - 3156

26
[ 19741-14-1 ]
[ 511545-49-6 ]
N^α-[[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-γ-glutamyl]-N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	Stage #1: 4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoic acid With O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In N,N-dimethyl-formamide at 20℃; for 2h; Stage #2: N^α-[L-γ-glutamyl]-N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycinamide With triethylamine In N,N-dimethyl-formamide

Reference： [1]Francis, Craig L.; Yang, Qi; Hart, Noel K.; Widmer, Fred; Manthey, Michael K.; He-Williams, H. Ming [Australian Journal of Chemistry, 2002, vol. 55, # 10, p. 635 - 645]

27
[ 19741-14-1 ]
[ 511545-51-0 ]
N^α-[[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-γ-glutamyl]-N-[1,1-bis(hydroxymethyl)-2-[(1-oxohexadecyl)oxy]ethyl]glycinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	Stage #1: 4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoic acid With O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In N,N-dimethyl-formamide at 20℃; Stage #2: N^α-[L-γ-glutamyyl]-N-[1,1-bis(hydroxymethyl)-2-[(1-oxohexadecyl)oxy]ethyl]glycinamide With triethylamine In N,N-dimethyl-formamide at 20 - 40℃;

Reference： [1]Francis, Craig L.; Yang, Qi; Hart, Noel K.; Widmer, Fred; Manthey, Michael K.; He-Williams, H. Ming [Australian Journal of Chemistry, 2002, vol. 55, # 10, p. 635 - 645]

28
[ 19741-14-1 ]
[ 511545-53-2 ]
N^α-[[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-γ-glutamyl]-N-[2-[(1-oxohexadecyl)oxy]-1,1-bis[[(1-oxohexadecyl)oxy]methyl]ethyl]glycinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	Stage #1: 4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoic acid With O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In N,N-dimethyl-formamide at 20℃; for 4.5h; Stage #2: N^α-[N-L-γ-glutamyl]-N-[2-[(1-oxohexadecyl)oxy]-1,1-bis[[(1-oxohexadecyl)oxy]methyl]ethyl]glycinamide With triethylamine In dichloromethane; N,N-dimethyl-formamide at 20 - 40℃; for 25.5h;

Reference： [1]Francis, Craig L.; Yang, Qi; Hart, Noel K.; Widmer, Fred; Manthey, Michael K.; He-Williams, H. Ming [Australian Journal of Chemistry, 2002, vol. 55, # 10, p. 635 - 645]

29
[ 19741-14-1 ]
[ 511545-15-6 ]
N^α-[[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-(α-benzyloxy)glutamoyl]-N-[2-[(1-oxohexadecyl)oxy]-1,1-bis[[(1-oxohexadecyl)oxy]methyl]ethyl]glycinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	Stage #1: 4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoic acid With diethyl cyanophosphonate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 0.916667h; Stage #2: N^α-[L-(α-benzyloxy)glutamoyl]-N-[2-[(1-oxohexadecyl)oxy]-1,1-bis[[(1-oxohexadecyl)oxy]methyl]ethyl]glycinamide With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 42.5h;

Reference： [1]Francis, Craig L.; Yang, Qi; Hart, Noel K.; Widmer, Fred; Manthey, Michael K.; He-Williams, H. Ming [Australian Journal of Chemistry, 2002, vol. 55, # 10, p. 635 - 645]

30
[ 19741-14-1 ]
(S)-1-(3,3-Dimethyl-2-oxo-pentanoyl)-piperidine-2-carboxylic acid (R)-1-[3-((S)-4-amino-4-tert-butoxycarbonyl-butyrylamino)-phenyl]-3-(3,4-dimethoxy-phenyl)-propyl ester [ No CAS ]
1-(3,3-dimethyl-2-oxopentanoyl)piperidine-2-carboxylic acid 1-[3-(4-tert-butoxycarbonyl-4-{4-[(2,4-diaminopteridin-6-ylmethyl)-methylamino]benzoylamino}butyrylamino)phenyl]-3-(3,4-dimethoxyphenyl)propyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40 mg	Stage #1: 4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoic acid With diethyl cyanophosphonate; triethylamine In N,N-dimethyl-formamide for 3h; Stage #2: (S)-1-(3,3-Dimethyl-2-oxo-pentanoyl)-piperidine-2-carboxylic acid (R)-1-[3-((S)-4-amino-4-tert-butoxycarbonyl-butyrylamino)-phenyl]-3-(3,4-dimethoxy-phenyl)-propyl ester In N,N-dimethyl-formamide for 20h;

Reference： [1]Braun, Patrick D.; Barglow, Katherine T.; Lin, Yun-Ming; Akompong, Thomas; Briesewitz, Roger; Ray, Gregory T.; Haldar, Kasturi; Wandless, Thomas J. [Journal of the American Chemical Society, 2003, vol. 125, # 25, p. 7575 - 7580]

31
[ 13030-09-6 ]
[ 19741-14-1 ]
[ 89106-05-8 ]

Reference： [1]Journal of the American Chemical Society,2003,vol. 125,p. 14970 - 14971

32
[ 45120-30-7 ]
[ 19741-14-1 ]
[ 76-05-1 ]
2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-pentanedioic acid 1-tert-butyl ester; compound with trifluoro-acetic acid [ No CAS ]

Reference： [1]Tetrahedron,2005,vol. 61,p. 803 - 812

33
[ 19741-14-1 ]
[ 844486-60-8 ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: 4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoic acid; H-Glu[Glu(OtBu)-Glu(OtBu)-Glu(OtBu)-HMPB-MBHA resin]-OtBu With N-ethyl-N,N-diisopropylamine; HATU In dimethyl sulfoxide for 4h; Stage #2: With trifluoroacetic acid In dichloromethane for 0.5h;

Reference： [1]Castex, Cédric; Lalanne, Christophe; Mouchet, Patrick; Lemaire, Marc; Lahana, Roger [Tetrahedron, 2005, vol. 61, # 4, p. 803 - 812]

34
[ 19741-14-1 ]
[ 67022-39-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 1.) diethyl cyanophosphonate, N-ethyldiisopropylamine, 2.) N-ethyldiisopropylamine / 1.) DMF, 4 h, 2.) room temperature, 48 h 2: 88 percent / boron trifluoride etherate / 1,2-dichloro-ethane / 18 h

Reference： [1]Davey, Ross A.; Davey, Mary W.; Cullen, Karen V.; Wells, Xanthe E.; Francis, Craig L.; Williams, Hua-Ming; Yang, Qi; Moghaddam, Minoo J.; Widmer, Fred; Whittaker, Robert G. [British Journal of Pharmacology, 2002, vol. 137, # 8, p. 1280 - 1286]
[2]Kralovec; Spencer; Blair; Mammen; Singh; Ghose [Journal of Medicinal Chemistry, 1989, vol. 32, # 11, p. 2426 - 2431]

35
[ 19741-14-1 ]
4-{2-[2-(2-{2-[4-(2-amino-9H-purin-6-yloxymethyl)-benzyloxy]-ethoxy}-ethoxy)-ethoxy]-ethylcarbamoyl}-2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-butyric acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: diisopropylethylamine; PyBOP / dimethylsulfoxide / 0.5 h / 20 °C 1.2: 35 percent / K₂CO₃ / dimethylsulfoxide / 0.17 h / 50 °C 2.1: PyBOP; 1-hydroxybenzotriazole / 1-methyl-pyrrolidin-2-one / 0.5 h / 20 °C 2.2: diisopropylethylamine / 1-methyl-pyrrolidin-2-one / 24 h 3.1: 54 mg / aq. NaOH / acetonitrile

Reference： [1]Gendreizig, Susanne; Kindermann, Maik; Johnsson, Kai [Journal of the American Chemical Society, 2003, vol. 125, # 49, p. 14970 - 14971]

36
[ 19741-14-1 ]
4-{2-[2-(2-{2-[4-(2-amino-9H-purin-6-yloxymethyl)-benzyloxy]-ethoxy}-ethoxy)-ethoxy]-ethylcarbamoyl}-2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-butyric acid benzyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: diisopropylethylamine; PyBOP / dimethylsulfoxide / 0.5 h / 20 °C 1.2: 35 percent / K₂CO₃ / dimethylsulfoxide / 0.17 h / 50 °C 2.1: PyBOP; 1-hydroxybenzotriazole / 1-methyl-pyrrolidin-2-one / 0.5 h / 20 °C 2.2: diisopropylethylamine / 1-methyl-pyrrolidin-2-one / 24 h

Reference： [1]Gendreizig, Susanne; Kindermann, Maik; Johnsson, Kai [Journal of the American Chemical Society, 2003, vol. 125, # 49, p. 14970 - 14971]

37
[ 19741-14-1 ]
4-{11-[4-(2-amino-9H-purin-6-yloxymethyl)-benzylcarbamoyl]-undecylcarbamoyl}-2-{4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoylamino}-butyric acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: diisopropylethylamine; PyBOP / dimethylsulfoxide / 0.5 h / 20 °C 1.2: 35 percent / K₂CO₃ / dimethylsulfoxide / 0.17 h / 50 °C 2.1: PyBOP; 1-hydroxybenzotriazole / 1-methyl-pyrrolidin-2-one / 0.5 h / 20 °C 2.2: diisopropylethylamine / 1-methyl-pyrrolidin-2-one / 24 h 3.1: 14 mg / aq. NaOH / acetonitrile

Reference： [1]Gendreizig, Susanne; Kindermann, Maik; Johnsson, Kai [Journal of the American Chemical Society, 2003, vol. 125, # 49, p. 14970 - 14971]

38
[ 19741-14-1 ]
[ 680622-97-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: diisopropylethylamine; PyBOP / dimethylsulfoxide / 0.5 h / 20 °C 1.2: 35 percent / K₂CO₃ / dimethylsulfoxide / 0.17 h / 50 °C 2.1: PyBOP; 1-hydroxybenzotriazole / 1-methyl-pyrrolidin-2-one / 0.5 h / 20 °C 2.2: diisopropylethylamine / 1-methyl-pyrrolidin-2-one / 24 h

Reference： [1]Gendreizig, Susanne; Kindermann, Maik; Johnsson, Kai [Journal of the American Chemical Society, 2003, vol. 125, # 49, p. 14970 - 14971]

39
[ 19741-14-1 ]
[ 59-05-2 ]

Reference： [1]Journal of the American Chemical Society,1997,vol. 119,p. 10004 - 10013

40
[ 19741-14-1 ]
[ 79640-75-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 1.) diethyl cyanophosphonate, N-ethyldiisopropylamine, 2.) N-ethyldiisopropylamine / 1.) DMF, room temperature, 4 h, 2.) room temperature, 72 h 2: 91 percent / N₂H₄*H₂O / methanol / 48 h / Ambient temperature
	Multi-step reaction with 3 steps 1: 1.) diethyl cyanophosphonate, N-ethyldiisopropylamine, 2.) N-ethyldiisopropylamine / 1.) DMF, 4 h, 2.) room temperature, 48 h 2: 88 percent / boron trifluoride etherate / 1,2-dichloro-ethane / 18 h 3: 91 percent / N₂H₄*H₂O / methanol / 48 h / Ambient temperature

Reference： [1]Kralovec; Spencer; Blair; Mammen; Singh; Ghose [Journal of Medicinal Chemistry, 1989, vol. 32, # 11, p. 2426 - 2431]
[2]Kralovec; Spencer; Blair; Mammen; Singh; Ghose [Journal of Medicinal Chemistry, 1989, vol. 32, # 11, p. 2426 - 2431]

