Name: 662116-67-8|4,5-Dichloro-3-nitropyridin-2-amine|95%
Brand: Ambeed
SKU: A127704
Rating: 97 (29 reviews)

1
[ 662116-67-8 ]
[ 1007126-18-2 ]
[ 1007125-91-8 ]

Yield	Reaction Conditions	Operation in experiment
82%	With N-ethyl-N,N-diisopropylamine In ethanol	78.a A solution of 4,5-dichloro-3-nitropyridin-2-amine (0.0365 g, 0.000175 mol) (Johansson, H; Lawitz, K; Nikitidis, G; Sjoe, P; Storm, P. PCT Int. Application WO2004/01661-1), (1R,3S,4S)-3-[tert-butyl(dimethyl)silyl]oxy}-4-([tert-butyl(dimethyl)silyl]-oxy}methyl)cyclopentanamine (0.0947 g, 0.000263 mol) and DIPEA (0.0907 g, 0.000702 mol) in ethanol (10.0 mL) was refluxed overnight. The reaction was concentrated and purified by flash chromatography (30% EtOAc/hexanes) to afford the title compound (0.0768 g, 82%) as a yellow solid.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2008/51404, 2008, A1 Location in patent: Page/Page column 110

2
[ 662116-67-8 ]
[ 662116-66-7 ]

Yield	Reaction Conditions	Operation in experiment
92%	With hydrogenchloride; iron In methanol; ethanol; water at 80℃; for 1.5h;	INTERMEDIATE 4 4,5-Dichloropyridine-2,3-diamine INTERMEDIATE 4 4,5-Dichloropyridine-2,3-diamine To a mixture of 4,5-dichloro-3-nitropyridine-2-amine (INTERMEDIATE 3, 1.00 g, 4.81 mmol) in EtOH (15 mL), water (1 mL) and MeOH (2 mL) was added Fe(s) (1.47 g, 26.3 mmol, 5.46 equiv.) and cone. HC1 (3 drops). The mixture was stirred at 80 °C. LCMS indicated total conversion to the title product after 90 min. The mixture was allowed to cool to room temperature and aqueous 15% NaOH (6 drops) was added and the mixture was stirred for 15 minutes and then centrifuged resulting in a clear solution. The supernatant was collected and the solid centrifugate was washed with MeOH (10 mL) and centrifuged. The combined supernatants were filtered through a 0.45 μ filter and the filtrate was evaporated to furnish 790 mg (92%) of title product as beige solid. 1H NMR (600 MHz, CD3OD) δ ppm 7.40 (s, 1 1 H). MS (ESI+) m/z 178, 180 [M+H]+ chlorine isotopic pattern.
82%	With water; iron; ammonium chloride In methanol at 20℃;
67%	With calcium chloride; zinc In ethanol; water for 1h; Heating / reflux;	206.a a) 2, 3-Diamino-4, 5-dichloropvridine 2-Amino-4, 5-dichloro-3-nitropyridine (Example 206b) (1.04 g, 5.0 mmol), zinc powder (2.4 g, 37 mmol) and anhydrous calcium chloride (3 g, 27 mmol) were mixed in 95% ethanol (30 [ML)] and heated to reflux for 1 h. When cool, the reaction mixture was filtered through celite and evaporated in vacuo. The residue was dissolved in methanol/dichloromethane 1 : 1 and chromatographed through a short column of silica (10 g) eiuting with [METHANOL/DICHLOROMETHANE] 3: 7. The fraction containing the product was concentrated in vacuo and the residue dissolved in methanol/acetonitrile 1: 9 and again concentrated in vacuo together with silica. The product thus adsorbed on silica gel was again subjected to chromatography on silica gel (EtOAc) to afford the pure product as a off-white powder (0.60 g, 67%). APCI-MS [M/Z :. 178. 1,] 180.2 [MH+]. H-NMR (400 MHz, [DMSO-D6)] : [8] 7.36 (s, 1H), 5.95 (s, 2H), 5.27 (s, 2H).

57.5%	With acetic acid; zinc at 20℃; for 3.33333h;	30 To a solution of 4,5-dichloro-3-nitropyridin-2-amine (300 mg, 1.44 mmol) in 5 mL AcOH was added portionwise zinc dust (472 mg, 7.2 mmol) over 20 min. After addition, the mixture was stirred for another 3 h then added dropwise to 100 mL saturated Na2CO3 and extracted with ethyl acetate. The combined extracts were washed with brine, dried, evaporated and purified by column chromatography to give 4,5-dichloropyridine-2,3-diamine (148 mg, 57.5%).
	reduction;
	With ethanol; calcium chloride; zinc at 100℃; for 1h;	67.d Synthesis of 4,5-dichloropyridin-2,3-diamine 4,5-Dichloro-3-nitropyridin-2-amine (548.0 mg, 2.63 mmol), Zn powder (1274.0 mg, 19.50 mmol) and anhydrous CaCl2 (1578.0 mg, 14.20 mmol) were added to 95% of EtOH (20.0 mL), and the mixture was stirred at 100° C. for one hour. The reaction mixture was filtered through celite, and evaporated under reduced pressure to obtain brown solid compound of 4,5-dichloropyridin-2,3-diamine. [0874] LCMS ESI (+): 178 (M+1), 180 (M+3), 182 (M+5)

Reference： [1]Current Patent Assignee: KANCERA AB - WO2016/124553, 2016, A1 Location in patent: Page/Page column 72-73
[2]Vasbinder, Melissa M.; Alimzhanov, Marat; Augustin, Martin; Bebernitz, Geraldine; Bell, Kirsten; Chuaqui, Claudio; Deegan, Tracy; Ferguson, Andrew D.; Goodwin, Kelly; Huszar, Dennis; Kawatkar, Aarti; Kawatkar, Sameer; Read, Jon; Shi, Jie; Steinbacher, Stefan; Steuber, Holger; Su, Qibin; Toader, Dorin; Wang, Haixia; Woessner, Richard; Wu, Allan; Ye, Minwei; Zinda, Michael [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 1, p. 60 - 67]
[3]Current Patent Assignee: ASTRAZENECA PLC - WO2004/16611, 2004, A1 Location in patent: Page 97
[4]Xie, Dongsheng; Lu, Jun; Xie, Jin; Cui, Junjun; Li, Teng-Fei; Wang, Yan-Chao; Chen, Yuan; Gong, Nian; Li, Xin-Yan; Fu, Lei; Wang, Yong-Xiang [European Journal of Medicinal Chemistry, 2016, vol. 117, p. 19 - 32]
[5]Bavetsias, Vassilios; Sun, Chongbo; Bouloc, Nathalie; Reynisson, Johannes; Workman, Paul; Linardopoulos, Spiros; McDonald, Edward [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 23, p. 6567 - 6571]
[6]Current Patent Assignee: JW PHARMACEUTICAL CO LTD - US2014/315888, 2014, A1 Location in patent: Paragraph 0873-0874

3
[ 188577-71-1 ]
[ 662116-67-8 ]

Yield	Reaction Conditions	Operation in experiment
53%	With sulfuric acid; nitric acid In water at 35℃; for 2.5h; Acidic aqueous solution;	206.b b) 2-Amino-4, [5-DICHLORO-3-NITROPYRIDINE N- (4, 5-DICHLOROPYRIDIN-2-YL)-2, 2-DIMETHYLPROPANAMIDEL] (72.0 g, 0.29 mol) was dissolved during) h in conc. sulfuric acid (400 ml) and cooled to 10 °C. To this solution, nitric acid (d= 1.52, 12 ml, 0.29 mol) diluted with [CONC.] sulfuric acid (15 ml) was added dropwise (10 min) while keeping the temperature below 14 [°C.] When the addition was complete, the cooling bath was exchanged for an oil bath and the reaction mixture was heated to 35 °C [UNTIL AT) STARTING] material had been consumed (2.5 h) as judged by LC/MS. The reaction mixture was then poured into a vigorously stirred mixture of ice and water (4.5 kg in total) causing a yellow precipitate to form. This solid was collected by filtration and washed with water until the washing liquid tested neutral (10 x 300 ml). The crude product was dried in vacuo to afford 53.2 g (75% purity, HPLC). Recrystallization from ethanol/water gave large dark brown needles (32.2 g, [53%)] of the pure product. [ES-MS M/ : 208. 0, 210.] 1 [[MH+].] H-NMR (400 MHz, [DMSO-D6)] : [8] 8.37 (s, [1H),] 7. 39 (s, 2H).
40%	With sulfuric acid; nitric acid at 65 - 100℃; for 1h;	1.3 Ste 3) Preparation of 2-amino-4,5-dichloro-3-nitropyridine The compound obtained in Step 2 (6.3 g, 0.025 mol) was dissolved in concentrated sulfuric acid (100 mL) at 100°C, and 60~62% nitric acid (2.4 mL) was added dropwise, followed by stirring for 1 hour at 65~70°C. The reaction solution was cooled to 0°C, and the pH value was adjusted to 7.0 using a 2 N aqueous solution of sodium chloride to obtain a solid, which was then subjected to stirring for 2 hours. The solid obtained was filtered under reduced pressure, washed with distilled water and dried to obtain the title compound (2.08 g, yield: 40%). 1H-NMR(300 MHz, DMSO-d6) δ 7.35 (s, 2H), 8.37 (s, 1H)
32%	With sulfuric acid; nitric acid In water at 20℃; for 2.5h;	67.c Synthesis of 4,5-dichloro-3-nitropyridin-2-amine N-(4,5-Dichloropyridin-2-yl)pivalamide (1990.0 mg, 8.05 mmol) was slowly added to and dissolved in conc. H2SO4 (11.0 mL) at 10° C., and then conc. HNO3/conc. H2SO4 (332.0 μL/415.0 μL) was slowly added thereto. The reaction mixture was stirred at room temperature for 2.5 hours, poured into ice water, alkalized with 1N NaOH aqueous solution (pH=9) and then extracted with EtOAc (200.0 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and then distilled under reduced pressure. The residue was purified by column chromatography (n-Hex:EtOAc=90:10 to 80:20) on silica. The fractions containing the product were collected and evaporated to obtain yellow solid compound of 4,5-dichloro-3-nitropyridin-2-amine (548.0 mg, 32%). [0872] LCMS ESI (+): 208 (M+1), 210 (M+3), 212 (M+5)

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2004/16611, 2004, A1 Location in patent: Page 97-98
[2]Current Patent Assignee: HANMI PHARM CO LTD - WO2013/100631, 2013, A1 Location in patent: Page/Page column 13; 15
[3]Current Patent Assignee: JW PHARMACEUTICAL CO LTD - US2014/315888, 2014, A1 Location in patent: Paragraph 0871-0872

4
[ 662116-67-8 ]
[ 173341-02-1 ]
[ 1034769-99-7 ]

Yield	Reaction Conditions	Operation in experiment
84%	In butan-1-ol; at 120℃; for 1.5h;Microwave irradiation;	Synthesis 21-1 -A; te/t-Butyl (4-(2-amino-5-chloro-3-nitropyridin-4-yl)morpholin-2-yl)methylcarbamate; A solution of morpholin-2-ylmethyl-carbamic acid tert-butyl ester (0.155 g, 0.72 mmol) and 2-amino-4,5 dichloro-3-nitropyridine (0.150 g, 0.72 mmol) in n-butanol (2.2 mL) was heated at 120C for 90 minutes in a microwave reactor. The solvent was removed in vacuo and the crude mixture was purified by flash chromatography on silica, eluting with ethyl acetate-petroleum ether (1:1), to give the title compound as a yellow solid (0.237 g, 84%). <n="116"/>LC-MS (2) -R, 4.66 min; m/z (ESI) 288 [MH+].

Reference： [1]Patent: WO2008/75007,2008,A1 .Location in patent: Page/Page column 114-115

5
[ 662116-67-8 ]
[ 880361-73-9 ]
[ 942950-70-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 65℃; for 17h;	172 5-Chloro-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine tert-Butyl 4-((2-methylthiazol-4-yl)methyl)piperazine-1-carboxylate (0.380 g, 1.28 mmol, 1.1 eq) was dissolved in DCM (4 mL) and the mixture cooled in a ice-water bath before the dropwise addition of TFA (4 mL). Stirring was continued at this temperature for 1 h. Solvents were removed in vacuo and the resulting crude material was azeotroped with toluene and dried. 2-Methyl-4-(piperazin-1-ylmethyl)thiazole (supposedly 0.250 g, 1.28 mmol, 1.1 eq) was suspended in iPrOH (3.9 mL) and DIPEA (1 mL). To this solution, the 4,5-dichloro-3-nitropyridin-2-amine (0.240 g, 1.16 mmol, 1 eq) was added and the mixture heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.210 g, 44%); 1H-NMR (500 MHz, DMSO-d6): δ 2.52-2.59 (m, 4H, piperazine N(CH2)2), 2.63 (s, 3H, thiazole Me), 3.06 (m, 4H, piperazine N(CH2)2), 3.59 (s, 2H, NCH2), 6.94 (s, 2H, NH2), 7.28 (s, 1H, thiazole 5-H), 8.05 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): R=2.06 min-369/371 [(M+H)+, Cl isotopic pattern].
	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 65℃; for 17h;	17 Example 175-Chloro-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine te/t-Butyl 4-((2-methylthiazol-4-yl)methyl)piperazine-1-carboxylate (prepared as described in example 144 of PCT/GB2006/004854, 0.24 g, 0.79 mmol) was suspended in DCM (2.4 mL) and the mixture cooled in an ice bath. TFA (0.75 mL) was added and the resulting solution was allowed to warm up to room temperature and stirred for 2 h. The resulting 2-methyl-4-(piperazin-1-ylmethyl)thiazole ( supposedly 0.20 g, 0.79 mmol, 1.1 eq) was suspended in 1PrOH (2.4 mL) and DIPEA (0.6 mL). To this solution, 4,5-dichloro-3-nitropyridin-2-amine (0.150 g, 0.72 mmol, 1 eq) was added and the mixture heated and stirred for 17 h at 65°C. The mixture was filtered, washed with 1PrOH (3 x 3 mL), cold H2O (3 x 3 mL), Et2O (2 x 3 mL), and dried to give the title compound (0.17 g, 60%); 1H-NMR (500 MHz, DMSO-Cf6): δ 2.51-2.59 (m, 4H, piperazine N(CH2)2), 3.06 (t, 4H, J = 4.3, piperazine N(CH2J2), 3.59 (s, 2H, NCH2), 6.94 (brs, 2H, NH2), 7.28 (s, 1H. thiazole 5-H), 8.05 (s, 1H, pyridine 6- H); LC (Method B) - MS (ESI, m/z): Rt = 2.00 min - 369/371 [(M+H+), Cl isotopic pattern, 100%].

Reference： [1]Current Patent Assignee: UNIVERSITY OF LONDON - US2009/247507, 2009, A1 Location in patent: Page/Page column 96
[2]Current Patent Assignee: CHROMA THERAPEUTICS LIMITED - WO2009/1021, 2008, A1 Location in patent: Page/Page column 30-31

6
[ 82534-54-1 ]
[ 662116-67-8 ]
[ 1095380-82-7 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 65℃; for 17.0h;	The resulting <strong>[82534-54-1]1-(cyclobutylmethyl)piperazine</strong> (supposedly 0.057 g, 0.37 mmol, 1.1 eq) was suspended in 'PrOH (0.37 mL) and DIPEA (0.19 mL). To this solution, 4,5- <n="11"/>dichloro-3-nitropyridin-2-amine (0.07 g, 0.34 mmol, 1 eq) was added and the reaction mixture was heated and stirred for 17 h at 650C. The mixture was filtered, washed with 1PrOH (3 x 3 mL), Et2O (2 x 3 mL), and dried to give the title compound as a bright yellow powder (0.045 g, 37%); 1H-NMR (500 MHz, DMSO-Cf6): delta 1.58-1.71 (m, 2H), 1.74-1.92 (m, 2H), 1.95-2.07 (m, 2H), 2.37 (d, J = 7.0 Hz, 2H, NCH2), 2.41-2.54 (m, 5H), 2.97-3.10 (m, 4H), 6.93 (s, 2H, NH2), 8.05 (s, 1 H, pyridine 6-H); LC (Method B) - MS (ESI, m/z): Rt = 1.90 min - 326/328 [(M+H+), Br isotopic pattern, 100%].

Reference： [1]Patent: WO2009/1021,2008,A1 .Location in patent: Page/Page column 9-10

7
[ 662116-67-8 ]
2-(piperazin-1-yl)-N-(thiazol-2-yl)acetamide dihydrochloride [ No CAS ]
[ 942947-92-4 ]

Yield	Reaction Conditions	Operation in experiment
80%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 45℃; for 17h;
80%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 45℃; for 17h;	34 Example 342-(4-(2-Amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)-/V-(thiazol-2-yl)acetamide2-(Piperazin-1-yl)-λ/-(thiazol-2-yl)acetamide X 2HCI salt (0.209 g, 0.70 mmol) was suspended in iPrOH (12 ml_) and diisopropylethylamine (0.295 g, 2.30 mmol). To this solution, 4,5-dichloro-3-nitropyridin-2-amine (0.130 g, 0.63 mmol) was added and the mixture heated and stirred for 17 h at 45°C. The mixture was then allowed to cool to room temperature, diluted with isopropanol (10 ml_), filtered, washed with 'PrOH (3 x 3 ml_), and Et2O (2 x 5 ml_), and dried to give the title compound (0.200 g, 80%); 1H-NMR (500 MHz, DMSO-c/6): δ 2.60-2.71 (m, 4H, piperazine N(CH2J2), 3.03-3.14 (m, 4H, piperazine N(CH2J2), 3.38 (s, 2H, NCH2CO), 6.95 (brs, 2H, NH2), 7.22 (d, 1H, J = 3.5 Hz), 7.47 (d, 1 H, J = 3.5 Hz) (thiazole 4-H and thiazole 5-H), 8.07 (s, 1H, pyridine 6-H)1 11.90 (br s, 1 H, CONH); LC (Method B) - MS (ESI, m/z): Rt = 3.01 min - 398/400 [(M+H+), Cl isotopic pattern, 100%].

Reference： [1]Location in patent: experimental part Bavetsias, Vassilios; Large, Jonathan M.; Sun, Chongbo; Bouloc, Nathalie; Kosmopoulou, Magda; Matteucci, Mizio; Wilsher, Nicola E.; Martins, Vanessa; Reynisson, Jóhannes; Atrash, Butrus; Faisal, Amir; Urban, Frederique; Valenti, Melanie; De Haven Brandon, Alexis; Box, Gary; Raynaud, Florence I.; Workman, Paul; Eccles, Suzanne A.; Bayliss, Richard; Blagg, Julian; Linardopoulos, Spiros; McDonald, Edward [Journal of Medicinal Chemistry, 2010, vol. 53, # 14, p. 5213 - 5228]
[2]Current Patent Assignee: CHROMA THERAPEUTICS LIMITED - WO2009/1021, 2008, A1 Location in patent: Page/Page column 53

8
[ 662116-67-8 ]
[ 1095380-87-2 ]
[ 1095381-06-8 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 65℃; for 17h;	8 5-Chloro-4-(4-((5-fluoropyridin-3-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine te/t-Butyl 4-((5-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (0.12 g, 0.42 mmol, 1.1 eq) was dissolved in DCM (1 mL) and the mixture cooled in a ice-water bath before the dropwise addition of TFA (0.5 mL). Stirring was continued at this temperature for 1 h and the solvents were removed in vacuo. The resulting crude material was azeotroped with toluene and dried. The resulting 1-((5-fluoropyridin-3- yl)methyl)piperazine (supposedly 0.082 g, 0.42 mmol, 1 eq) was suspended in 1PrOH (0.4 mL) and DIPEA (0.15 mL). To this solution, the 4,5-dichloro-3-nitropyridin- 2-amine (0.08 g, 0.38 mmol, 1.0 eq) was added, and the mixture heated and stirred for 17 h at 65°C. The mixture was filtered, washed with 1PrOH (3 x 3 mL), cold H2O (3 x 3 mL), Et2O (2 x 3 mL) and dried to give the title compound as a bright yellow solid (0.122 g, 44%); LC (Method B) - MS (ESI, m/z): Rt = 2.30 min - 367/369 [(M+H)+, Cl isotopic pattern, 100%].

Reference： [1]Current Patent Assignee: CHROMA THERAPEUTICS LIMITED - WO2009/1021, 2008, A1 Location in patent: Page/Page column 18-19

9
[ 662116-67-8 ]
[ 1095381-14-8 ]
[ 1095381-13-7 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 65℃; for 17h;	10 1-((6-(Trifluoromethyl)pyridin-3-yl)methyl)piperazine (supposedly 0.261 g, 1.06 mmol, 1.1 eq) was suspended in 1PrOH (3.2 ml_) and DIPEA (0.8 ml_). To this solution, 4,5- dichloro-3-nitropyridin-2-amine (0.20 g, 0.96 mmol, 1 eq) was added and the mixture heated and stirred for 17 h at 65°C. The mixture was filtered, washed with 1PrOH (3 x 3 mL), cold H2O (3 x 3 ml_), Et2O (2 x 3 mL), and dried to give the title compound (0.308 g, 70%); 1H-NMR (500 MHz, DMSO-d6): δ 2.50-2.62 (m, 4H, piperazine N(CH2)2), 3.02-3.14 (m, 4H, piperazine N(CH2J2), 3.70 (s, 2H, NCH2), 6.96 (brs, 2H, NH2), 7.88 (d, J = 8.0 Hz, 1 H, CF3py-H), 8.04 (d, J = 8.0 Hz, 1 H. CF3py-H), 8.06 (s, 1 H, chloropyridine 6-H), 8.72 (s, 1 H, CF3py-H) ; LC (Method B) - MS (ESI, m/z): Rt = 3.22 min - 417/419 [(M+H+), Cl isotopic pattern, 100%].