41
[ 19741-14-1 ]
[ 121788-83-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 1.) diethyl cyanophosphonate, N-ethyldiisopropylamine, 2.) N-ethyldiisopropylamine / 1.) DMF, room temperature, 4 h, 2.) room temperature, 72 h 2: 91 percent / N₂H₄*H₂O / methanol / 48 h / Ambient temperature 3: tert-butyl nitrite, 2.4 M HCl / dimethylformamide; tetrahydrofuran / 1 h / -20 °C
	Multi-step reaction with 4 steps 1: 1.) diethyl cyanophosphonate, N-ethyldiisopropylamine, 2.) N-ethyldiisopropylamine / 1.) DMF, 4 h, 2.) room temperature, 48 h 2: 88 percent / boron trifluoride etherate / 1,2-dichloro-ethane / 18 h 3: 91 percent / N₂H₄*H₂O / methanol / 48 h / Ambient temperature 4: tert-butyl nitrite, 2.4 M HCl / dimethylformamide; tetrahydrofuran / 1 h / -20 °C

Reference： [1]Kralovec; Spencer; Blair; Mammen; Singh; Ghose [Journal of Medicinal Chemistry, 1989, vol. 32, # 11, p. 2426 - 2431]
[2]Kralovec; Spencer; Blair; Mammen; Singh; Ghose [Journal of Medicinal Chemistry, 1989, vol. 32, # 11, p. 2426 - 2431]

42
[ 19741-14-1 ]
[ 121788-84-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 1.) diethyl cyanophosphonate, N-ethyldiisopropylamine, 2.) N-ethyldiisopropylamine / 1.) DMF, room temperature, 4 h, 2.) room temperature, 72 h 2: 91 percent / N₂H₄*H₂O / methanol / 48 h / Ambient temperature 3: dimethylformamide; tetrahydrofuran / 18 h / 25 °C
	Multi-step reaction with 4 steps 1: 1.) diethyl cyanophosphonate, N-ethyldiisopropylamine, 2.) N-ethyldiisopropylamine / 1.) DMF, 4 h, 2.) room temperature, 48 h 2: 88 percent / boron trifluoride etherate / 1,2-dichloro-ethane / 18 h 3: 91 percent / N₂H₄*H₂O / methanol / 48 h / Ambient temperature 4: dimethylformamide; tetrahydrofuran / 18 h / 25 °C

Reference： [1]Kralovec; Spencer; Blair; Mammen; Singh; Ghose [Journal of Medicinal Chemistry, 1989, vol. 32, # 11, p. 2426 - 2431]
[2]Kralovec; Spencer; Blair; Mammen; Singh; Ghose [Journal of Medicinal Chemistry, 1989, vol. 32, # 11, p. 2426 - 2431]

43
[ 19741-14-1 ]
[ 112113-80-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 53 percent / Et₃N, diethyl phosphorocyanidate / dimethylformamide / 96 h / Ambient temperature 2: 76 percent / Ba(OH)2*8H₂O / aq. ethanol / Ambient temperature

Reference： [1]Rosowsky, Andre; Bader, Henry; Forsch, Ronald A.; Moran, Richard G.; Freisheim, James H. [Journal of Medicinal Chemistry, 1988, vol. 31, # 4, p. 763 - 768]

44
[ 19741-14-1 ]
[ 102682-15-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 1.) diethyl phosphorocyanidate, Et₃N, 2.)Et₃N / 1.) DMF, 4 h, 2.) DMF, 25 degC, 24 h 2: 82 percent / NaOH / methanol; H₂O

Reference： [1]Rosowsky, Andre; Bader, Henry; Radike-Smith, Mary; Cucchi, Carol A.; Wick, Michael M.; Freisheim, James H. [Journal of Medicinal Chemistry, 1986, vol. 29, # 9, p. 1703 - 1709]

45
[ 19741-14-1 ]
[ 86669-33-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine / dimethylformamide / 0.25 h / Ambient temperature 2: triethylamine / dimethylformamide / 0.5 h / 80 °C

Reference： [1]Rosowsky, A.; Yu, C.-S. [Journal of Medicinal Chemistry, 1983, vol. 26, # 10, p. 1448 - 1452]

46
[ 19741-14-1 ]
[ 80407-73-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 86 percent / Et₃N / dimethylformamide / 5 h / 55 °C 2: Et₃N / dimethylformamide / 72 h / 55 °C 3: 80 percent / trifluoroacetic acid / 3 h
	Multi-step reaction with 2 steps 1: 1.) (iPr)2NEt, diethyl phosphorocyanidate (DEPC) / 1.) DMF, 4 h, 2.) DMF, RT, 2 d 2: 80 percent / trifluoroacetic acid / 3 h
	Multi-step reaction with 4 steps 1: N-methylmorpholine / various solvent(s) / 0.33 h / 0 °C 2: N-methylmorpholine / various solvent(s) / 1 h / 60 °C 3: 86 percent / 70percent aq. trifluoroacetic acid / 6 h / Ambient temperature 4: 64 percent / 1 M boron tris(trifluoroacetate) (BTFA) / trifluoroacetic acid / 7 h / 0 °C

Reference： [1]Rosowsky; Freisheim; Moran; Solan; Bader; Wright; Radike-Smith [Journal of Medicinal Chemistry, 1986, vol. 29, # 5, p. 655 - 660]
[2]Rosowsky; Freisheim; Moran; Solan; Bader; Wright; Radike-Smith [Journal of Medicinal Chemistry, 1986, vol. 29, # 5, p. 655 - 660]
[3]Kempton, Robert J.; Black, Angelique M.; Anstead, Gregory M.; Kumar, A. Ashok; Blankenship, Dale T.; Freisheim, James H. [Journal of Medicinal Chemistry, 1982, vol. 25, # 4, p. 475 - 477]

47
[ 19741-14-1 ]
[ 80407-56-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 56.1 percent / Et₃N, diethyl phosphorocyanidate (DEPC) / dimethylformamide / 20.5 h / 0 - 23 °C 2: 70percent aq. TFA / various solvent(s) / 4.5 h / Ambient temperature
	Multi-step reaction with 4 steps 1: N-methylmorpholine / various solvent(s) / 0.33 h / 0 °C 2: N-methylmorpholine / 1 h / 60 °C 3: 67 percent / 70percent aq. trifluoroacetic acid / 6 h / Ambient temperature 4: 44 percent / 1 M boron tris(trifluoroacetate) (BTFA) / trifluoroacetic acid / 9 h / 5 °C
	Multi-step reaction with 4 steps 1: Et₃N / dimethylformamide / 3.5 h / Ambient temperature 2: Et₃N / dimethylformamide / 72 h / Ambient temperature 3: 84 percent / aq. piperidine / 1.5 h / 0 - 10 °C 4: 78 percent / BBr₃, TFA / 1 h

Multi-step reaction with 3 steps 1: Et₃N / dimethylformamide / 3.5 h / Ambient temperature 2: Et₃N / dimethylformamide / 72 h / Ambient temperature 3: 91 percent / HBr (gas), TFA / 0.08 h / Heating

Reference： [1]Kumar; Freisheim; Kempton; Anstead; Black; Judge [Journal of Medicinal Chemistry, 1983, vol. 26, # 1, p. 111 - 113]
[2]Kempton, Robert J.; Black, Angelique M.; Anstead, Gregory M.; Kumar, A. Ashok; Blankenship, Dale T.; Freisheim, James H. [Journal of Medicinal Chemistry, 1982, vol. 25, # 4, p. 475 - 477]
[3]Rosowsky; Wright; Ginty; Uren [Journal of Medicinal Chemistry, 1982, vol. 25, # 8, p. 960 - 964]
[4]Rosowsky; Wright; Ginty; Uren [Journal of Medicinal Chemistry, 1982, vol. 25, # 8, p. 960 - 964]

48
[ 19741-14-1 ]
[ 82339-36-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: Et₃N / dimethylformamide / 3.5 h / Ambient temperature 2: Et₃N / dimethylformamide / 72 h / Ambient temperature 3: 84 percent / aq. piperidine / 1.5 h / 0 - 10 °C 4: 78 percent / BBr₃, TFA / 1 h 5: 32 percent / methanol / 0.75 h / 55 - 60 °C
	Multi-step reaction with 4 steps 1: Et₃N / dimethylformamide / 3.5 h / Ambient temperature 2: Et₃N / dimethylformamide / 72 h / Ambient temperature 3: 91 percent / HBr (gas), TFA / 0.08 h / Heating 4: 32 percent / methanol / 0.75 h / 55 - 60 °C

Reference： [1]Rosowsky; Wright; Ginty; Uren [Journal of Medicinal Chemistry, 1982, vol. 25, # 8, p. 960 - 964]
[2]Rosowsky; Wright; Ginty; Uren [Journal of Medicinal Chemistry, 1982, vol. 25, # 8, p. 960 - 964]

49
[ 19741-14-1 ]
[ 51865-82-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-methylmorpholine / various solvent(s) / 0.33 h / 0 °C 2: N-methylmorpholine / 1 h / 60 °C 3: 67 percent / 70percent aq. trifluoroacetic acid / 6 h / Ambient temperature
	Multi-step reaction with 3 steps 1: Et₃N / dimethylformamide / 3.5 h / Ambient temperature 2: Et₃N / dimethylformamide / 72 h / Ambient temperature 3: 84 percent / aq. piperidine / 1.5 h / 0 - 10 °C

Reference： [1]Kempton, Robert J.; Black, Angelique M.; Anstead, Gregory M.; Kumar, A. Ashok; Blankenship, Dale T.; Freisheim, James H. [Journal of Medicinal Chemistry, 1982, vol. 25, # 4, p. 475 - 477]
[2]Rosowsky; Wright; Ginty; Uren [Journal of Medicinal Chemistry, 1982, vol. 25, # 8, p. 960 - 964]

50
[ 19741-14-1 ]
[ 94790-37-1 ]
[ 951288-67-8 ]

Yield	Reaction Conditions	Operation in experiment
	With N,N-dimethyl acetamide; N-ethyl-N,N-diisopropylamine; at 20℃; for 20h;	(0.650 g; 2.00 mmol) was suspended in DMAc (15 mL).DIPEA (0.79 g; 6.14 mmol) and HBTU (0.92 g; 2.43 mmol) were added, and the reaction mixture was stirred at 200C for 20 hr. The precipitate was filtered, washed with DMAc and ether, and dried to yield the intermediate HOBt-ester (0.668 g; 1.51 mmol). Triethylammonium 3-diphenylphosphine-4-hydroxybenzoate (17) (0.639 g;1.51 mmol) was suspended in DMSO (5 mL), and potassium tert-butoxidc (0.339 g; 3.02 mmol) was added. To this solution was added a solution of the intermediate HOBt-ester in DMSO (5 mL), and the reaction mixture was stirred at 200C for 20 hr. Subsequently, it was filtered, poured in water (100 mL), neutralized with acetic acid and centrifuged. The mother liquor was decanted, and the precipitate was stirred in water (100 mL), and again centrifuged and decanted. The residue was dissolved in acetone (100 mL) and recrystallized at -200C, to yield the product as a yellow powder (0.360 g; 29%). 1H-NMR (DMSO): delta 8.60 (s, IH), 8.01 (dd, 2H, J=2, 8.6 Hz), 7.65 (br.s, 2H), 7.50 (d, 2H, J=9.2 Hz), 7.42 (br. m, 8H), 7.23 (m, 3H), 6.76 (d, 2H, J=9.2 Hz), 6.62 (br. s, 2H), 4.81 (s, 2H), 3.25 (s, 3H) ppm. 31P-NMR (DMSO): - 16.6 (product), +23.4 (small, phosphine oxide) ppm. FT-IR (ATR): V 3319, 3182, 3053, 1717, 1634, 1600, 1523, 1435, 1367, 1272, 1244, 1172, 1115, 1063, 1045, 742, 691 cm"1. LC-MS (CH3CN / H2O): tr=8.9 min: m/z=630.1 (M+H)+; tr=7.5 min: m/z=646.0 (phosphine oxide).