Reference： [1]Current Patent Assignee: CHROMA THERAPEUTICS LIMITED - WO2009/1021, 2008, A1 Location in patent: Page/Page column 23

10
[ 662116-67-8 ]
[ 23145-88-2 ]
[ 942948-56-3 ]

Yield	Reaction Conditions	Operation in experiment
77%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 45℃; for 18h;	1 5-Chloro-4-(4-(4-chlorobenzyl)piperazin-1-yl)-3-nitropyridin-2-amine [00119] To a mixture of 2-amino-4,5-dichloro-3-nitropyridine (0.152 g, 0.73 mmol) and isopropanol (22 mL) was added 1 -(4-chlorobenzyl)piperazine (0.165 g, 0.78 mmol) followed by diisopropylethylamine (0.17 mL, 0.97 mmol). The reaction mixture was heated at 45 °C for 18 h, then allowed to cool to room temperature, and diluted with isopropanol (5 mL). The precipitate was collected by filtration, washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.215 g, 77%); 1H-NMR (500 MHz, DMSO-d6) 2.48 (br s, obscured by DMSO peak, 4H, piperazine C-H), 3.06 (br t, J = 4.3 Hz, 4H, piperazine C-H), 3.52 (s, 2H, NCH2C6H4CI), 6.95 (s, 2H, NH2), 7.35 (d, J = 8.5 Hz, 2H) and 7.38 (d, J = 8.5 Hz, 2H) (3,5-ArH and 2,6- ArH), 8.06 (s, 1 H, 6-H); LC - MS (ESI, m/z): Rt = 1 .70 min - 382, 384, 386 [(M+H)+, Cl2 isotopic pattern].
77%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 45℃; for 18h;
50%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 45℃; for 18h;	37 5-Chloro-4-(4-(4-chlorobenzyl)piperazin-1-yl)-3-nitropyridin-2-amine To a mixture of 2-amino-4,5-dichloro-3-nitropyridine (0.038 g, 0.18 mmol) and isopropanol (3 ml) was added 1-(4-chlorobenzyl)piperazine (0.042 g, 0.20 mmol) with the aid of isopropanol (0.5 ml) followed by diisopropylethylamine (0.035 ml, 0.20 mmol). The reaction mixture was heated at 45° C. for 18 h, then allowed to cool to room temperature, and diluted with isopropanol (4 ml). The precipitate was collected by filtration, washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.034 g, 50%); 1H-NMR (500 MHz, DMSO-d6) 2.48 (br s, obscured by DMSO peak, 4H, piperazine N(CH2)2), 3.06 (br s, 4H, piperazine N(CH2)2), 3.52 (s, 2H, NCH2), 6.95 (s, 2H, NH2), 7.35 (d, J=8.50 Hz, 2H) and 7.38 (d, J=8.55 Hz, 2H) (3,5-ArH and 2,6-ArH), 8.06 (s, 1H, 6-H);LC (Method B)-MS (ESI, m/z): Rt=2.89 min-382, 384, 386 [(M+H)+, Cl2 isotopic pattern].

Reference： [1]Current Patent Assignee: THE INSTITUTE OF CANCER RESEARCH ROYAL CANCER HOSPITAL GB - WO2013/190319, 2013, A1 Location in patent: Paragraph 00119
[2]Bavetsias, Vassilios; Crumpler, Simon; Sun, Chongbo; Avery, Sian; Atrash, Butrus; Faisal, Amir; Moore, Andrew S.; Brown, Nathan; Sheldrake, Peter W.; Bush, Katherine; Henley, Alan; Box, Gary; Valenti, Melanie; De Haven Brandon, Alexis; Raynaud, Florence I.; Workman, Paul; Eccles, Suzanne A.; Linardopoulos, Spiros; Blagg, Julian; Kosmopoulou, Magda; Bayliss, Richard [Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8721 - 8734,14]
[3]Current Patent Assignee: UNIVERSITY OF LONDON - US2009/247507, 2009, A1 Location in patent: Page/Page column 28

11
[ 188577-68-6 ]
[ 662116-67-8 ]

Yield	Reaction Conditions	Operation in experiment
62.6%		To 30 mL 98% H2SO4 was added portionwise <strong>[188577-68-6]4,5-dichloropyridin-2-amine</strong> (1.0 g, 6.13 mmol) at -5 C. After the solid material was completely dissolved, 3.7 mL fuming HNO3 was added dropwise over 5 min maintaining internal temperature ?0 C. The mixture was allowed to warm to 50 C over 2 h, and then stirred for another 1 h at this temperature before poured onto 150 g crushed ice. The aqueous solution was basified to pH = 7.3 with ammonia and extracted with ethyl acetate. The combined extracts were dried, concentrated and purified by column chromatography to give 4,5-dichloro-3-nitropyridin-2-amine (0.80 g, 62.6%).
26%	With sulfuric acid; nitric acid; In water; at 0 - 55℃; for 1.11667h;Cooling with ice-bath;	To a 50 ml round-bottomed flask containing <strong>[188577-68-6]2-amino-4,5-dichloropyridine</strong> (0.275 g, 1.65 mmol) and cooled into an ice-bath was added conc. H2SO4 (2.79 g). The reaction mixture was stirred for 3 min and then HNO3 (70%; 0.186 g) was dropwise added. The reaction mixture was stirred at 0 C. (ice-bath) for 7 min, then heated to 55 C. and stirred at this temperature for 1 h, allowed to cool to room temperature, diluted with ice-water (15 ml) and the pH was adjusted to 7.5 with 10% aqueous NaOH. The yellow precipitate was collected by filtration, washed with water and dried in vacuo over P2O5, then absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column. Elution with 2% ethyl acetate in dichloromethane afforded the title compound as a yellow solid (0.090 g, 26%); 1H-NMR (250 Mz, DMSO-d6) 7.39 (s, 2H, NH2), 8.39 (s, 1H, 6-H); LC-MS (ESI, m/z) 6.54 min-208, 210, 212 [(M+H)+, Cl2 isotopic pattern].
11.7 g		INTERMEDIATE 2 4,5-Dichloro- V-nitropyridine-2-amine 4,5-Dichloropyridin-2-amine (INTERMEDIATE 1, 45.2 g, 283.0 mmol) was added to 270 mL of ice cold cone. H2SO4, in small portions over ca 20 min. When dissolved, cone. HNO3 (22 g) was added dropwise and the mixture was stirred at ca 5 C for 3.5 h. LCMS indicated total conversion to expected product. The cold mixture was poured on crushed ice/water mixture (3 L), stirred for ca 5 min and then filtered. The solid was collected and slurried in ice cold water (500 mL) and filtered. The procedure was repeated until neutral pH. When semi dry on the filter, the solid was dissolved in EtOAc (ca. 3 L) , washed with brine (ca. 100 mL) and the organic layer was dried with Na2S04, filtered, and evaporated to furnish 46.2 g (78%) of 97% pure title product as beige-orange solid. 1H NMR (600 MHz, CD3OD) delta ppm 8.47 (s, 1 H) 8.08 (s, 1 H). MS: (ESI+) m/z 208, 210, 212 [M+H]+, di-chlorine isotopic pattern. INTERMEDIATE 3 4,5-Dichloro-3-nitropyridine-2-amine 4,5-Dichloro-N-nitropyridin-2-amine (INTERMEDIATE 2, 20.0 g, 96.2 mmol) was added to 200 mL of cone. H2S04 at room temperature. After stirring at 40 C for 2.5 h the mixture was cooled to below room temperature and poured onto crushed ice (2 L) while stirring. After the ice had melted, the volume was adjusted to ca. 2 L with ice cold water and the yellow precipitate was collected by filtration and washed with ice cold water until neutral pH (3 x 250 mL). The solid was allowed to semi-dry on the filter and was then dissolved in EtOAc (ca. 800 mL). The organic phase was washed with 0.25 M NaOH (3x30 mL), water (3x15 mL) and brine (15 mL), dried (Na2S04), filtered and the solvent evaporated to furnish 11.7 g (59%) of 99% pure title product as yellow solid. 1H NMR (600 MHz, CD3OD) delta ppm 8.26 (s, 1 H). MS: (ESI+) m/z 208, 210, 212 [M+H]+ chlorine isotopic pattern.

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 117,p. 19 - 32
[2]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 60 - 67
[3]Patent: US2009/247507,2009,A1 .Location in patent: Page/Page column 7
[4]Journal of Medicinal Chemistry,2010,vol. 53,p. 5213 - 5228
[5]Patent: WO2016/124553,2016,A1 .Location in patent: Page/Page column 72
[6]Patent: WO2018/11138,2018,A1

12
[ 662116-67-8 ]
[ 39244-80-9 ]
[ 942949-32-8 ]

Yield	Reaction Conditions	Operation in experiment
75%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 45℃; for 20.0h;	To a mixture of 2-amino-4,5-dichloro-3-nitropyridine (0.030 g, 0.14 mmol) and isopropanol (3.0 ml) was added 1-[(3-pyridyl)-methyl)-piperazine (0.028 g, 0.16 mmol) followed by diisopropylethylamine (0.03 ml, 0.18 mmol). The reaction mixture was heated at 45 C. for 20 h, then allowed to cool to room temperature, and diluted with isopropanol (2.5 ml). The precipitate was collected by filtration and washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.036 g, 75%); 1H-NMR (500 MHz, DMSO-d6) 3.06 (br t, 4H, piperazine N(CH2)2), 3.57 (s, 2H, NCH2pyridyl), 6.95 (s, 2H, NH2), 7.36 (dd, J=7.8, 5.4 Hz, 1H, pyridine 5-H), 7.73 (dt, J=7.8, 1.8 Hz, 1H, pyridine 4-H), 8.07 (s, 1H, 6-H), 8.47 (dd, J=4.8, 1.6 Hz, 1H, pyridine 6-H), 8.51 (d, J=1.7 Hz, 1H, pyridine 2-H);LC (Method B)-MS (ESI, m/z) Rt=1.77 min-349, 351 [(M+H)+, Cl isotopic pattern].

Reference： [1]Patent: US2009/247507,2009,A1 .Location in patent: Page/Page column 50

13
1-(2-chloro-6-fluorobenzyl)piperazine [ No CAS ]
[ 662116-67-8 ]
[ 942948-16-5 ]

Yield	Reaction Conditions	Operation in experiment
62%	In isopropyl alcohol at 45℃; for 22h;	16 5-Chloro-4-(4-(2-chloro-6-fluorobenzyl)piperazin-1-yl)-3-nitropyridin-2-amine A mixture of 1-(2-chloro-6-fluorobenzyl)piperazine (0.063 g, 0.28 mmol), isopropanol (4.3 ml), and 2-amino-4,5-dichloro-3-nitropyridine (0.042 g, 0.20 mmol) was heated at 45° C. for 22 h. The reaction mixture was allowed to cool to room temperature, and concentrated in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted first with 30% petroleum ether 60-80° C., and then ethyl acetate. The title compound was obtained as a yellow solid (0.050 g, 62%); 1H-NMR (500 Mz, DMSO-d6) 2.56 (br s, 4H, piperazine N(CH2)2), 3.01 (br s, 4H, piperazine N(CH2)2), 3.66 (s, 2H, NCH2), 6.94 (s, 2H, 2-NH2), 7.23 (t, J=8.91 Hz, 1H) and 7.38 (m, 2H) (ArH), 8.06 (s, 1H, 6-H); LC-MS (ESI, m/z) 4.85 min-400, 402, 404 [(M+H)+, Cl2 isotopic pattern].

Reference： [1]Current Patent Assignee: UNIVERSITY OF LONDON - US2009/247507, 2009, A1 Location in patent: Page/Page column 15

14
[ 662116-67-8 ]
[ 268550-76-1 ]
[ 942949-34-0 ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: 4-[(5-methylisoxazol-3-yl)methyl]piperazine-1-carboxylic acid tert-butyl ester With trifluoroacetic acid In dichloromethane at 20℃; for 1.5h; Stage #2: 4,5-dichloro-3-nitropyridin-2-ylamine With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 45℃; for 20h;	80 5-Chloro-4-[4-(5-methyl-isoxazol-3-ylmethyl)-piperazin-1-yl]-3-nitro-pyridin-2-ylamine A solution of 4-(5-methyl-isoxazol-3-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.126 g, 0.45 mmol) in dichloromethane (3.7 ml) and TFA (5 ml) was stirred at room temperature for 1.5 h then concentrated in vacuo, and the resulting residue was dried in vacuo. Part of this material (estimated 0.15 mmol) was dissolved in isopropanol (3 ml) and to this solution 2-amino-4,5-dichloro-3-nitropyridine (0.031 g, 0.15 mmol) was added followed by diisopropylethylamine (0.15 ml, 0.80 mmol). The reaction mixture was stirred at 45° C. for 20 h, then allowed to cool to room temperature and diluted with isopropanol (3 ml). The resulting yellow precipitate was collected by filtration, washed with isopropanol (2×3 ml), diethyl ether (2×3 ml), and dried (0.038 g, 73%); 1H-NMR (500 MHz, DMSO-d6) 2.38 (s, 3H, isoxazole 5-CH3), 2.52 (br s 4H, piperazine N(CH2)2), 3.06 (br t, J=4.1 Hz, 4H, piperazine N(CH2)2), 3.56 (s, 2H, NCH2 isoxale), 6.21 (s, 1H, isoxazole 4-H), 6.96 (s, 2H, NH2), 8.06 (s, 1H, pyridine 6-H);LC (Method B)-MS (ESI, m/z): Rt=2.49 min-353, 355 [(M+H)+, Cl isotopic pattern].

Reference： [1]Current Patent Assignee: UNIVERSITY OF LONDON - US2009/247507, 2009, A1 Location in patent: Page/Page column 51

15
[ 662116-67-8 ]
[ 5321-49-3 ]
[ 942950-75-6 ]

Yield	Reaction Conditions	Operation in experiment
64%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 65℃;	176 5-Chloro-3-nitro-4-(4-phenethylpiperazin-1-yl)pyridin-2-amine 1-Phenethylpiperazine (0.100 g, 0.52 mmol, 1.1 eq) was suspended in iPrOH (1 mL). DIPEA (0.13 mL, 0.79 mmol, 1.5 eq) was added followed by 4,5-dichloro-3-nitropyridin-2-amine (0.099 g, 0.48 mmol, 1 eq). The mixture was heated and stirred at 65° C. overnight. The mixture was cooled to room temperature and filtered. The bright yellow solid was washed with iPrOH (3×2 mL), Et2O (2×2 mL) and dried to give the title compound as a bright yellow solid (0.112 g, 64%); 1H-NMR (500 MHz, DMSO-d6): δ 2.53-2.63 (m, 6H), 2.71-2.78 (m, 2H), 3.06 (m, 4H, piperazine N(CH2)2), 6.95 (s, 2H, NH2), 7.15-7.21 (m, 1H), 7.22-7.31 (m, 4H), 8.06 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): Rt=2.31 min-362/364 [(M+H)+, Cl isotopic pattern].

Reference： [1]Current Patent Assignee: UNIVERSITY OF LONDON - US2009/247507, 2009, A1 Location in patent: Page/Page column 98

16
[ 662116-67-8 ]
[ 62089-74-1 ]
[ 942948-52-9 ]

Yield	Reaction Conditions	Operation in experiment
81%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 45℃; for 24h;	To a mixture of 2-amino-4,5-dichloro-3-nitropyridine (0.052 g, 0.25 mmol) and isopropanol (4.5 ml) was added <strong>[62089-74-1]1-[(4-pyridyl)-methyl]-piperazine</strong> (0.049 g, 0.28 mmol) followed by diisopropylethylamine (0.05 ml, 0.28 mmol). The reaction mixture was heated at 45 C. for 24 h, then allowed to cool to room temperature, and diluted with isopropanol (3 ml). The precipitate was collected by filtration and washed with isopropanol and diethyl ether. The title compound was thus obtained as yellow solid (0.035 g). The filtrate was concentrated in vacuo, and purification of the residue on a isolute silica column using 0 to 5% methanol in ethyl acetate/dichloromethane (v/v; 1:1) as eluant gave an additional 0.036 g of the product (total yield: 81%); 1H-NMR (500 MHz, DMSO-d6) 3.09 (br s, 4H, piperazine N(CH2)2), 3.57 (s, 2H, NCH2), 6.96 (s, 2H, NH2), 7.34 (d, J=5.81 Hz, 2H), and 8.51 (d, J=5.88 Hz, 2H) (pyrid-4-yl protons), 8.06 (s, 1H, 6-H);LC (Method B)-MS (ESI, m/z): Rt=1.95 min-349, 351 [(M+H)+, Cl isotopic pattern].

Reference： [1]Patent: US2009/247507,2009,A1 .Location in patent: Page/Page column 27
[2]Journal of Medicinal Chemistry,2010,vol. 53,p. 5213 - 5228

17
[ 662116-67-8 ]
[ 942949-11-3 ]
[ 942949-12-4 ]

Yield	Reaction Conditions	Operation in experiment
63%	Stage #1: tert-butyl 4-(2-(3-methylisoxazol-5-ylamino)-2-oxoethyl)piperazine-1-carboxylate With trifluoroacetic acid In dichloromethane at 20℃; for 1.75h; Stage #2: 4,5-dichloro-3-nitropyridin-2-ylamine With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 45℃; for 18h;	63 2-(4-(2-Amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)-N-(3-methylisoxazol-5-yl)acetamide To a solution of tert-butyl 4-(2-(3-methylisoxazol-5-ylamino)-2-oxoethyl)piperazine-1-carboxylate (0.087 g, 0.27 mmol) in anhydrous dichloromethane (3 ml) was added TFA (3.7 ml). The reaction mixture was stirred at room temperature for 1 h and 45 min, then the solvent was removed in vacuo and the residue was dried in vacuo over P2O5. To a solution of this material (supposedly 0.27 mmol) in isopropanol (5 ml) was added 2-amino-4,5-dichloro-3-nitro-pyridine (0.050 g, 0.24 mmol) followed by diisopropylethylamine (0.22 ml, 1.25 mmol). The reaction mixture was stirred at 45° C. for 18 h, then allowed to cool to room temperature, and diluted with isopropanol (6 ml). The precipitate was collected by filtration, washed with isopropanol (2×6 ml), and diethyl ether (2×6 ml), and dried. The title compound was obtained as an orange solid (0.042 g). The filtrate was concentrated in vacuo, and purification of the residue by chromatography (10 g isolute column) on elution with dichloromethane/ethyl acetate (v/v; 1:1), and 2% methanol in dichloromethane/ethyl acetate (v/v; 1:1) afforded an additional 0.025 g of the product (overall yield: 63%). 1H-NMR (500 MHz, DMSO-d6) 2.18 (s, 3H, CH3), 2.63 (s, 4H, piperazine N(CH2)2), 3.28 (s, 2H, NCH2CO), 3.10 (s, 4H, piperazine N(CH2)2), 6.15 (s, 1H, isoxazole C-H), 7.00 (s, 2H, NH2), 8.07 (s, 1H, 6-H), 11.37 (s, 1H, CONH);LC (Method B)-MS (ESI, m/z): Rt=2.99 min-396, 398 [(M+H)+, Cl isotopic pattern].

Reference： [1]Current Patent Assignee: UNIVERSITY OF LONDON - US2009/247507, 2009, A1 Location in patent: Page/Page column 42

18
[ 5308-28-1 ]
[ 662116-67-8 ]
[ 942948-54-1 ]

Yield	Reaction Conditions	Operation in experiment
60%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 45℃; for 18h;	36 5-Chloro-4-(4-isobutylpiperazin-1-yl)-3-nitropyridin-2-amine To a mixture of 2-amino-4,5-dichloro-3-nitropyridine (0.060 g, 0.29 mmol) and isopropanol (4.5 ml) was added 1-isobutyl-piperazine (0.045 g, 0.32 mmol) with the aid of isopropanol (0.5 ml) followed by diisopropylethylamine (0.06 ml, 0.32 mmol). The reaction mixture was heated at 45° C. for 18 h, then allowed to cool to room temperature, and concentrated in vacuo. The residue was absorbed on silica gel, the free running powder was placed on a 10 g isolute silica column which was eluted with ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as an orange solid (0.054 g, 60%); 1H-NMR (500 MHz, DMSO-d6) 0.87 (d, J=6.57 Hz, 6H, CH(CH3)2), 1.77 (m, 1H, CH(CH3)2), 2.08 (d, J=7.39 Hz, 2H, N-CH2), 2.45 (br s, 4H, piperazine N(CH2)2), 3.05 (br s, 4H, piperazine N(CH2)2), 6.94 (s, 2H, NH2), 8.06 (s, 1H, 6-H);LC (Method B)-MS (ESI, m/z): Rt=1.70 min-314, 316 [(M+H)+, Cl isotopic pattern].