Reference： [1]Patent: WO2007/110811,2007,A2 .Location in patent: Page/Page column 24

51
[ 10541-83-0 ]
[ 52853-40-4 ]
[ 19741-14-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N,N-dimethyl acetamide; N-ethyl-N,N-diisopropylamine; at 20℃; for 72h;	2,4-diamino-6-(hydroxymethyl)pteridine hydrochloride (4.40 g; 19.19 mmol) was dissolved in hot water (150 mL) and the solution was neutralized by addition of 1 M NaOH (ca. 20 mL). The precipitate was filtered, washed with water, and dried in vacuo over P2O5. Subsequently, this was suspended in DMAc (25 mL), and triphenylphosphine dibromide (18.12 g; 42.92 mmol) was added. The turbid reaction mixture was stirred for 20 hr at 200C. 4-(Methylamino)benzoic acid (2.95 g; 19.50 mmol) and DIPEA (5.04 g; 39.00 mmol) were added, and the turbid reaction mixture was stirred for 3 days at 200C. Then, it was poured in 0.33 M NaOH-solution (250 mL), the precipitate was filtered off, and the filtrate was neutralized by addition of 10% acetic acid in water (ca. 20 mL). The precipitate was filtered, washed with water, triturated with methanol (30 mL), and dried in vacuo over P2O5, to yield the product as a beige/orange powder (3.48 g; 56%).1H-NMR (DMSO): delta 8.59 (s, IH), 7.53 (d, 2H, 8.8 Hz), 7.7 (br. s, IH), 7.5 (br. s, IH), 6.83 (d, 2H, 8.8 Hz), 4.79 (s, 2H), 3.23 (s, 3H) ppm. FT-IR (ATR): V 3335, 3194, 2964, 1651, 1597, 1292, 1187 cm"1.

Reference： [1]Patent: WO2007/110811,2007,A2 .Location in patent: Page/Page column 23

52
[ 19741-14-1 ]
[ 34582-33-7 ]
[ 79648-88-7 ]

Reference： [1]Archiv der Pharmazie,2007,vol. 340,p. 389 - 395

53
C₃₁H₄₂N₄O₈ [ No CAS ]
[ 19741-14-1 ]
[ 866455-81-4 ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In 1-methyl-pyrrolidin-2-one at 0 - 20℃; for 96h;	1.1.d (d) Production of MTX-α-PhePhe-NH-C2H4-NH-Boc (Compound 1d); Compound 1c (348 mg, 0.476 mmol) was suspended in 10 mL of methanol and 10 mL of tetrahydrofuran, to which 33 mg of 10% palladium carbon was then added, followed by stirring at room temperature for 1.5 hours under an atmosphere of hydrogen. The catalyst was filtered off from the reaction mixture, followed by concentration under reduced pressure. This residue, 4-[N-(2,4-diamino-6-pteridinylmethyl)-N-methylamino]benzoic acid (197 mg, 0.547 mmol), and HOBT (76 mg, 0.499 mmol) were dissolved in 4 mL of N-methylpyrrolidone (NMP), to which N-methylmorpholine (NMM, 55 μL, 0.499 mmol) and EDC (105 mg, 0.547 mmol) were then added under stirring and cooling with ice, followed by stirring at room temperature for 4 days. A 5% sodium bicarbonate solution was added to the reaction solution, and the generated precipitate was purified by silica gel column chromatography (elution solvent: dichloromethane:methanol=10:1) and then amine silica gel (NH-DM1020, 100-200 mesh, from Fuji Silysia Chemical Ltd.) column chromatography (elution solvent: dichloromethane:methanol=10:1) to provide 362 mg of the title compound as a yellow powder.1H-NMR (270 MHz, DMSO-d6): δ1.35 (9H, s), 1.78-1.94 (2H, m), 2.23 (2H, m), 2.69-3.10 (8H, m), 3.22 (3H, s), 3.55 (3H, s), 4.27-4.52 (3H, m), 4.79 (2H, s), 6.63 (2H, br.s), 6.70 (1H, br.t), 6.82 (2H, d, J=8.9 Hz), 7.06-7.25 (10H, m), 7.46 (1H, br.s), 7.66-7.88 (5H, m), 8.06-8.17 (2H, m), 8.56 (1H, s)LC/MS: 905.5 (M+H+)

Reference： [1]Current Patent Assignee: DENKA COMPANY LIMITED - US2009/93414, 2009, A1 Location in patent: Page/Page column 10-11

54
C₃₉H₅₈N₄O₁₁ [ No CAS ]
[ 19741-14-1 ]
[ 866455-82-5 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 48h;	1.2.d (d) Production of MTX-α-PhePhe-NH-C10H20O3-NH-Boc (Compound 2d); Compound 2c (514 mg, 0.576 mmol) was suspended in 30 mL of methanol, to which 100 mg of 10% palladium carbon was then added, followed by stirring at room temperature for 1.5 hours under an atmosphere of hydrogen. The catalyst was filtered off from the reaction mixture, followed by concentration under reduced pressure. This residue, 4-[N-(2,4-diamino-6-pteridinylmethyl)-N-methylamino]benzoic acid (281 mg, 0.864 mmol), and HOBT (132 mg, 0.864 mmol) were dissolved in 5 mL of DMF, to which EDC (166 mg, 0.864 mmol) were then added under stirring and cooling with ice, followed by stirring at room temperature for 2 days. A 5% sodium bicarbonate solution was added to the reaction solution, and the generated precipitate was purified by amine silica gel (NH-DM1020, 100-200 mesh, from Fuji Silysia Chemical Ltd.) column chromatography (elution solvent: 1st elution; dichloromethane:methanol=100:7, 2nd elution; chloroform:methanol=100:4) to provide 415 mg of the title compound as a yellow powder.1H-NMR (270 MHz, DMSO-d6): δ1.36 (9H, s), 1.48-1.61 (4H, m), 1.81-1.92 (2H, m), 2.24 (2H, t, J=7.9 Hz), 2.70-3.10 (8H, m), 3.22 (3H, s), 3.25-3.47 (12H, m), 3.54 (3H, s), 4.25-4.50 (3H, m), 4.79 (2H, s), 6.61 (2H, br.s), 6.76-6.83 (3H, m), 7.06-7.24 (10H, m), 7.45 (1H, br.s), 7.67-7.80 (4H, m), 7.86 (1H, d, J=8.1 Hz), 8.09 (1H, d, J=7.4 Hz), 8.15 (1H, d, J=8.1 Hz), 8.56 (1H, s)LC/MS: 1087.5 (M+Na+)

Reference： [1]Current Patent Assignee: DENKA COMPANY LIMITED - US2009/93414, 2009, A1 Location in patent: Page/Page column 12

55
[ 23853-09-0 ]
[ 19741-14-1 ]

Yield	Reaction Conditions	Operation in experiment
80%	With water; sodium hydroxide In dimethyl sulfoxide for 3h;
76%	Stage #1: 4-[(2,4-diaminopteridin-6-ylmethyl)-N-methylamino]benzoic acid methyl ester With water; sodium hydroxide In dimethyl sulfoxide for 3.5h; Stage #2: With acetic acid In water; dimethyl sulfoxide at 0℃;

Reference： [1]Stockmann, Henning; Todorovic, Viktor; Richardson, Paul L.; Marin, Violeta; Scott, Victoria; Gerstein, Clare; Lake, Marc; Wang, Leyu; Sadhukhan, Ramkrishna; Vasudevan, Anil [Journal of the American Chemical Society, 2017, vol. 139, # 46, p. 16822 - 16829]
[2]Location in patent: experimental part Homma, Akie; Sato, Haruhiko; Okamachi, Akira; Emura, Takashi; Ishizawa, Takenori; Kato, Tatsuya; Matsuura, Tetsu; Sato, Shigeo; Tamura, Tatsuya; Higuchi, Yoshinobu; Watanabe, Tomoyuki; Kitamura, Hidetomo; Asanuma, Kentaro; Yamazaki, Tadao; Ikemi, Masahisa; Kitagawa, Hironoshin; Morikawa, Tadashi; Ikeya, Hitoshi; Maeda, Kazuaki; Takahashi, Koichi; Nohmi, Kenji; Izutani, Noriyuki; Kanda, Makoto; Suzuki, Ryochi [Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 13, p. 4647 - 4656]

56
[ 1218772-56-5 ]
[ 19741-14-1 ]
[ 1268279-57-7 ]

Yield	Reaction Conditions	Operation in experiment
92.4%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In 1-methyl-pyrrolidin-2-one at 55℃; for 4h;

Reference： [1]Location in patent: experimental part Homma, Akie; Sato, Haruhiko; Tamura, Tatsuya; Okamachi, Akira; Emura, Takashi; Ishizawa, Takenori; Kato, Tatsuya; Matsuura, Tetsu; Sato, Shigeo; Higuchi, Yoshinobu; Watanabe, Tomoyuki; Kitamura, Hidetomo; Asanuma, Kentaro; Yamazaki, Tadao; Ikemi, Masahisa; Kitagawa, Hironoshin; Morikawa, Tadashi; Ikeya, Hitoshi; Maeda, Kazuaki; Takahashi, Koichi; Nohmi, Kenji; Izutani, Noriyuki; Kanda, Makoto; Suzuki, Ryohchi [Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 3, p. 1062 - 1075]

57
[ 1218772-52-1 ]
[ 35661-60-0 ]
[ 19741-14-1 ]
[ 84793-07-7 ]
[ 86060-85-7 ]
[ 86060-92-6 ]
[ 76-05-1 ]
2C₂HF₃O₂*C₆₃H₉₄N₁₆O₁₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 1062 - 1075

58
[ 1218772-52-1 ]
[ 35661-60-0 ]
[ 19741-14-1 ]
[ 71989-18-9 ]
[ 86060-85-7 ]
[ 86060-92-6 ]
[ 76-05-1 ]
2C₂HF₃O₂*C₆₃H₉₄N₁₆O₁₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 1062 - 1075

59
[ 1218772-52-1 ]
[ 19741-14-1 ]
[ 84793-07-7 ]
[ 86060-92-6 ]
[ 71989-16-7 ]
[ 76-05-1 ]
2C₂HF₃O₂*C₆₆H₉₂N₁₆O₁₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%	Stage #1: N-{1-[3-(2-{2-[3-(9H-fluoren-9-ylmethoxycarbonylamino)propoxy]ethoxy}ethoxy)propylcarbamoyl]-2,2-dimethylpropyl}succinamic acid With benzotriazol-1-ol; diisopropyl-carbodiimide In N,N-dimethyl-formamide for 6h; solid phase reaction; Stage #2: With piperidine In N,N-dimethyl-formamide solid phase reaction; Stage #3: 4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoic acid; Fmoc-Glu-OtBu; N-α-Fmoc-L-phenylalanine pentafluorophenyl ester; Fmoc-Asn-OH; trifluoroacetic acid Further stages;