Reference： [1]Current Patent Assignee: UNIVERSITY OF LONDON - US2009/247507, 2009, A1 Location in patent: Page/Page column 27

19
[ 662116-67-8 ]
[ 13484-37-2 ]
[ 942948-06-3 ]

Yield	Reaction Conditions	Operation in experiment
88%	In isopropyl alcohol at 45℃; for 18h;	9 5-Chloro-3-nitro-4-[4-(2-phenoxy-ethyl)-piperazin-1-yl]-pyridin-2-ylamine A mixture of 1-(2-phenoxy-ethyl)-piperazine (0.047 g, 0.23 mmol), isopropanol (4.0 ml), and 2-amino-4,5-dichloro-3-nitropyridine (0.034 g, 0.16 mmol) was heated at 45° C. for 18 h. The reaction mixture was allowed to cool to room temperature, absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 10% ethyl acetate in dichloromethane, 20% ethyl acetate in dichloromethane and finally 1% methanol in ethyl acetate/dichloromethane (v/v; 1:4). The title compound was obtained as a yellow solid (0.053 g, 88%); 1H-NMR (500 Mz, DMSO-d6) 2.62 (br s, 4H, piperazine N(CH2)2), 2.76 (t, J=5.62 Hz, 2H, NCH2CH2O), 3.06 (br s, 4H, piperazine N(CH2)2), 4.09 (t, J=5.37 Hz, 2H, NCH2CH2O), 6.95 (m, 5H, 2-NH2 and o-ArH and p-ArH), 7.27 (t, J=11.20 Hz, 2H, m-ArH), 8.06 (s, 1H, 6-H); LC-MS (ESI, m/z) 3.79 min-378, 380 [(M+H)+, Cl isotopic pattern].

Reference： [1]Current Patent Assignee: UNIVERSITY OF LONDON - US2009/247507, 2009, A1 Location in patent: Page/Page column 11; 12

20
[ 662116-67-8 ]
[ 84587-70-2 ]
[ 942947-92-4 ]

Yield	Reaction Conditions	Operation in experiment
55%	In isopropyl alcohol at 45℃; for 22h;	1.5 2-[4-(2-Amino-5-chloro-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide 2-(piperazin-yl)-acetic acid N-(2-thiazolyl)-amide×2HCl (0.360 g) was partitioned between saturated aqueous NaHCO3 (40 ml) and ethyl acetate (30 ml). The aqueous layer was extracted with ethyl acetate (2×30 ml), dichloromethane (5×25 ml) and the combined organics were dried (Na2SO4), and then concentrated in vacuo to give 0.165 g of the free base. A mixture of this free base (0.054 g, 0.24 mmol), isopropanol (4.3 ml), and 2-amino-4,5-dichloro-3-nitropyridine (0.040 g, 0.19 mmol) was heated at 45° C. for 22 h. The reaction mixture was allowed to cool to room temperature, absorbed on silica gel, and the free running powder was placed on a 10 g isolute silica column which was eluted with ethyl acetate/dichloromethane (v/v; 1:1) and then 5% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a yellow solid (0.041 g, 55%); 1H-NMR (250 Mz, DMSO-d6) 2.68 (m, 4H, piperazine N(CH2)2), 3.12 (m, 4H, piperazine N(CH2)2), 3.38 (s, 2H, NCH2CO), 6.98 (s, 2H, NH2, exchangeable with D2O), 7.23 (d, J=3.55 Hz, 1H) and 7.49 (d, J=3.54 Hz, 1H) (thiazole 4-H, 5-H), 8.08 (s, 1H, pyridine 6-H); 11.98 (s, 1H, CONH); LC-MS (ESI, m/z) 4.35 min-398, 400 [(M+H)+, Cl isotopic pattern].
	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 45℃; for 17h;

Reference： [1]Current Patent Assignee: UNIVERSITY OF LONDON - US2009/247507, 2009, A1 Location in patent: Page/Page column 7; 8
[2]Location in patent: experimental part Bavetsias, Vassilios; Large, Jonathan M.; Sun, Chongbo; Bouloc, Nathalie; Kosmopoulou, Magda; Matteucci, Mizio; Wilsher, Nicola E.; Martins, Vanessa; Reynisson, Jóhannes; Atrash, Butrus; Faisal, Amir; Urban, Frederique; Valenti, Melanie; De Haven Brandon, Alexis; Box, Gary; Raynaud, Florence I.; Workman, Paul; Eccles, Suzanne A.; Bayliss, Richard; Blagg, Julian; Linardopoulos, Spiros; McDonald, Edward [Journal of Medicinal Chemistry, 2010, vol. 53, # 14, p. 5213 - 5228]

21
[ 662116-67-8 ]
[ 1018633-51-6 ]
[ 942948-30-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 45℃; for 20h;	23 To a solution of tert-butyl 4-(2-(4-methylthiazol-2-ylamino)-2-oxoethyl)piperazine-1-carboxylate (0.072 g, 0.21 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (2.5 ml). The reaction mixture was stirred at room temperature for 1.5 h, then the solvents were removed under reduced pressure to afford N-(4-methylthiazol-2-yl)-2-(piperazin-1-yl)acetamide (a semi-solid material) that was dried in vacuo. To a mixture of this material (supposedly 0.20 mmol) and isopropanol (3.5 ml) was added 2-amino-4,5-dichloro-3-nitropyridine (0.031 g, 0.15 mmol) followed by diisopropylethylamine (0.14 ml, 0.80 mmol). The reaction mixture was stirred at 45° C. for 20 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 20% ethyl acetate in dichloromethane. The title compound was obtained as an orange solid (0.044 g, 54%). 1H-NMR (500 MHz, DMSO-d6) 2.26 (s, 3H, CH3), 2.65 (br s, 4H, piperazine N(CH2)2), 3.10 (br s, 4H, piperazine N(CH2)2), 3.33 (s, 2H, NCH2CO), 6.76 (s, 1H, thiazole 5-H), 6.96 (br s, 2H, NH2), 8.07 (s, 1H, 6-H), 11.75 (s, 1H, CONH);LC (Method B)-MS (ESI, m/z): Rt=3.29 min-412, 414 [(M+H)+, Cl isotopic pattern].

Reference： [1]Current Patent Assignee: UNIVERSITY OF LONDON - US2009/247507, 2009, A1 Location in patent: Page/Page column 19

22
[ 662116-67-8 ]
[ 933737-25-8 ]
[ 942950-77-8 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 65℃; for 17h;	177 5-Chloro-3-nitro-4-(4-(thiazol-4-ylmethyl)piperazin-1-yl)pyridin-2-amine tert-Butyl 4-(thiazol-4-ylmethyl)piperazine-1-carboxylate (0.220 g, 0.79 mmol, 1.1 eq) was dissolved in DCM (2 mL) and the mixture cooled in a ice-water bath before the dropwise addition of TFA (2 mL). Stirring was continued at this temperature for 1 h. The solvents were removed in vacuo and the resulting crude material was azeotroped with toluene and dried. 4-(piperazin-1-ylmethyl)thiazole (supposedly 0.140 g, 0.79 mmol, 1.1 eq) was suspended in iPrOH (0.8 mL) and DIPEA (0.3 mL). To this solution, 4,5-dichloro-3-nitropyridin-2-amine (0.15 g, 0.72 mmol, 1 eq) was added and the mixture was heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.080 g, 27%); 1H-NMR (500 MHz, DMSO-d6): δ 2.52-2.60 (m, 4H, piperazine N(CH2)2), 3.07 (m, 4H, piperazine N(CH2)2), 3.72 (s, 2H, NCH2), 6.94 (s, 2H, NH2), 7.54 (s, 1H, thiazole 5-H), 8.05 (s, 1H, pyridine 6-H), 9.04 (s, 1H, thiazole 2-H); LC (Method B)-MS (ESI, m/z): Rt=1.71 min-355/357 [(M+H)+, Cl isotopic pattern].

Reference： [1]Current Patent Assignee: UNIVERSITY OF LONDON - US2009/247507, 2009, A1 Location in patent: Page/Page column 99

23
[ 662116-67-8 ]
N-phenyl-2-piperazin-1-yl-acetamide dihydrochloride [ No CAS ]
[ 942948-27-8 ]

Yield	Reaction Conditions	Operation in experiment
71%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 45℃; for 18h;	22 2-(4-(2-Amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)-N-phenylacetamide To a mixture of 2-amino-4,5-dichloro-3-nitropyridine (0.031 g, 0.15 mmol) and isopropanol (3.5 ml) was added N-phenyl-2-piperazin-1-yl-acetamide×2HCl salt (0.048 g, 0.16 mmol) followed by diisopropylethylamine (0.10 ml, 0.54 mmol). The reaction mixture was heated at 45° C. for 18 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 10% to 30% ethyl acetate in dichloromethane. The title compound was obtained as a yellow solid (0.041 g, 71%); 1H-NMR (500 MHz, DMSO-d6) 2.64 (br s, 4H, piperazine N(CH2)2), 3.13 (br s, 4H, piperazine N(CH2)2), 3.19 (s, 2H, NCH2CO), 7.00 (br s, 2H, 2-NH2), 7.06 (t, J=7.34 Hz, 1H, p-ArH), 7.31 (t, J=8.26 Hz, 2H, m-ArH), 7.63 (d, J=7.34 Hz, 2H, o-ArH), 8.07 (s, 1H, 6-H), 9.76 (s, 1H, CONH);LC-MS (ESI, m/z): Rt=4.50 min-391, 393 [(M+H)+, Cl isotopic pattern].
71%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 45℃; for 18h;

Reference： [1]Current Patent Assignee: UNIVERSITY OF LONDON - US2009/247507, 2009, A1 Location in patent: Page/Page column 18; 19
[2]Location in patent: experimental part Bavetsias, Vassilios; Large, Jonathan M.; Sun, Chongbo; Bouloc, Nathalie; Kosmopoulou, Magda; Matteucci, Mizio; Wilsher, Nicola E.; Martins, Vanessa; Reynisson, Jóhannes; Atrash, Butrus; Faisal, Amir; Urban, Frederique; Valenti, Melanie; De Haven Brandon, Alexis; Box, Gary; Raynaud, Florence I.; Workman, Paul; Eccles, Suzanne A.; Bayliss, Richard; Blagg, Julian; Linardopoulos, Spiros; McDonald, Edward [Journal of Medicinal Chemistry, 2010, vol. 53, # 14, p. 5213 - 5228]