Reference： [1]Location in patent: experimental part Homma, Akie; Sato, Haruhiko; Tamura, Tatsuya; Okamachi, Akira; Emura, Takashi; Ishizawa, Takenori; Kato, Tatsuya; Matsuura, Tetsu; Sato, Shigeo; Higuchi, Yoshinobu; Watanabe, Tomoyuki; Kitamura, Hidetomo; Asanuma, Kentaro; Yamazaki, Tadao; Ikemi, Masahisa; Kitagawa, Hironoshin; Morikawa, Tadashi; Ikeya, Hitoshi; Maeda, Kazuaki; Takahashi, Koichi; Nohmi, Kenji; Izutani, Noriyuki; Kanda, Makoto; Suzuki, Ryohchi [Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 3, p. 1062 - 1075]

60
[ 1218772-52-1 ]
[ 19741-14-1 ]
[ 84793-07-7 ]
[ 86060-92-6 ]
[ 76-05-1 ]
2C₂HF₃O₂*C₅₃H₇₇N₁₃O₁₁ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18%	Stage #1: N-{1-[3-(2-{2-[3-(9H-fluoren-9-ylmethoxycarbonylamino)propoxy]ethoxy}ethoxy)propylcarbamoyl]-2,2-dimethylpropyl}succinamic acid With benzotriazol-1-ol; diisopropyl-carbodiimide In N,N-dimethyl-formamide for 6h; solid phase reaction; Stage #2: With piperidine In N,N-dimethyl-formamide solid phase reaction; Stage #3: 4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoic acid; Fmoc-Glu-OtBu; N-α-Fmoc-L-phenylalanine pentafluorophenyl ester; trifluoroacetic acid Further stages;

Reference： [1]Location in patent: experimental part Homma, Akie; Sato, Haruhiko; Tamura, Tatsuya; Okamachi, Akira; Emura, Takashi; Ishizawa, Takenori; Kato, Tatsuya; Matsuura, Tetsu; Sato, Shigeo; Higuchi, Yoshinobu; Watanabe, Tomoyuki; Kitamura, Hidetomo; Asanuma, Kentaro; Yamazaki, Tadao; Ikemi, Masahisa; Kitagawa, Hironoshin; Morikawa, Tadashi; Ikeya, Hitoshi; Maeda, Kazuaki; Takahashi, Koichi; Nohmi, Kenji; Izutani, Noriyuki; Kanda, Makoto; Suzuki, Ryohchi [Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 3, p. 1062 - 1075]

61
[ 1218772-52-1 ]
[ 19741-14-1 ]
[ 84793-07-7 ]
[ 86060-92-6 ]
[ 76-05-1 ]
2C₂HF₃O₂*C₆₂H₈₆N₁₄O₁₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16%	Stage #1: N-{1-[3-(2-{2-[3-(9H-fluoren-9-ylmethoxycarbonylamino)propoxy]ethoxy}ethoxy)propylcarbamoyl]-2,2-dimethylpropyl}succinamic acid With benzotriazol-1-ol; diisopropyl-carbodiimide In N,N-dimethyl-formamide for 6h; solid phase reaction; Stage #2: With piperidine In N,N-dimethyl-formamide solid phase reaction; Stage #3: 4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoic acid; Fmoc-Glu-OtBu; N-α-Fmoc-L-phenylalanine pentafluorophenyl ester; trifluoroacetic acid Further stages;

Reference： [1]Location in patent: experimental part Homma, Akie; Sato, Haruhiko; Tamura, Tatsuya; Okamachi, Akira; Emura, Takashi; Ishizawa, Takenori; Kato, Tatsuya; Matsuura, Tetsu; Sato, Shigeo; Higuchi, Yoshinobu; Watanabe, Tomoyuki; Kitamura, Hidetomo; Asanuma, Kentaro; Yamazaki, Tadao; Ikemi, Masahisa; Kitagawa, Hironoshin; Morikawa, Tadashi; Ikeya, Hitoshi; Maeda, Kazuaki; Takahashi, Koichi; Nohmi, Kenji; Izutani, Noriyuki; Kanda, Makoto; Suzuki, Ryohchi [Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 3, p. 1062 - 1075]

62
[ 1218772-52-1 ]
[ 19741-14-1 ]
[ 71989-18-9 ]
[ 86060-92-6 ]
[ 71989-16-7 ]
[ 76-05-1 ]
2C₂HF₃O₂*C₆₆H₉₂N₁₆O₁₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14%	Stage #1: N-{1-[3-(2-{2-[3-(9H-fluoren-9-ylmethoxycarbonylamino)propoxy]ethoxy}ethoxy)propylcarbamoyl]-2,2-dimethylpropyl}succinamic acid With benzotriazol-1-ol; diisopropyl-carbodiimide In N,N-dimethyl-formamide for 6h; solid phase reaction; Stage #2: With piperidine In N,N-dimethyl-formamide solid phase reaction; Stage #3: 4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoic acid; Fmoc-Glu(OtBu)-OH; N-α-Fmoc-L-phenylalanine pentafluorophenyl ester; Fmoc-Asn-OH; trifluoroacetic acid Further stages;

Reference： [1]Location in patent: experimental part Homma, Akie; Sato, Haruhiko; Tamura, Tatsuya; Okamachi, Akira; Emura, Takashi; Ishizawa, Takenori; Kato, Tatsuya; Matsuura, Tetsu; Sato, Shigeo; Higuchi, Yoshinobu; Watanabe, Tomoyuki; Kitamura, Hidetomo; Asanuma, Kentaro; Yamazaki, Tadao; Ikemi, Masahisa; Kitagawa, Hironoshin; Morikawa, Tadashi; Ikeya, Hitoshi; Maeda, Kazuaki; Takahashi, Koichi; Nohmi, Kenji; Izutani, Noriyuki; Kanda, Makoto; Suzuki, Ryohchi [Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 3, p. 1062 - 1075]

63
[ 1218772-52-1 ]
[ 19741-14-1 ]
[ 71989-18-9 ]
[ 86060-92-6 ]
[ 76-05-1 ]
2C₂HF₃O₂*C₅₃H₇₇N₁₃O₁₁ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18%	Stage #1: N-{1-[3-(2-{2-[3-(9H-fluoren-9-ylmethoxycarbonylamino)propoxy]ethoxy}ethoxy)propylcarbamoyl]-2,2-dimethylpropyl}succinamic acid With benzotriazol-1-ol; diisopropyl-carbodiimide In N,N-dimethyl-formamide for 6h; solid phase reaction; Stage #2: With piperidine In N,N-dimethyl-formamide solid phase reaction; Stage #3: 4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoic acid; Fmoc-Glu(OtBu)-OH; N-α-Fmoc-L-phenylalanine pentafluorophenyl ester; trifluoroacetic acid Further stages;

Reference： [1]Location in patent: experimental part Homma, Akie; Sato, Haruhiko; Tamura, Tatsuya; Okamachi, Akira; Emura, Takashi; Ishizawa, Takenori; Kato, Tatsuya; Matsuura, Tetsu; Sato, Shigeo; Higuchi, Yoshinobu; Watanabe, Tomoyuki; Kitamura, Hidetomo; Asanuma, Kentaro; Yamazaki, Tadao; Ikemi, Masahisa; Kitagawa, Hironoshin; Morikawa, Tadashi; Ikeya, Hitoshi; Maeda, Kazuaki; Takahashi, Koichi; Nohmi, Kenji; Izutani, Noriyuki; Kanda, Makoto; Suzuki, Ryohchi [Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 3, p. 1062 - 1075]

64
[ 1218772-52-1 ]
[ 19741-14-1 ]
[ 71989-18-9 ]
[ 86060-92-6 ]
[ 76-05-1 ]
2C₂HF₃O₂*C₆₂H₈₆N₁₄O₁₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13%	Stage #1: N-{1-[3-(2-{2-[3-(9H-fluoren-9-ylmethoxycarbonylamino)propoxy]ethoxy}ethoxy)propylcarbamoyl]-2,2-dimethylpropyl}succinamic acid With benzotriazol-1-ol; diisopropyl-carbodiimide In N,N-dimethyl-formamide for 6h; solid phase reaction; Stage #2: With piperidine In N,N-dimethyl-formamide solid phase reaction; Stage #3: 4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoic acid; Fmoc-Glu(OtBu)-OH; N-α-Fmoc-L-phenylalanine pentafluorophenyl ester; trifluoroacetic acid Further stages;

Reference： [1]Location in patent: experimental part Homma, Akie; Sato, Haruhiko; Tamura, Tatsuya; Okamachi, Akira; Emura, Takashi; Ishizawa, Takenori; Kato, Tatsuya; Matsuura, Tetsu; Sato, Shigeo; Higuchi, Yoshinobu; Watanabe, Tomoyuki; Kitamura, Hidetomo; Asanuma, Kentaro; Yamazaki, Tadao; Ikemi, Masahisa; Kitagawa, Hironoshin; Morikawa, Tadashi; Ikeya, Hitoshi; Maeda, Kazuaki; Takahashi, Koichi; Nohmi, Kenji; Izutani, Noriyuki; Kanda, Makoto; Suzuki, Ryohchi [Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 3, p. 1062 - 1075]

65
[ 10541-83-0 ]
[ 73978-41-3 ]
[ 19741-14-1 ]