24
[ 662116-67-8 ]
N-(3-chlorophenyl)-2-(piperazin-1-yl)acetamide trifluoroacetate [ No CAS ]
[ 942948-33-6 ]

Yield	Reaction Conditions	Operation in experiment
56%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 45℃; for 18h;	24 2-(4-(2-Amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)-N-(3-chlorophenyl)acetamide To a solution of tert-butyl 4-(2-(3-chlorophenylamino)-2-oxoethyl)piperazine-1-carboxylate (0.061 g, 0.17 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (2.5 ml). The reaction mixture was stirred at room temperature for 1.5 h, then the solvents were removed under reduced pressure to afford N-(3-chlorophenyl)-2-(piperazin-1-yl)acetamide trifluoroacetate salt (an oily material) that was dried in vacuo. To a mixture of this material (supposedly 0.17 mmol) and isopropanol (3.5 ml) was added 2-amino-4,5-dichloro-3-nitropyridine (0.031 g, 0.15 mmol) followed by diisopropylethylamine (0.14 ml, 0.80 mmol). The reaction mixture was stirred at 45° C. for 18 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 15% ethyl acetate in dichloromethane. The title compound was obtained as an orange solid (0.040 g, 56%). 1H-NMR (500 MHz, DMSO-d6) 2.65 (br s, 4H, piperazine N(CH2)2), 3.14 (br s, 4H, piperazine N(CH2)2), 3.21 (s, 2H, NCH2CO), 6.95 (s, 2H, NH2), 7.11 (dd, J=7.94, 1.23 Hz, 1H) and 7.54 (dd, J=8.29, 0.98 Hz, 1H) (4-ArH and 6-ArH), 7.34 (t, J=8.07 Hz, 1H, 5-ArH), 7.84 (t, J=1.80 Hz, 1H, 2-ArH), 8.07 (s, 1H, 6-H), 9.91 (s, 1H, CONH);LC (Method B)-MS (ESI, m/z): Rt=3.89 min-425, 427, 429 [(M+H)+, Cl2 isotopic pattern].

Reference： [1]Current Patent Assignee: UNIVERSITY OF LONDON - US2009/247507, 2009, A1 Location in patent: Page/Page column 20

25
[ 662116-67-8 ]
N-(3-chlorophenyl)-2-(piperazin-1-yl)acetamide trifluoroacetate [ No CAS ]
[ 942948-33-6 ]

Yield	Reaction Conditions	Operation in experiment
0.04 g	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 45℃; for 18h;

Reference： [1]Bavetsias, Vassilios; Large, Jonathan M.; Sun, Chongbo; Bouloc, Nathalie; Kosmopoulou, Magda; Matteucci, Mizio; Wilsher, Nicola E.; Martins, Vanessa; Reynisson, Jóhannes; Atrash, Butrus; Faisal, Amir; Urban, Frederique; Valenti, Melanie; De Haven Brandon, Alexis; Box, Gary; Raynaud, Florence I.; Workman, Paul; Eccles, Suzanne A.; Bayliss, Richard; Blagg, Julian; Linardopoulos, Spiros; McDonald, Edward [Journal of Medicinal Chemistry, 2010, vol. 53, # 14, p. 5213 - 5228]

26
[ 662116-67-8 ]
[ 69628-75-7 ]
[ 942948-18-7 ]

Yield	Reaction Conditions	Operation in experiment
81%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 45℃; for 17h;

Reference： [1]Bavetsias, Vassilios; Large, Jonathan M.; Sun, Chongbo; Bouloc, Nathalie; Kosmopoulou, Magda; Matteucci, Mizio; Wilsher, Nicola E.; Martins, Vanessa; Reynisson, Jóhannes; Atrash, Butrus; Faisal, Amir; Urban, Frederique; Valenti, Melanie; De Haven Brandon, Alexis; Box, Gary; Raynaud, Florence I.; Workman, Paul; Eccles, Suzanne A.; Bayliss, Richard; Blagg, Julian; Linardopoulos, Spiros; McDonald, Edward [Journal of Medicinal Chemistry, 2010, vol. 53, # 14, p. 5213 - 5228]

27
[ 662116-67-8 ]
5-methyl-3-(N-piperazinomethyl) isoxazole [ No CAS ]
[ 942949-34-0 ]

Yield	Reaction Conditions	Operation in experiment
0.162 g	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 45℃; for 20h;

Reference： [1]Bavetsias, Vassilios; Large, Jonathan M.; Sun, Chongbo; Bouloc, Nathalie; Kosmopoulou, Magda; Matteucci, Mizio; Wilsher, Nicola E.; Martins, Vanessa; Reynisson, Jóhannes; Atrash, Butrus; Faisal, Amir; Urban, Frederique; Valenti, Melanie; De Haven Brandon, Alexis; Box, Gary; Raynaud, Florence I.; Workman, Paul; Eccles, Suzanne A.; Bayliss, Richard; Blagg, Julian; Linardopoulos, Spiros; McDonald, Edward [Journal of Medicinal Chemistry, 2010, vol. 53, # 14, p. 5213 - 5228]

28
[ 19798-80-2 ]
[ 662116-67-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: pyridine / 5 h / 20 °C 2: N-chloro-succinimide / acetonitrile / 5 h / 100 °C 3: sulfuric acid; nitric acid / 1 h / 65 - 100 °C
	Multi-step reaction with 2 steps 1.1: sulfuric acid / 0.08 h / Cooling with ice 1.2: 1.17 h / 0 - 55 °C 2.1: N-chloro-succinimide / acetonitrile / 1 h / 80 °C
	Multi-step reaction with 2 steps 1.1: sulfuric acid / 0.08 h / Cooling with ice 1.2: 1.17 h / 0 - 55 °C / Cooling with ice 2.1: N-chloro-succinimide / acetonitrile / 1 h / 80 °C

	Multi-step reaction with 3 steps 1: pyridine / 12 h / 0 - 20 °C 2: N-chloro-succinimide / acetonitrile / 2 h / 70 °C 3: sulfuric acid; nitric acid / water / 2.5 h / 20 °C
	Multi-step reaction with 2 steps 1: N-chloro-succinimide / acetonitrile / 20 °C 2: sulfuric acid; nitric acid / -10 - 55 °C
	Multi-step reaction with 2 steps 1.1: N-chloro-succinimide / N,N-dimethyl-formamide / 24 h / -20 - 20 °C 2.1: sulfuric acid / -5 °C 2.2: 3.08 h / 0 - 50 °C
	Multi-step reaction with 2 steps 1.1: N-chloro-succinimide / ethyl acetate / 28 h / 20 °C 2.1: sulfuric acid; nitric acid / 3.5 h / 5 °C / Cooling with ice 2.2: 2.5 h / 40 °C
	Multi-step reaction with 3 steps 1.1: N-chloro-succinimide / ethyl acetate / 28 h / 20 °C 2.1: sulfuric acid / 0.33 h / Cooling with ice 2.2: 3.5 h / 5 °C 3.1: sulfuric acid / 2.5 h / 40 °C
	Multi-step reaction with 2 steps 1: sulfuric acid; nitric acid / 1.17 h / 0 - 55 °C 2: N-chloro-succinimide / acetonitrile / 1 h / 80 °C

Reference： [1]Current Patent Assignee: HANMI PHARM CO LTD - WO2013/100631, 2013, A1
[2]Current Patent Assignee: CANCER RESEARCH UK - WO2013/190320, 2013, A1
[3]Current Patent Assignee: THE INSTITUTE OF CANCER RESEARCH ROYAL CANCER HOSPITAL GB - WO2013/190319, 2013, A1
[4]Current Patent Assignee: JW PHARMACEUTICAL CO LTD - US2014/315888, 2014, A1
[5]Vasbinder, Melissa M.; Alimzhanov, Marat; Augustin, Martin; Bebernitz, Geraldine; Bell, Kirsten; Chuaqui, Claudio; Deegan, Tracy; Ferguson, Andrew D.; Goodwin, Kelly; Huszar, Dennis; Kawatkar, Aarti; Kawatkar, Sameer; Read, Jon; Shi, Jie; Steinbacher, Stefan; Steuber, Holger; Su, Qibin; Toader, Dorin; Wang, Haixia; Woessner, Richard; Wu, Allan; Ye, Minwei; Zinda, Michael [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 1, p. 60 - 67]
[6]Xie, Dongsheng; Lu, Jun; Xie, Jin; Cui, Junjun; Li, Teng-Fei; Wang, Yan-Chao; Chen, Yuan; Gong, Nian; Li, Xin-Yan; Fu, Lei; Wang, Yong-Xiang [European Journal of Medicinal Chemistry, 2016, vol. 117, p. 19 - 32]
[7]Current Patent Assignee: KANCERA AB - WO2016/124553, 2016, A1
[8]Current Patent Assignee: KANCERA AB - WO2018/11138, 2018, A1
[9]Bavetsias, Vassilios; Crumpler, Simon; Sun, Chongbo; Avery, Sian; Atrash, Butrus; Faisal, Amir; Moore, Andrew S.; Brown, Nathan; Sheldrake, Peter W.; Bush, Katherine; Henley, Alan; Box, Gary; Valenti, Melanie; De Haven Brandon, Alexis; Raynaud, Florence I.; Workman, Paul; Eccles, Suzanne A.; Linardopoulos, Spiros; Blagg, Julian; Kosmopoulou, Magda; Bayliss, Richard [Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8721 - 8734,14]

29
[ 6980-08-1 ]
[ 662116-67-8 ]

Yield	Reaction Conditions	Operation in experiment
85%	With N-chloro-succinimide; In acetonitrile; at 80℃; for 1h;	4-Chloro-3-nitropyridin-2-amine (0.1 0 g, 0.58 mmol) was dissolved in dryacetonitrile (20 ml). To the stirred solution was then added N-chlorosuccinimide (0.0945 g, 0.70 mmol), and the reaction mixture was heated at 80 C for 1 h. Volatiles wereremoved in vacuo and the residue purified by silica column chromatography (elution withdichloromethane) to provide the product as a pale brown powder (0.125 g, 85%). 1 HNMR(500 MHz, DMSO-d6) 7.35 (s, 2H, NH2), 8.36 (s, 1 H, 6-H).
85%	With N-chloro-succinimide; In acetonitrile; at 80℃; for 1h;	[00118] 4-Chloro-3-nitropyridin-2-amine (0.10 g, 0.58 mmol) was dissolved in dry acetonitrile (20 mL). To the stirred solution was then added A/-chlorosuccinimide (0.094 g, 0.70 mmol), and the reaction mixture was heated at 80 C for 1 h. Volatiles were removed in vacuo and the residue purified by silica column chromatography (elution with dichloromethane) to provide the title compound as a pale brown powder (0.125 g, 85%). 1 H-NMR (500 MHz, DMSO-d6) 7.35 (s, 2H, NH2), 8.36 (s, 1 H, 6-H).
71%	With N-chloro-succinimide; In acetonitrile; at 80℃;	4-Chloro-3-nitro-pyridin-2-amine (5.00 g, 28.85 mmol) in acetonitrile (150 mL)To the suspension was added 1-chloropyrrolidine-2,5-dione (5.39 g, 40.36 mmol).The reaction mixture was stirred at 80 C overnight.It was then concentrated under reduced pressure.The residue obtained was purified by silica gel column chromatography (EtOAc)The crude product was subjected to silica gel column chromatography.(EA/PE (v/v) = 1/5 to 1/3) purified to give the title compound as a yellow solid(4.26 g, yield 71%).

71%

With N-chloro-succinimide; In acetonitrile; at 80℃;

To a suspension of 4-chloro-3-nitro-pyridin-2-amine (5.00g, 28.85 mmol) in acetonitrile (150 mL) was added l-chloropyrrolidine-2,5-dione (5.39 g, 40.36 mmol). The mixture was heated at 80 C overnight. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with DCM). The crude product was once again purified by silica gel column chromatography (EA/PE (v/v) = 1/5 to 1/3) to afford the title compound as a yellow solid (4.26g, yield 71%).MS (ESI, pos. ion) m/z: 207.9 [M+H]+; NMR (400 MHz, CDCh) delta (ppm): 8.27 (s, 1H), 5.81 (s, 2H).

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8721 - 8734,14
[2]Patent: WO2013/190320,2013,A1 .Location in patent: Paragraph 00120
[3]Patent: WO2013/190319,2013,A1 .Location in patent: Paragraph 00118
[4]Patent: CN108570048,2018,A .Location in patent: Paragraph 0677; 0679-0680
[5]Patent: WO2018/169700,2018,A1 .Location in patent: Paragraph 00364

30
[ 662116-67-8 ]
[ 1042795-92-5 ]
[ 1402709-98-1 ]

Yield	Reaction Conditions	Operation in experiment
16%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 50℃; for 4h;
	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 50℃; for 4h;	2 4-(4-((1,2,4-oxadiazol-3-yl)methyl)piperazin-1-yl)-5-chloro-3-nitropyridin-2-amine To a solution of teri-butyl 4-((1 ,2,4-oxadiazol-3-yl)methyl)piperazine-1 - carboxylate (213 mg, 0.790 mmol) in CH2CI2 (18 mL) was added TFA (1 .8 mL, 23.8 mmol) and the solution was stirred at room temperature for 1 h. The reaction was concentrated in vacuo, azeotroping with toluene (x2) and dried in vacuum desiccator (containing KOH) overnight to give a yellow oil. The crude oil was dissolved in 'PrOH (4.4 mL) and both 2-amino-3-nitro-4,5-dichloropyridine (190 mg, 0.752 mmol) and DIPEA (520 μΙ, 3.00 mmol) were added. The solution was stirred at 50 °C for 4 h. On cooling, a yellow precipitate dropped out which was filtered, washed with Et20, dried in vacuo to yield the title compound as a yellow solid (165 mg, 0.486, 65%). The filtrate was concentrated in vacuo to give 715 mg oily yellow solid. Purification was accomplished by flash chromatography on silica gel (4 x 1 1 ) eluting with EtOAc/hexane (40-50%) to yield the title compound (42 mg, 16%) as a yellow solid.[00126] 1 H-NMR (500 MHz, CDCI3) 2.74 (app t, J = 4.1 Hz, 4H, -CH2-), 3.25 (t, J = 4.8 Hz, 4H, -CH2-), 3.85 (s, 2H, -CH2C-), 5.77 (s, 2H, NH2), 7.99 (s, 1 H, CHar), 8.72 (s, 1 H, - C(CI)CH-). [00127] LC - MS (ESI, m/z): Rt = 1 .56 min - 340, 342 [(M + H)+, CI isotopic pattern].

Reference： [1]Bavetsias, Vassilios; Crumpler, Simon; Sun, Chongbo; Avery, Sian; Atrash, Butrus; Faisal, Amir; Moore, Andrew S.; Brown, Nathan; Sheldrake, Peter W.; Bush, Katherine; Henley, Alan; Box, Gary; Valenti, Melanie; De Haven Brandon, Alexis; Raynaud, Florence I.; Workman, Paul; Eccles, Suzanne A.; Linardopoulos, Spiros; Blagg, Julian; Kosmopoulou, Magda; Bayliss, Richard [Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8721 - 8734,14]
[2]Current Patent Assignee: THE INSTITUTE OF CANCER RESEARCH ROYAL CANCER HOSPITAL GB - WO2013/190319, 2013, A1 Location in patent: Paragraph 00125

31
[ 662116-67-8 ]
[ 1042795-92-5 ]
[ 1402709-90-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 4 h / 50 °C 2: sodium dithionite / ethanol; water / 15 h / 80 °C

Reference： [1]Bavetsias, Vassilios; Crumpler, Simon; Sun, Chongbo; Avery, Sian; Atrash, Butrus; Faisal, Amir; Moore, Andrew S.; Brown, Nathan; Sheldrake, Peter W.; Bush, Katherine; Henley, Alan; Box, Gary; Valenti, Melanie; De Haven Brandon, Alexis; Raynaud, Florence I.; Workman, Paul; Eccles, Suzanne A.; Linardopoulos, Spiros; Blagg, Julian; Kosmopoulou, Magda; Bayliss, Richard [Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8721 - 8734,14]

32
[ 662116-67-8 ]
[ 1235564-01-8 ]
[ 942950-13-2 ]

Yield	Reaction Conditions	Operation in experiment
54%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 45℃; for 18h;

Reference： [1]Bavetsias, Vassilios; Crumpler, Simon; Sun, Chongbo; Avery, Sian; Atrash, Butrus; Faisal, Amir; Moore, Andrew S.; Brown, Nathan; Sheldrake, Peter W.; Bush, Katherine; Henley, Alan; Box, Gary; Valenti, Melanie; De Haven Brandon, Alexis; Raynaud, Florence I.; Workman, Paul; Eccles, Suzanne A.; Linardopoulos, Spiros; Blagg, Julian; Kosmopoulou, Magda; Bayliss, Richard [Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8721 - 8734,14]

33
[ 662116-67-8 ]
[ 1235564-01-8 ]
[ 1402709-94-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 18 h / 45 °C 2: sodium dithionite / ethanol; water / 18 h / 80 °C

Reference： [1]Bavetsias, Vassilios; Crumpler, Simon; Sun, Chongbo; Avery, Sian; Atrash, Butrus; Faisal, Amir; Moore, Andrew S.; Brown, Nathan; Sheldrake, Peter W.; Bush, Katherine; Henley, Alan; Box, Gary; Valenti, Melanie; De Haven Brandon, Alexis; Raynaud, Florence I.; Workman, Paul; Eccles, Suzanne A.; Linardopoulos, Spiros; Blagg, Julian; Kosmopoulou, Magda; Bayliss, Richard [Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8721 - 8734,14]

34
[ 662116-67-8 ]
[ 1083300-35-9 ]
[ 1402710-04-6 ]

Yield	Reaction Conditions	Operation in experiment
47%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 45℃; for 20h;

Reference： [1]Bavetsias, Vassilios; Crumpler, Simon; Sun, Chongbo; Avery, Sian; Atrash, Butrus; Faisal, Amir; Moore, Andrew S.; Brown, Nathan; Sheldrake, Peter W.; Bush, Katherine; Henley, Alan; Box, Gary; Valenti, Melanie; De Haven Brandon, Alexis; Raynaud, Florence I.; Workman, Paul; Eccles, Suzanne A.; Linardopoulos, Spiros; Blagg, Julian; Kosmopoulou, Magda; Bayliss, Richard [Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8721 - 8734,14]

35
[ 662116-67-8 ]
[ 1083300-35-9 ]
[ 1402709-95-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 20 h / 45 °C 2: sodium dithionite / ethanol; water / 20 h / 80 °C

Reference： [1]Bavetsias, Vassilios; Crumpler, Simon; Sun, Chongbo; Avery, Sian; Atrash, Butrus; Faisal, Amir; Moore, Andrew S.; Brown, Nathan; Sheldrake, Peter W.; Bush, Katherine; Henley, Alan; Box, Gary; Valenti, Melanie; De Haven Brandon, Alexis; Raynaud, Florence I.; Workman, Paul; Eccles, Suzanne A.; Linardopoulos, Spiros; Blagg, Julian; Kosmopoulou, Magda; Bayliss, Richard [Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8721 - 8734,14]

36
[ 662116-67-8 ]
[ 1368340-76-4 ]
[ 1402710-02-4 ]

Yield	Reaction Conditions	Operation in experiment
84%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 50℃; for 4.5h;

Reference： [1]Bavetsias, Vassilios; Crumpler, Simon; Sun, Chongbo; Avery, Sian; Atrash, Butrus; Faisal, Amir; Moore, Andrew S.; Brown, Nathan; Sheldrake, Peter W.; Bush, Katherine; Henley, Alan; Box, Gary; Valenti, Melanie; De Haven Brandon, Alexis; Raynaud, Florence I.; Workman, Paul; Eccles, Suzanne A.; Linardopoulos, Spiros; Blagg, Julian; Kosmopoulou, Magda; Bayliss, Richard [Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8721 - 8734,14]

37
[ 662116-67-8 ]
[ 1368340-76-4 ]
[ 1402709-92-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 4.5 h / 50 °C 2: sodium dithionite / ethanol; water / 89 h / 80 °C

Reference： [1]Bavetsias, Vassilios; Crumpler, Simon; Sun, Chongbo; Avery, Sian; Atrash, Butrus; Faisal, Amir; Moore, Andrew S.; Brown, Nathan; Sheldrake, Peter W.; Bush, Katherine; Henley, Alan; Box, Gary; Valenti, Melanie; De Haven Brandon, Alexis; Raynaud, Florence I.; Workman, Paul; Eccles, Suzanne A.; Linardopoulos, Spiros; Blagg, Julian; Kosmopoulou, Magda; Bayliss, Richard [Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8721 - 8734,14]

38
[ 662116-67-8 ]
[ 878617-56-2 ]
[ 1402709-96-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 50℃; for 14.5h;