Yield	Reaction Conditions	Operation in experiment
90%		Synthesis was performed following a published procedure [45]. Pteridine alcohol 5 hydrochloride (3.34g, 14.6mmol) was dissolved in hot water (120mL) and the solution was left to cool to 20C. The solution was neutralized with 1M NaOH (ca. 12mL) and the precipitate was collected by filtration, washed with water, and dried in vacuo over P2O5. The orange-beige solid was suspended in anhydrous DMA (20mL) and triphenylphosphine dibromide (13.9g, 32.9mmol) was then added. The turbid reaction mixture was stirred for 20hat 20C and 4-(methylamino)benzoic acid (2.45g, 16.2mmol) and DIPEA (5.34mL, 30.7mmol) were added. The turbid mixture was stirred for another 3 days at 20C and then poured into 0.33M NaOH (190mL). The precipitate was filtered off and the filtrate was acidified to approximately pH 4.5 with 10% AcOH in water (ca. 20mL). The precipitate was collected by filtration, washed with water, triturated with hot methanol (23mL), and dried in vacuo over P2O5 to give the title compound as an orange-beige solid (4.25g, 90%). 1H NMR (400MHz, DMSO-d6) delta 12.2 (br. s, 1H), 8.66 (s, 1H), 8.42 (br. s, 1H), 8.19 (br. s, 1H), 7.73 (d, J=9.0Hz, 2H), 7.21 (br. s, 2H), 6.83 (d, J=9.1Hz, 2H), 4.83 (s, 2H), 3.24 (s, 3H), (Litt. [45]). 13C NMR (101MHz, DMSO-d6) delta 167.4, 162.7, 159.5, 151.8, 150.7, 148.9, 148.2, 131.0, 121.9, 117.7, 111.2, 54.8, 39.2. IR (neat) cm-1: 3341, 3189, 2956, 2823, 1660, 1599, 1294, 1188 (Litt. [45]).
56%		0J 89j 4 FontWeight="Bold" FontSize="10" Araino FontWeight="Bold" FontSize="10" 4-deoxy-l O-A^nethyipterok Acid (APA, 2) ( raovec. I; Spencer, G.; Blair, A. H.; Mammen, M; Singh, M,; Ghose, T. J. Med Chem., 1989, 32, 2426). A mixture of 249 rag (0.59 mraol) dibromotripheaylphosphorane and 45,0 mg (0.20 tnmol) 2,4-diaraino-6-(hydr )xymethyl)pteridin.e hydrochloride (1) in 1 .5 mL of anhydrous dmieihylacetamide was stirred at room iemperatare for 24 h under an argon atmosphere. To the reaction mixture were added 41 mg (0.27 mmol) of 4-(methylamino)benzoic acid and 0,16 mL { 116 mg, 0,90 mmol) of DIPEA and the reaction mixture was stirred at room temperature for 48 h, and then at 60 '"'C for 24 fi. The cooled reaction mixture was poured into 25 mL of 0.33 M aq NaOH and the precipitate was filtered. The filtrate was adjusted to H 5.5 with 10% acetic acid and the resulting precipitate was collected through filtration, washed wi h water and dried under diminished pressure at 80 C overnight to obtain 2 as an orange solid: yield 42 mg (56%); silica gel TLC - 0.47 (5:4: 1 chlorofornv-methanol-water); lH NM (DMSO-<&) o 3.19 (s, 3H), 4.76 (s, 2H), 6.61 (s, 2H>, 6.78 (d, 21i J- 8.9 Hz), 7.72 (d, 2H, J- 8.7 Hz) and 8.56 (s, 1H).
		To a solution of pteridine 8 (5 g, 21.9 mmol) in DMA (50 ml) was added Ph3P (17.2 g, 65.6 mmol). The reaction mixture was cooled to 0 C. Br2 (3.4 ml, 65.6 mmol) was added dropwise to the reaction mixture at 0 C. The reaction was warmed to room temperature and stirred for 20 h. DIEA (11 ml), 60 mmol) was added to the reaction mixture followed by 4-methylamino benzoic acid (3.31 g, 21.9 mmol). The reaction mixture was heated to 60-70 C. and stirred for 24 h. The reaction mixture was cooled to room temperature and poured into excess 1 N NaOH solution. The resulting solids were filtered. The filtrate was extracted with Et2O (3×). The aqueous layer was acidified to pH 3-4 with 1N HCl solution. The resulting solid was filtered and dried under vacuum at 50 C. overnight to give the 4.2 g of 9.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 156,p. 738 - 746
[2]Patent: WO2014/145109,2014,A1 .Location in patent: Paragraph 0189
[3]Patent: US7230101,2007,B1 .Location in patent: Page/Page column 60; 79

66
[ 19741-14-1 ]
[ 1286737-12-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide 2: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 0 - 20 °C 3: trifluoroacetic acid / dichloromethane / 1.5 h / 20 °C
	Multi-step reaction with 3 steps 1: (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 2: HATU 3: trifluoroacetic acid
	Multi-step reaction with 3 steps 1: (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide 2: HATU / N,N-dimethyl-formamide 3: trifluoroacetic acid / dichloromethane

Multi-step reaction with 3 steps 1: (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide 2: HATU / N,N-dimethyl-formamide / 0 - 20 °C 3: trifluoroacetic acid / dichloromethane / 1.5 h / 20 °C

Reference： [1]Huang, Baohua; Desai, Ankur; Zong, Hong; Tang, Shengzhuang; Leroueil, Pascale; Baker Jr., James R. [Tetrahedron Letters, 2011, vol. 52, # 13, p. 1411 - 1414]
[2]Huang, Baohua; Kukowska-Latallo, Jolanta F.; Tang, Shengzhuang; Zong, Hong; Johnson, Kali B.; Desai, Ankur; Gordon, Chris L.; Leroueil, Pascale R.; Baker Jr., James R. [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 9, p. 3152 - 3156]
[3]Goonewardena, Sascha N.; Kratz, Jeremy D.; Zong, Hong; Desai, Ankur M.; Tang, Shengzhuang; Emery, Sarah; Baker Jr., James R.; Huang, Baohua [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 10, p. 2872 - 2875]
[4]Current Patent Assignee: UNIVERSITY OF MICHIGAN - US9402911, 2016, B2

67
[ 1402928-21-5 ]
[ 19741-14-1 ]
[ 1402928-23-7 ]

Yield	Reaction Conditions	Operation in experiment
45%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide for 18h; Inert atmosphere;	1.6 6) Synthesis of compound 8 To a stirring solution of 6 (0.7g, 1 mmol), N-(3-dimethylaminopropyl)-.V- ethylcarbodiimide hydrochloride (0.67 g, 3.5 mmol) and 1-hydroxybenzotriazole hydrate (0.54 g, 3.5 mmol) in anhydrous dimethyl formamide (20 mL) was added 71 (0.98 g, 3.0 mmol). Then anhydrous triethylamine (1.4 mL, 10 mmol) was added dropwise to the reaction mixture under Ar and continued stirring for 18 hrs. After evaporating the solvents the resulting slurry was loaded on to silica and purified by flash chromatography (0-20 % CH3OH/l%Et3N in CH2Cl2/l%Et3N) to provide 8 as a yellow solid (1.0 g, 77%). Second flash chromatographic purification (0-20 % CH3OH/l%Et3N in CH2Cl2/l%Et3N) was necessary to remove minor impurities (0.66 g, 45%). ESI-MS calcd for C63H92N20O12 [M+2H]2+ 660.3602, found 660.3612.

Reference： [1]Current Patent Assignee: TYCHON BIOSCIENCE - WO2013/109939, 2013, A1 Location in patent: Page/Page column 32; 33

68
[ 19741-14-1 ]
[ 73839-20-0 ]
4-amine-4-deoxy-10-N-methylpteroic acid 6-(tert-butoxy)-6-oxohexyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With dmap; dicyclohexyl-carbodiimide In dimethyl sulfoxide at 20℃; for 24h;	1 [0191 J 4-Amine-4-tieoxy-10-A'-nietlij lpteroic Acid 6-{fef-/-Btoxy)-6- oxohexjl Ester (8). To a solution of 36 mg (0.2 mraol) of 7, 12 mg (37 pmol) of 6 and 45 mg (0.4 mrno'l) of DMAP in I mh of anhydrous DMSO was added 39 rag (0.2 mmol) of DCC and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was filtered and the filtrate was purified on a C? s reversed phase semi -preparative (250 χ 10 mm, 10 um) HPLC column using 0.1% aq TFA and CH3CN mobile phases. A linear gradient was employed (99: 1 0.1% aq TFA~CH;CN FontWeight="Bold" FontSize="10" 1:99 0.1 % aq TFA-€H3CN) over a period of 30 min at a flow rate of 3 mL/min. Fractions containing the desired product eiuted at 25.8 min (monitoring at 292 ran) and were collected, frozen, and iyophilked to give 8 as a yellow solid: yield 1 1 mg (60%); MR (CDCN) 5 1.40 (m, 9H)5 1.58 (m, 2H), 1.70 (m, 2.H.), 2, 19 (t, 2H, J- 7.3 Hz), 3.24 (s, 3HI 4J 9 (i, 2H, = 6.4 11/), 4.84 (s, 2H), 5.45 (s, 2H), 6.79 (m, 2H), 7.26 (s, IH), 7.72 (s, IB), 7.8 Cm, 2H) and 8.73 (s, I H); mass spectrum (ES), m/z 496.2676 (M FontWeight="Bold" FontSize="10" < FontWeight="Bold" FontSize="10" Η' equires m/z 496.2667).

Reference： [1]Current Patent Assignee: ARIZONA BOARD OF REGENTS - WO2014/145109, 2014, A1 Location in patent: Paragraph 0191

69
C₂₅H₄₅NO₈ [ No CAS ]
[ 19741-14-1 ]
MTX-di-tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With N-ethyl-N,N-diisopropylamine; HATU In dimethyl sulfoxide at 20℃; for 48h;	2 (01971 MTX-di-fcr/hut l ester (13). To a solution of 25 mg (35 ηιο) of compound 11 in 0,5 mL of anhydrous DMF was added 0.1 mL of piperidine and the solution was stirred at room temperature for 1 h. The reaction mixture was concentrated under diminished pressure. The residue was purified by flash chromatography on a silica gel column (5 χ 3 cm). Elation with 4: 1 hexanes-ethyl acetate- 100% ethyl acetate gave compound 12 as a colorless oil: yield 12 mg (70%); mass spectrum (MALD1), m/z 510.36 CM + Na)';' (CjsHtsNOs arequires m/z 510.30). To a solution containing 10 mg (20 pmol) of the amine 12, 5 mg (15 μηιο) of A? A (2) and 25 pL (18 mg, 0.14 mmol) o f Df P EA in 0.25 mL of anhydrous DMSO was added 30 mg (79 uraol) of HATU and the reaction mixture was stirred at room temperature for 48 h. The reaciion mixture was filtered and the filtrate was purified on a C m reversed phase serai-preparative (250 * 10 mm, 10 ura) HPLC column using 0.1% aq. TFA and CCN mobile phases. A linear gradient was employed (99: 1 0.1 % aq TFA- CN- 1 :99 0.1 % aq TFA~CH.CN) over a period of 30 min with a flow rate of 3 mL/rom. Fractions containing the desired product eluted at 20.1 min (monitoring at 292 nm) and were collected, frozen, and lyophilized to give 13 as an orange solid: yield 2.5 mg (20%); mass spectrum (MALDf), m 795.29 (M + H) GHNaO requires m/z 795.44), m/z 817.28 (M + Naf (C^Hss sO^ a requires m z 817.42).

Reference： [1]Current Patent Assignee: ARIZONA BOARD OF REGENTS - WO2014/145109, 2014, A1 Location in patent: Paragraph 0197

70
BLM-disaccharide linker [ No CAS ]
[ 19741-14-1 ]
APA-BLM-disaccharide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	With N-ethyl-N,N-diisopropylamine; HATU In dimethyl sulfoxide at 20℃; for 16h;	1 {01901 APA-BLM-disacehande (4). {01901 APA-BLM-disacehande (4). To a solution containing 3.5 mg (7.4 pmol) of BLM-di saccharide linker 3, 2.5 mg (7,6 umol) of 6 and 3.0 μ (2.2 mg; 17 μχηο) of DIPEA in 0.12 mL of anhydrous DMSO was added 4.3 rag (I S μχηο) ofRATU. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was purified on an Econosil Cm reversed phase semi- preparative (250 x 10 mm, 10 μηι) HPLC column using 0.1% aq TFA and QC mobile phases. A inear gradient was employed (99; 1 0. i% aq TPA-CCN -> 45:55 0.1 % aq TFA~CH;;C ) over a period of 30 min. at a flow rate of 3 mL/min. Fractions containing the desired product eiuted at 26.5 min (monitoring at 292 nm) and were collected, frozen, and lyophilized to give APA-BLM-disaccharide conjugate 4 as a yellow solid: yield 2.2 mg (37%); mass spectrum (ESI), m/z 780.3168 (M +

Reference： [1]Current Patent Assignee: ARIZONA BOARD OF REGENTS - WO2014/145109, 2014, A1 Location in patent: Paragraph 0190

71
EC₀₄₀₁ [ No CAS ]
[ 19741-14-1 ]
EC₀₄₀₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25 mg	With dmap; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; benzotriazol-1-ol; triethylamine In N,N-dimethyl-formamide at 20℃; for 18h;	Synthesis of Methotrexate-OtBu-Hydrazide Pyridyldisulfide-ethanol Carbazate EC0402 Synthesis of Methotrexate-OtBu-Hydrazide Pyridyldisulfide-ethanol Carbazate EC0402 To a well stirred solution of pyridyldithio-derivative of glutamic acid EC0401 (45 mg, 1 eq.) in dry DMF was added 4-[N-(2,4-diamino-6-pteridinylmethyl)-N-methylamino]benzoic acid (25 mg, 1 eq.) followed by PyBop (39 mg, 1.1 eq.), 1-hydroxybenzotriazole (10 mg, 1.1 eq.), and 4-(dimethylamino)pyridine (9 mg, 1.1 eq.). After 5 min of stirring, triethylamine (29 μL, 3 eq.) was added. The reaction mixture was allowed to stir at room temperature for 18 h. The solvent was removed under reduced pressure. The t-butyl-protected pyridyldithio-derivative of methotrexate EC0402 (25 mg) was purified by preparative HPLC (10 mM NH4OAc, pH=7 and acetonitrile). ESI-MS: (M+H)+=738.1; 1H NMR (DMSO-d6 & D2O) δ 8.57 (s, 1H), 8.46 (d, 1H), 7.80 (m, 2H), 7.73 (d, 2H), 7.24 (t, 1H), 6.81 (d, 2H), 4.79 (s, 2H), 4.22 (m, 1H), 4.20 (t, 2H), 3.21 (s, 3H), 3.09 (t, 2H), 2.21 (t, 2H), 2.01 (m, 1H), 1.91 (m, 1H), 1.39 (s, 9H).

Reference： [1]Current Patent Assignee: PURDUE UNIVERSITY SYSTEM; Novartis (w/o Sandoz); NOVARTIS AG - US9192682, 2015, B2 Location in patent: Page/Page column 36-37

72
[ 19741-14-1 ]
[ 159002-17-2 ]
C₂₃H₂₉N₉O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Diisopropylethylamine (120 uL, 0.691 mmol) was added to a solution of N10-Methyl-4-amino-4-deoxypteroic acid (75 mg, 0.23 mmol), HATU (88 mg, 0.23 mmol) in DMF (5 mL) and stirred at 23 C for 15 minutes (solution A). In another flask Compound (32-a) (47 mg, 0.23 mmol) was dissolved in DMSO (5 mL) and added Diisopropylethylamine (120 uL, 0.691 mmol) (Solution B ). Solution B was added to solution A via cannula and stirred the content for 1 h. Upon completion the reaction mixture was purified by preparative HPLC using C18 column. (2- carboxyethyl)triphenylphosphonium bromide (121 mg, 0.337 mmol) in DMF (3.5 mL). The reaction content was stirred at 23 C for 1 h. Upon completion, the reaction mixture was added to ether (500 mL) and precipitated solid was filtered and dried under high vacuum to obtain compound (53) as thick oil.

Reference： [1]Patent: WO2017/44443,2017,A1 .Location in patent: Paragraph 00199

73
Glu(OH)-OtBu [ No CAS ]
[ 19741-14-1 ]
C₂₄H₃₀N₈O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere;	10.2 TAG Y-C3-MTX was chemically synthesized as shown in FIG. 4. In Step [2] of the scheme 4-[[(2,4-Diamino-6-pteridinyl)methyl]methylamino]-Benzoic acid (33 mg) was mixed with 38mg of HBTU (N,N,N',N'-Tetramethyl-0-(lH-benzotriazol-l-yl) uronium hexafluorophosphate) and 12.9mg of DIEA (Ν,Ν-Diisopropylethylamine) in 4 mL DMF (Dimethylformamide). The resulting mixture was stirred at room temperature under Argon. To the above mixture was added 20.3 mg of L-Glu(OH)-OtBu in 3 mL of N,N- dimethylformamide and stirred at RT for 2 hr. under Argon. The solvent was removed under reduced pressure lOmL (2X) of dichloromethane was added and removed under reduced pressure.

Reference： [1]Current Patent Assignee: DEFINED DIAGNOSTICS - WO2017/7889, 2017, A1 Location in patent: Paragraph 00113

74
[ 929-59-9 ]
[ 19741-14-1 ]
C₂₁H₂₉N₉O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	Stage #1: 4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoic acid With O-(N-succinimidyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 3,6-dioxa-1,8-diaminooctane In dimethyl sulfoxide at 20℃; for 0.25h; Inert atmosphere;

Reference： [1]Xue, Lin; Yu, Qiuliyang; Griss, Rudolf; Schena, Alberto; Johnsson, Kai [Angewandte Chemie - International Edition, 2017, vol. 56, # 25, p. 7112 - 7116][Angew. Chem., 2017, vol. 129, # 25, p. 7218 - 7222,5]

75
[ 945-24-4 ]
[ 19741-14-1 ]

Reference： [1]Journal of the American Chemical Society,2017,vol. 139,p. 16822 - 16829
[2]Patent: EP3312273,2018,A1

76
[ 19741-14-1 ]
[ 23150-65-4 ]
[ 34378-65-9 ]

Yield	Reaction Conditions	Operation in experiment
2.39 g	Stage #1: 4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 21℃; for 0.5h; Inert atmosphere; Stage #2: L-glutamic dimethyl ester hydrochloride In N,N-dimethyl-formamide at 21℃; for 5h; Inert atmosphere;
2.39 g	Stage #1: 4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 21℃; for 0.5h; Inert atmosphere; Stage #2: L-glutamic dimethyl ester hydrochloride In N,N-dimethyl-formamide for 5h;	8 ( 4-( ( ( 2,4-diaminopteridin-6-yl)methyl) ( methyl)amino )benzoyl)-L-glutamate To a solution of 4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzoic acid (7) (3.0 g, 9.2 mmol) in anhydrous DMF (80 mL) was added Et3N (6.4 mL, 46.1 mmol) followed by PyBOP (6.48 g, 12.4 mmol) . The mixture was stirred at 21 °C under a N2 atmosphere for 30 min. Dimethyl L-glutamate hydrochloride (6-HCI) (2.1 g, 9.9 mmol) was added and the reaction mixture was stirred for 5 h. The crude mixture was filtered through a path of celite to remove solids and the filtrate concentrated in vacuo. The solid residue was triturated with a mixture of EtOAc/CHCI3 (150 mL, 1/1) and poured into 750 mL of Et20 at 0 °C under strong stirring . The resultant suspension was filtered, washed with Et20 and cold water, triturated with hot MeOH, and filtered again. The resultant orange solid wash purified by flash column chromatography on silica gel using a mixture of CH2CI2/MeOH (92.5/7.5, v/v) as the eluent to give the title compound 8 (2.39 g, 54%) as a yellow solid . XH NMR (400 MHz, DMSO-d5) δ 8.56 (s, 1H), 8.34 (d, 3 = 7.4 Hz, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.65 (br s, 1H), 7.43 (br s, 1H), 6.82 (d, J = 8.8 Hz, 2H), 6.61 (br s, 2H), 4.78 (s, 2H), 4.39 (ddd, J = 9.4, 7.4, 5.6 Hz, 1H), 3.61 (s, 3H), 3.57 (s, 3H), 3.21 (s, 3H), 2.41 (t, J = 7.4 Hz, 2H), 2.17 - 2.03 (m, 1 H), 2.01 - 1.72 (m, 1H) ; 13C NMR (101 MHz, DMSO-d5) δ 172.7, 172.6, 166.4, 162.9, 162.7, 155.2, 151.0, 149.2, 145.9, 129.0, 121.4, 120.7, 111.0, 54.9, 51.8, 51.7, 51.4, 38.7, 30.0, 25.8; HRMS (ESI) m/z: calcd for C22H27N805 [M + H]+ 483.2099, found 483.2119.

Reference： [1]Peiró Cadahía, Jorge; Bondebjerg, Jon; Hansen, Christian A.; Previtali, Viola; Hansen, Anders E.; Andresen, Thomas L.; Clausen, Mads H. [Journal of Medicinal Chemistry, 2018, vol. 61, # 8, p. 3503 - 3515]
[2]Current Patent Assignee: TECHNICAL UNIVERSITY OF DENMARK - WO2018/37120, 2018, A1 Location in patent: Page/Page column 28; 29; 32

77
[ 59368-16-0 ]
[ 10541-83-0 ]
[ 19741-14-1 ]

Yield	Reaction Conditions	Operation in experiment
69%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide Inert atmosphere;	13 (Synthesis of compound 21 (MTX-NH2)) The compound 13 was allowed to react with triphenylphosphine dibromide in DMA to obtain a compound 14.The compound 14 was dissolved in DMA under nitrogen gas stream, and then the compound 15 and DIEA were addedand reacted to obtain a compound 16 (yield: 69%). Subsequently, the compound 16 and the compound 17 were dissolvedin DMSO under nitrogen gas stream, and condensation reaction was performed with a BOP reagent to obtain a compound18 (yield: 46%). Subsequently, the compound 18 and the compound 19 were dissolved in DMA under nitrogen gasstream, and condensation reaction was performed with HATU to obtain a compound 20 (yield: 69%). Then, the compound20 was dissolved in dichloromethane, and deprotection was performed with TFA to obtain a compound 21 (MTX-NH2).

Reference： [1]Current Patent Assignee: THE UNIVERSITY OF TOKYO; TOKYO UNIVERSITY OF SCIENCE - EP3312273, 2018, A1 Location in patent: Sheet 0163; 0165

78
[ 79640-72-5 ]
[ 19741-14-1 ]
[ 79640-70-3 ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: 4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: L-glutamic acid 1-tert-butyl ester 5-methyl ester In N,N-dimethyl-formamide for 16h; Stage #3: With barium(II) hydroxide In ethanol; water at 20℃;	2.3 4.2.3. (S)-5-(Tert-butoxy)-4-(4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)-benzamido)-5-oxopentanoic acid (7) To a solution of pteroic acid 6 (3.15g, 8.71mmol, 90% purity) in anhydrous DMF (200mL) were added PyBOP (6.55g, 12.6mmol) and triethylamine (6.00mL, 45.2mmol) and the turbid reaction mixture was stirred 30minat 20°C. H-Glu (OMe)-OtBu hydrochloride (2.58g, 10.2mmol) was added and the mixture was stirred for another 16h. The reaction mixture was filtered over celite, concentrated in vacuo to 75mL, and then poured slowly into a vigorously stirred solution of ice-cooled diethyl ether (2L). The suspension was left on ice for 3h and precipitate was collected by filtration and washed with cold diethyl ether. The filter cake was suspended in a mixture of EtOH:H2O 1:1 (150mL) and Ba(OH)2•8H2O (6.11g, 13.4mmol) was added. The suspension was stirred for 24hat 20°C and precipitate was then removed by filtration. To the filtrate was added sat. aq. Na2SO4 (25mL), stored at 4°C for 5h, and filtered over celite to remove precipitated BaSO4. The filtrate was acidified to pH 3 using 0.5M HCl and the desired product 7 was collected as an orange solid after washing H2O, ether, and pentane and drying in vacuo (4.48g, 79%, 90% purity). 1H NMR (400MHz, DMSO-d6) δ 12.17 (br. s, 1H), 9.24 (br. s, 1H), 9.04 (br. s, 1H), 8.72 (s, 1H), 8.56 (br. s, 1H), 8.21 (d, J=7.6Hz, 1H), 7.74 (d, J=9.0Hz, 2H), 7.35 (br. s, 1H), 6.82 (d, J=9.0Hz, 2H), 4.87 (s, 2H), 4.29 (ddd, J=9.7, 7.5, 5.2Hz, 1H), 3.25 (s, 3H), 2.32 (t, J=7.5Hz, 2H), 2.06-1.96 (m, 1H), 1.90 (ddt, J=14.1, 9.3, 7.2Hz, 1H), 1.39 (s, 9H), (Litt. [46]). 13C NMR (101MHz, DMSO-d6) δ 173.9, 171.5, 166.4, 162.8 (2C), 155.9, 151.2, 150.7, 148.8, 129.0, 122.3, 121.4, 111.2, 80.5, 54.9, 52.5, 40.2, 30.4, 27.7, 26.0, (Litt. [46]). IR (neat) cm-1: 3342, 3118, 2976, 2931, 1716, 1639, 1601, 1506, 1364, 1152, 832.

Reference： [1]Andersen, Nikolaj S.; Peiró Cadahía, Jorge; Previtali, Viola; Bondebjerg, Jon; Hansen, Christian A.; Hansen, Anders E.; Andresen, Thomas L.; Clausen, Mads H. [European Journal of Medicinal Chemistry, 2018, vol. 156, p. 738 - 746]

79
[ 127-19-5 ]
[ 945-24-4 ]
[ 150-13-0 ]
[ 19741-14-1 ]

Yield	Reaction Conditions	Operation in experiment
91%		<strong>[945-24-4]2,4-diamino-6-(hydroxymethyl)pteridine</strong> hydrochloride (4.40 g, 19.2 mmol) was dissolved in hot water (150 mL) and after cooling to 21 C the solution was neutralized with 1M NaOH aq. solution to pH 7 (ca. 20 mL) . The formed precipitates were collected by filtration, washed with water, and dried in vacuo over P205 to afford an orange-beige solid corresponding to 2,4-diamino-6- (hydroxymethyl)pteridine. The solid was suspended in dry DMAc (25 mL) and triphenylphosphine dibromide ( 18.1 g, 42.9 mmol) was added to the suspension. The turbid and dark mixture was stirred for 24 h at 20 C under a N2 atmosphere. Then 4-aminobenzoic acid (2.97 g, 19.6 mmol) was added to the reaction and stirred for 3 additional days. The reaction mixture was poured into 250 mL of 0.33M NaOH and the precipitate was filtered off. The filtrate was neutralized with 10% aq . acetic acid (ca. 20 mL and the precipitate form upon neutralization was filtered, washed with water, triturated with MeOH, filtered, and dried in vacuo to afford 7 as an orange-beige solid (5.70 g, 91%) . XH NMR (400 MHz, DMSO-d5) delta 12.15 (br s, 1H), 8.63 (s, 1H), 8.17 (br s, 1H), 7.94 (br s, 1H), 7.73 (d, J = 9.0 Hz, 2H), 7.04 (br s, 2H), 6.83 (d, J = 9.0 Hz, 2H), 4.81 (s, 2H), 3.23 (s, 3H); 13C NMR (101 MHz, DMSO-d5) delta 167.8, 163.2, 161.1, 152.3, 149.5, 147.8, 131.5, 122.2, 118.1, 111.7, 100.0, 55.2, 39.6.

Reference： [1]Patent: WO2018/37120,2018,A1 .Location in patent: Page/Page column 27; 28; 32

80
[ 19741-14-1 ]
[ 56-12-2 ]
[ 68352-96-5 ]

Yield	Reaction Conditions	Operation in experiment
49%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 20℃;	1 Example 1. Preparation of methotrexate derivative Weigh 50mg 4-amino-4-deoxy-10-methylpteric acid, 19mg 4-aminobutyric acid,96mg benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate, 40mg N, N-diisopropylethylamine, dissolved in 1.5ml dimethyl sulfoxide,Stir at room temperature for 1 h. 7 ml of ice water was added to the liquid after the reaction, and the precipitate was filtered and washed with water.Let it dry. After the oily liquid was purified by column chromatography, wave layer chromatography (developing agent was:Dichloromethane: methanol: acetic acid = 5: 1: 0.05; UV detection at 254 nm) A yellow spot was seen. 2 mol / L sodium hydroxide was added to the yellow oil to adjust the pH to 4, and the precipitated solid was filtered, washed with ice water, and lyophilized. 31 mg of methotrexate derivative as a yellow solid was finally obtained,Yield 49%.

Reference： [1]Current Patent Assignee: ZHEJIANG ZHUNCE BIOTECHNOLOGY - CN110357886, 2019, A Location in patent: Paragraph 0128-0131

81
[ 19741-14-1 ]
methyl N5-((2S)-5-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)amino)-1-methoxy-1,5-dioxopentan-2-yl)-L-glutaminate [ No CAS ]
methyl N2-(4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzoyl)-N5-((2S)-5-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)amino)-1-methoxy-1,5-dioxopentan-2-yl)-L-glutaminate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide for 24h;	12 Methyl N2-(4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzoyl)-N5-((2S)-5-((8-((2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)amino)-1-methoxy-1,5-dioxopentan-2-yl)-L- glutaminate (SAR005-019; NCGC00687567) Dissolved 4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzoic acid (8.53 mg, 0.026 mmol), and methyl N5-((2S)-5-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)amino)-1- methoxy-1,5-dioxopentan-2-yl)-L-glutaminate (18 mg, 0.026 mmol) in DMF (1 ml) followed by the addition of TEA (18.27 μl, 0.131 mmol) and PyBOP (20.46 mg, 0.039 mmol). Reaction mixture was stirred for 24 hours, dilute with NaHCO3 and extracted with ethyl acetate. The solvent was dried under MgSO4 and purified by reverse phase HPLC. LC- MS retention time: 4.48 min (method 2) MS-ESI (+) calcd m/z for C36H38N12O11+ 994.45 (M+H)+, found 994.5

Reference： [1]Current Patent Assignee: GOVERNMENT OF THE UNITED STATES - WO2021/262693, 2021, A1 Location in patent: Page/Page column 99; 101

82
[ 2419-56-9 ]
[ 19741-14-1 ]
[ 79640-76-9 ]

Yield	Reaction Conditions	Operation in experiment
64%	Stage #1: 4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoic acid With N-ethyl-N,N-diisopropylamine; O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate In N,N-dimethyl-formamide for 0.25h; Stage #2: L-Glu-γ-tert-butyl ester In N,N-dimethyl-formamide for 24h;	25 ((S)-5-(tert-butoxy)-2-(4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzamido)-5- oxopentanoic acid (SAR006-060) Taken 4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzoic acid (100 mg, 0.307 mmol) in DMF (2 ml) and added HATU (175 mg, 0.461 mmol) and DIEA (268 μl, 1.537 mmol). Reaction was stirred for 15 minutes followed by the addition of (S)-2-amino-5-(tert-butoxy)-5-oxopentanoic acid (75.0 mg, 0.369 mmol). Continue stirring for additional 24 hours. Solvent was removed and the crude was purified by column chromatography to yield product as a brown solid (100 mg, 64%). LC: 2.66 min (method 1). MS- ESI (+) calcd m/z for C24H30N8O5+ 511.23 (M+H)+, found 511.2

Reference： [1]Current Patent Assignee: GOVERNMENT OF THE UNITED STATES - WO2021/262693, 2021, A1 Location in patent: Page/Page column 115-116

83
[ 19741-14-1 ]
methyl (S)-4-amino-5-((8-((tert-butoxycarbonyl)amino)octyl)amino)-5-oxopentanoate [ No CAS ]
methyl (S)-5-((8-((tert-butoxycarbonyl)amino)octyl)amino)-4-(4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzamido)-5-oxopentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoic acid With benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 30℃; for 0.5h; Stage #2: methyl (S)-4-amino-5-((8-((tert-butoxycarbonyl)amino)octyl)amino)-5-oxopentanoate In N,N-dimethyl-formamide for 24h;	23 Methyl (S)-5-((8-((tert-butoxycarbonyl)amino)octyl)amino)-4-(4-(((2,4-diaminopteridin-6- yl)methyl)(methyl)amino)benzamido)-5-oxopentanoate (SAR005-092) To a solution of 4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzoic acid (50 mg, 0.154 mmol) in DMF ( 3ml) was added TEA (107 μl, 0.768 mmol) and PyBOP (120 mg, 0.231 mmol). The reaction mixture was stirred at 30°C for 30 minutes resulting in dark brown solution. To this was added a solution of methyl (S)-4-amino-5-((8-((tert-butoxycarbonyl)amino)octyl)amino)-5-oxopentanoate (59.6 mg, 0.154 mmol) in DMF (1 mL). The resulting reaction mixture was stirred for an additional 24 hours. Solvent was removed under reduced pressure and the crude was purified by column chromatography.

Reference： [1]Current Patent Assignee: GOVERNMENT OF THE UNITED STATES - WO2021/262693, 2021, A1 Location in patent: Page/Page column 113-114

84
[ 19741-14-1 ]
4-amino-5-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)amino)-5-oxopentanoic acid trifluoroacetic acid [ No CAS ]
4-(4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzamido)-5-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)amino)-5-oxopentanoic acid trifluoroacetic acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoic acid With benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate; triethylamine In dimethyl sulfoxide for 0.5h; Stage #2: 4-amino-5-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)amino)-5-oxopentanoic acid trifluoroacetic acid In dimethyl sulfoxide for 24h;	24 4-(4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzamido)-5-((8-((2-(2,6-dioxopiperidin-3- yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)amino)-5-oxopentanoic acid (SAR006-037; NCGC00690075) Taken 4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzoic acid (15.16 mg, 0.047 mmol) in DMSO (1 ml) followed by the addition of TEA (32.5 μl, 0.233 mmol) and PyBOP (48.5 mg, 0.093 mmol). Reaction was stirred for 30 min. In another vial, taken 4-amino-5-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)octyl)amino)-5-oxopentanoic acid, TFA (30 mg, 0.047 mmol) in DMSO (1 ml) and added activated acid to it. The reaction was stirred for 24 hours and the crude was purified by reverse phase HPLC to yield product as a TFA salt. LC- MS retention time: 4.36 min (method 2) MS-ESI (+) calcd m/z for C41H48N12O8+ 837.37 (M+H)+, found 837.4 1H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), 11.07 (s, 1H), 9.26 (s, 1H), 9.06 (s, 1H), 8.69 (s, 1H), 8.60 (s, 2H), 7.98 (d, J = 7.9 Hz, 1H), 7.82 (t, J = 5.7 Hz, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.55 (t, J = 7.8 Hz, 1H), 7.47 (s, 1H), 7.05 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 7.0 Hz, 1H), 6.79 (d, J = 8.6 Hz, 2H), 6.49 (d, J = 6.0 Hz, 1H), 5.03 (dd, J = 12.9, 5.3 Hz, 1H), 4.85 (s, 2H), 4.33 (td, J = 8.5, 5.4 Hz, 1H), 3.24 (d, J = 13.6 Hz, 5H), 3.12 - 3.04 (m, 1H), 3.00 (td, J = 6.6, 3.7 Hz, 49H), 2.92 - 2.81 (m, 1H), 2.57 (d, J = 17.6 Hz, 2H), 2.27 - 2.18 (m, 2H), 2.01 (dt, J = 12.4, 4.6 Hz, 2H), 1.94 (t, J = 7.3 Hz, 1H), 1.86 - 1.78 (m, 1H), 1.77 - 1.66 (m, 47H), 1.52 (q, J = 7.2 Hz, 3H), 1.36 (t, J = 6.2 Hz, 2H), 1.28 (s, 5H), 1.28 - 1.20 (m, 7H).

Reference： [1]Current Patent Assignee: GOVERNMENT OF THE UNITED STATES - WO2021/262693, 2021, A1 Location in patent: Page/Page column 114-115

85
[ 74124-79-1 ]
[ 19741-14-1 ]
2,5-dioxopyrrolidin-1-yl 4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dimethyl sulfoxide at 50℃; for 1h;	43 2,5-dioxopyrrolidin-1-yl 4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzoate (SAR008-040) Taken 4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzoic acid (50 mg, 0.154 mmol) in DMSO (1 ml) followed by the addition of bis(2,5-dioxopyrrolidin-1-yl) carbonate (118 mg, 0.461 mmol) and triethylamine (105 μl, 0.768 mmol). Reaction was heat to 50 °C for 1 hour. Reaction was washed with NaHC03 and extract with ethyl acetate, washed brine, dried MgS04, concentrated under reduced pressure to yield SAR008-040 as a yellow solid (36 mg, 56%). LC- MS retention time: 2.55 min (method 1) MS-ESI (+) calcd m/z for C19H18N8O4+ 423.15 (M+H)+, found 423.2 1H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H), 9.28 (s, 1H), 8.99 (s, 1H), 8.78 (s, 1H), 8.66 (s, 1H), 7.87 (s, 1H), 7.81 (d, J = 7.7 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 4.92 (s, 2H), 3.30 (s, 3H), 2.81 (s, 4H).

Reference： [1]Current Patent Assignee: GOVERNMENT OF THE UNITED STATES - WO2021/262693, 2021, A1 Location in patent: Page/Page column 134

86
[ 19741-14-1 ]
methyl (S)-21-amino-2,2-dimethyl-4,18-dioxo-3,8,11,14-tetraoxa-5,17-diazadocosan-22-oate [ No CAS ]
methyl (S)-21-(4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzamido)-2,2-dimethyl-4, 18-dioxo-3,8,11,14-tetraoxa-5,17-diazadocosan-22-oate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56.9%	With 4-methyl-morpholine; 1-hydroxy-7-aza-benzotriazole; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dimethyl sulfoxide for 24h;	45 Methyl (S) - 1 -amino- 16- (4- (((2,4-diaminopteridin-6-yl)methyl) (methyl)amino)benzamido) - 13-oxo- 3.6.9-trioxa-12-azaheptadecan-17-oate (SAR008-035) To a solution of 4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzoic acid (50 mg, 0.154 mmol) in DMSO (2 ml) was added methyl (S)-21-amino-2,2-dimethyl-4,18-dioxo-3,8,ll,14-tetraoxa-5,17- diazadocosan-22-oate (80 mg, 0.184 mmol), EDCI (58.7 mg, 0.307 mmol), HOAT (41.8 mg, 0.307 mmol) and NMM (68.2 μl, 0.615 mmol). The reaction was stirred for 24 hours. The crude was purified by reverse phase HPLC to yield methyl (S)-21-(4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzamido)-2,2- dimethyl-4, 18-dioxo-3, 8, 11,14-tetraoxa-5,17-diazadocosan-22-oate (65 mg, 0.088 mmol, 56.9 % yield). MS-ESI (+) calcd m/z for C34H50N10O9+ 743.38 (M+H)+, found 743.4; LC retention time: 2.69 min (method 1). The compound was dissolved I n DCM and added 10 equivalents of TFA. The reaction was stirred for 3h and the solvent was removed under the reduced pressure. The crude was used as such in the next step without further purification. MS-ESI (+) calcd m/z for C29H42N10O7+ 643.32 (M+H)+, found 643.4; LC retention time: 2.33 min (method 1).

Reference： [1]Current Patent Assignee: GOVERNMENT OF THE UNITED STATES - WO2021/262693, 2021, A1 Location in patent: Page/Page column 137-138

87
(S)-4-amino-5-(tert-butoxy)-5-oxopentanoic acid hydrochloride [ No CAS ]
[ 19741-14-1 ]
[ 79640-70-3 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-[(2,4-diaminopteridin-6-ylmethyl)methylamino]benzoic acid With benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate; triethylamine In dimethyl sulfoxide at 30℃; for 2h; Stage #2: (S)-4-amino-5-(tert-butoxy)-5-oxopentanoic acid hydrochloride With potassium carbonate In dimethyl sulfoxide for 18h;	3 (S)-5-(tert-butoxy)-4-(4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzamido)-5- oxopentanoic acid (SAR003-016) To a solution of 4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzoic acid (100 mg, 0.307 mmol) in 3 ml of DMSO was added TEA (64.3 μl, 0.461 mmol) and PyBOP (192 mg, 0.369 mmol). The mixture was stirred at 30 °C for 2 hours resulting in dark brown solution. To that was added (S)-4-amino-5-(tert- butoxy)-5-oxopentanoic acid HC1 (88.0 mg, 0.369 mmol) and K2CO3 (21.24 mg, 0.154 mmol). The reaction mixture was stirred for 18 hours. The crude was purified by reverse phase HPLC (10 - 100% CH3CN in water, 0.01% TFA). LC-MS retention time: 2.69 min (method 1) MS-ESI (+) calcd m/z for C24H30N8O5+ 511.23 (M+H)+, found 511.3 1H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 8.57 (s, 1H), 8.17 (d, J = 7.6 Hz, 1H), 7.89 (s, 1H), 7.75 - 7.68 (m, 2H), 7.67 (s, 1H), 6.85 - 6.77 (m, 4H), 4.78 (s, 2H), 4.26 (ddd, J = 9.8, 7.4, 5.2 Hz, 1H), 3.20 (s, 3H), 2.30 (t, J = 7.5 Hz, 2H), 2.06 - 1.94 (m, 1H), 1.88 (ddt, J = 14.0, 9.4, 7.3 Hz, 1H), 1.37 (s, 9H).

Reference： [1]Current Patent Assignee: GOVERNMENT OF THE UNITED STATES - WO2021/262693, 2021, A1 Location in patent: Page/Page column 87-88

88
[ 19741-14-1 ]
methyl (S)-2-amino-5-(5-amino-1,3-dioxoisoindolin-2-yl)pentanoate [ No CAS ]
methyl (S)-5-(5-amino-1,3-dioxoisoindolin-2-yl)-2-(4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)amino)benzamido)pentanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate; isobutyl chloroformate In N,N-dimethyl-formamide at 20℃; for 3.17h;	Methyl (S)-5-(5-amino-1,3-dioxoisoindolin-2-yl)-2-(4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)-amino)benzamido)pentanoate (XT19) To a suspension of acid XX9 (150 mg, 0.461 mmol) and triethylamine (1.16 mL, 8.30 mmol) in DMF (5 mL) at RT was added isobutyl chloroformate (0.061 mL, 0.461 mmol), and the reaction was stirred for 1 h. Amine XT6 (166 mg, 0.507 mmol) was added and the reaction was stirred for 1 h. More isobutyl chloroformate (0.030 mL, 0.230 mmol) was added and after 20 min more amine XT6 (83 mg, 0.254 mmol) was added. A third, and final portion of isobutyl chloroformate (0.015 mL, 0.115 mmol) was added, followed after 20 min by the addition of more XT6 (42 mg, 0.127 mmol). Despite multiple additions of chloroformate, the reaction stalled at 30% conversion. HATU (175 mg, 0.461 mmol) was added at RT for 30 min, followed by the addition of amine XT6 (166 mg, 0.507 mmol). After 30 min, the reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography (silica gel, MeOH:DCM 0:1 to 25:75) to yield aniline XT19 (294 mg, quant) as a yellow solid. MS (ESI+) calc. for C29H31N10O5+ [M+H]+ 599.25, found 599.29.
100%	With triethylamine; O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate; isobutyl chloroformate In N,N-dimethyl-formamide at 20℃; for 3.17h;	Methyl (S)-5-(5-amino-1,3-dioxoisoindolin-2-yl)-2-(4-(((2,4-diaminopteridin-6-yl)methyl)(methyl)-amino)benzamido)pentanoate (XT19) To a suspension of acid XX9 (150 mg, 0.461 mmol) and triethylamine (1.16 mL, 8.30 mmol) in DMF (5 mL) at RT was added isobutyl chloroformate (0.061 mL, 0.461 mmol), and the reaction was stirred for 1 h. Amine XT6 (166 mg, 0.507 mmol) was added and the reaction was stirred for 1 h. More isobutyl chloroformate (0.030 mL, 0.230 mmol) was added and after 20 min more amine XT6 (83 mg, 0.254 mmol) was added. A third, and final portion of isobutyl chloroformate (0.015 mL, 0.115 mmol) was added, followed after 20 min by the addition of more XT6 (42 mg, 0.127 mmol). Despite multiple additions of chloroformate, the reaction stalled at 30% conversion. HATU (175 mg, 0.461 mmol) was added at RT for 30 min, followed by the addition of amine XT6 (166 mg, 0.507 mmol). After 30 min, the reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography (silica gel, MeOH:DCM 0:1 to 25:75) to yield aniline XT19 (294 mg, quant) as a yellow solid. MS (ESI+) calc. for C29H31N10O5+ [M+H]+ 599.25, found 599.29.

Reference： [1]Current Patent Assignee: BYONDIS BV - WO2022/8419, 2022, A1 Location in patent: Page/Page column 73
[2]Current Patent Assignee: BYONDIS BV - WO2022/8419, 2022, A1 Location in patent: Page/Page column 73

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	19741-14-1	MDL No. :	MFCD00075774
Formula :	C₁₅H₁₅N₇O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LWCXZSDKANNOAR-UHFFFAOYSA-N
M.W :	325.33	Pubchem ID :	72441
Synonyms :	DAMPA

Num. heavy atoms :	24
Num. arom. heavy atoms :	16
Fraction Csp3 :	0.13
Num. rotatable bonds :	4
Num. H-bond acceptors :	6.0
Num. H-bond donors :	3.0
Molar Refractivity :	89.59
TPSA :	144.14 Å²

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-9.05 cm/s

Log Po/w (iLOGP) :	1.39
Log Po/w (XLOGP3) :	-1.08
Log Po/w (WLOGP) :	0.78
Log Po/w (MLOGP) :	0.31
Log Po/w (SILICOS-IT) :	-0.19
Consensus Log Po/w :	0.24

[ CAS No. 19741-14-1 ] {[proInfo.proName]}

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[ 19741-14-1 ] Synthesis Path-Downstream 1~88

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Lipinski :	0.0
Ghose :	None
Veber :	1.0
Egan :	1.0
Muegge :	0.0
Bioavailability Score :	0.56

Log S (ESOL) :	-1.41
Solubility :	12.8 mg/ml ; 0.0393 mol/l
Class :	Very soluble
Log S (Ali) :	-1.46
Solubility :	11.3 mg/ml ; 0.0349 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.86
Solubility :	0.0448 mg/ml ; 0.000138 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.61

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P280-P301+P312-P302+P352-P305+P351+P338	UN#:
Hazard Statements:	H302-H315-H319-H335	Packing Group:
GHS Pictogram:

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P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
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P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
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P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

[ CAS No. 19741-14-1 ] {[proInfo.proName]}

Quality Control of [ 19741-14-1 ]

Related Doc. of [ 19741-14-1 ]

Product Details of [ 19741-14-1 ]

Calculated chemistry of [ 19741-14-1 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 19741-14-1 ]

Application In Synthesis of [ 19741-14-1 ]

[ 19741-14-1 ] Synthesis Path-Upstream 1~1

[ 19741-14-1 ] Synthesis Path-Downstream 1~88

Similar Product of [ 19741-14-1 ]

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Similar Product of
[ 19741-14-1 ]