Reference： [1]Bavetsias, Vassilios; Crumpler, Simon; Sun, Chongbo; Avery, Sian; Atrash, Butrus; Faisal, Amir; Moore, Andrew S.; Brown, Nathan; Sheldrake, Peter W.; Bush, Katherine; Henley, Alan; Box, Gary; Valenti, Melanie; De Haven Brandon, Alexis; Raynaud, Florence I.; Workman, Paul; Eccles, Suzanne A.; Linardopoulos, Spiros; Blagg, Julian; Kosmopoulou, Magda; Bayliss, Richard [Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8721 - 8734,14]

39
[ 662116-67-8 ]
[ 878617-56-2 ]
[ 1402709-89-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 14.5 h / 50 °C 2: sodium dithionite / ethanol; water / 15 h / 80 °C

Reference： [1]Bavetsias, Vassilios; Crumpler, Simon; Sun, Chongbo; Avery, Sian; Atrash, Butrus; Faisal, Amir; Moore, Andrew S.; Brown, Nathan; Sheldrake, Peter W.; Bush, Katherine; Henley, Alan; Box, Gary; Valenti, Melanie; De Haven Brandon, Alexis; Raynaud, Florence I.; Workman, Paul; Eccles, Suzanne A.; Linardopoulos, Spiros; Blagg, Julian; Kosmopoulou, Magda; Bayliss, Richard [Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8721 - 8734,14]

40
[ 662116-67-8 ]
[ 1402709-99-2 ]
[ 1402710-00-2 ]

Yield	Reaction Conditions	Operation in experiment
69%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 45℃; for 23h;	3 2-amino-5-chloro-4-(4-(5-methyl-1,2,4-oxadiazol-3-yl)methylpiperazin-1-yl)-3-nitropyridine 1 -[(5-Methyl-1 ,2,4-oxadiazol-3-yl)methyl]piperazine hydrochloride (217 mg, 0.99 mmol) and 2-amino-4,5-dichloro-3-nitropyridine (208 mg, 1.0 mmol) were stirred in 2- propanol (5 mL) and diisopropylethylamine (523 μΙ_, 387 mg, 3.0 mmol) was added. The mixture was stirred and heated at 45°C for 23 h. The reaction was cooled and the product filtered off and washed with 2-propanol. Drying in vacuum gave the product (246 mg, 69%). 1H-NMR (500 MHz, CDCI3,) 2.63 (s, 3H, CH3), 2.77 (br m, 4H, piperazine C- H), 3.29 (m, 4H, piperazine C-H), 3.76 (s, 2H, CH2), 5.27 (s, 2H, NH2), 8.02 (s, 1 H, pyridine 6-H). [00133] LC - MS (ESI, m/z): Rt = 1 .66 min - 354 (M + H)+, 35Cl isotope.
69%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 45℃; for 23h;

Reference： [1]Current Patent Assignee: THE INSTITUTE OF CANCER RESEARCH ROYAL CANCER HOSPITAL GB - WO2013/190319, 2013, A1 Location in patent: Paragraph 00132
[2]Bavetsias, Vassilios; Crumpler, Simon; Sun, Chongbo; Avery, Sian; Atrash, Butrus; Faisal, Amir; Moore, Andrew S.; Brown, Nathan; Sheldrake, Peter W.; Bush, Katherine; Henley, Alan; Box, Gary; Valenti, Melanie; De Haven Brandon, Alexis; Raynaud, Florence I.; Workman, Paul; Eccles, Suzanne A.; Linardopoulos, Spiros; Blagg, Julian; Kosmopoulou, Magda; Bayliss, Richard [Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8721 - 8734,14]

41
[ 662116-67-8 ]
[ 1402709-99-2 ]
[ 1402709-91-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 23 h / 45 °C 2: sodium dithionite / ethanol; water / 16 h / 80 °C

Reference： [1]Bavetsias, Vassilios; Crumpler, Simon; Sun, Chongbo; Avery, Sian; Atrash, Butrus; Faisal, Amir; Moore, Andrew S.; Brown, Nathan; Sheldrake, Peter W.; Bush, Katherine; Henley, Alan; Box, Gary; Valenti, Melanie; De Haven Brandon, Alexis; Raynaud, Florence I.; Workman, Paul; Eccles, Suzanne A.; Linardopoulos, Spiros; Blagg, Julian; Kosmopoulou, Magda; Bayliss, Richard [Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8721 - 8734,14]

42
[ 662116-67-8 ]
[ 23145-88-2 ]
[ 1402709-93-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 18 h / 45 °C 2: sodium dithionite / ethanol; water / 24 h / 80 °C

Reference： [1]Bavetsias, Vassilios; Crumpler, Simon; Sun, Chongbo; Avery, Sian; Atrash, Butrus; Faisal, Amir; Moore, Andrew S.; Brown, Nathan; Sheldrake, Peter W.; Bush, Katherine; Henley, Alan; Box, Gary; Valenti, Melanie; De Haven Brandon, Alexis; Raynaud, Florence I.; Workman, Paul; Eccles, Suzanne A.; Linardopoulos, Spiros; Blagg, Julian; Kosmopoulou, Magda; Bayliss, Richard [Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8721 - 8734,14]

43
[ 662116-67-8 ]
[ 1446244-53-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: caesium carbonate / N,N-dimethyl-formamide / 5 h / 35 °C 2: iron; hydrogenchloride / water; ethanol / 1 h / 100 °C

Reference： [1]Current Patent Assignee: HANMI PHARM CO LTD - WO2013/100631, 2013, A1

44
[ 662116-67-8 ]
[ 1446244-32-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: caesium carbonate / N,N-dimethyl-formamide / 5 h / 35 °C 2: iron; hydrogenchloride / water; ethanol / 1 h / 100 °C 3: iron(III) chloride / N,N-dimethyl-formamide / 6 h / 120 °C

Reference： [1]Current Patent Assignee: HANMI PHARM CO LTD - WO2013/100631, 2013, A1

45
[ 662116-67-8 ]
[ 13040-21-6 ]
[ 1446244-52-5 ]

Yield	Reaction Conditions	Operation in experiment
65%	With caesium carbonate; In N,N-dimethyl-formamide; at 35℃; for 5.0h;	N,N-dimethylformamide (40 mL) was added to the compound obtained in Step 3 (2.0 g, 0.010 mol) and cesium carbonate (4.7 g, 0.001 mol), followed by stirring for 30 minutes at room temperature. The compound obtained in Step 4 (2.28 g, 0.001 mol) was slowly added thereto, followed by stirring for 5 hours at 35C. Ethylacetate was added to the reaction solution, and washed with water several times. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and distilled under reduced pressure. The resulting residue was separated by column chromatography (chloroform : methanol = 20 : 1 (v:v)) to obtain the title compound (2.0 g, yield: 65%). 1H-NMR(300 MHz, DMSO-d6) delta 5.72 (dd, 1H), 6.35 (dd, 1H), 6.41 (m, 2H), 6.69 (d, 1H), 7.03 (m, 2H), 7.32 (s, 1H), 7.50 (s, 1H), 8.46(s, 1H), 10.25 (s, 1H)

Reference： [1]Patent: WO2013/100631,2013,A1 .Location in patent: Page/Page column 13; 16

46
[ 188577-70-0 ]
[ 662116-67-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-chloro-succinimide / acetonitrile / 5 h / 100 °C 2: sulfuric acid; nitric acid / 1 h / 65 - 100 °C
	Multi-step reaction with 2 steps 1: N-chloro-succinimide / acetonitrile / 2 h / 70 °C 2: sulfuric acid; nitric acid / water / 2.5 h / 20 °C

Reference： [1]Current Patent Assignee: HANMI PHARM CO LTD - WO2013/100631, 2013, A1
[2]Current Patent Assignee: JW PHARMACEUTICAL CO LTD - US2014/315888, 2014, A1

47
[ 662116-67-8 ]
C₉H₁₄N₂O*(x)C₂HF₃O₂ [ No CAS ]
[ 1449504-19-1 ]

Yield	Reaction Conditions	Operation in experiment
84%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 60℃; for 15h;	General Procedure for synthesis of 6a,b,c,d: Compounds 5a-d (1.1 eq), 4,5-dichloro-3-nitropyridin-2-amine (1 eq) and diisopropylethylamine (5.3 eq) were heated in isopropanol at 60°C for 15h when an orange precipitate formed. TLC and LCMS indicated completion of reaction. The reaction mixtures were allowed to come to room temperature and the precipitates were filtered, washed well with isopropanol, and dried in vacuo.

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2013/116291, 2013, A1 Location in patent: Page/Page column 170

48
[ 662116-67-8 ]
[ 62122-98-9 ]
[ 1449504-45-3 ]

Yield	Reaction Conditions	Operation in experiment
92%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 60℃; for 24h;	Synthesis of 4-(2-amino-5-chloro-3-nitropyridin-4-ylamino)-1.7.7-trimethylbicyclo[2.2.1]heptan-2-one (9’): 4-amino-l,7,7-trimethylbicyclo[2.2.1]heptan-2-one (8) (l.lg, 5.29mmol) ) and 4,5- dichloro-3-nitropyridin-2-amine (lg, 4.81mmol) were taken in IPA (30ml) and DIPEA (4.6ml, 26.44mmol)) was added to the reaction mixture which was then heated at 60°C for 24h when TLC confirmed completion of reaction. The reaction mixture was cooled to rt and concentrated in vacuuo. Pure product (9) (1.63g, 92%) was obtained as a yellow solid after purification by column chromatography using silica gel (100-200 mesh). NMR : δ (, 400 MHz, CDC13): 0.87 (3H, s), 0.97 (3H, s), 1.05 (3H, s), 1.44-1.54 (1H, m), 1.70- 1.80 (1H, m), 1.90-2.20 (1H, m), 2.30-2.40 (1H, m), 2.47 (1H, dd, .7=3.2, 18.0Hz), 2.88 (1H, d, J=18.4Hz), 6.55 (2H, s), 7.85 (1H, s), 7.96 (1H, s) LCMS: (254nm): [M+H] + 339.10 (86.27 %)

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2013/116291, 2013, A1 Location in patent: Page/Page column 184; 185

49
[ 662116-67-8 ]
[ 1449504-57-7 ]
[ 1449504-58-8 ]

Yield	Reaction Conditions	Operation in experiment
34%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 60℃; for 15h;	(1 S,2R,3S,4R)-3-(2-amino-5-chloro-3-nitropyridin-4-ylamino)-7-oxabicyclo[2.2. 1]heptane-2-carboxamide (16): (lS,2R,3S,4R)-3-amino-7-oxabicyclo[2.2.1]heptane-2-carboxamide (15) (170mg, 0.67mmol), 4,5-dichloro-3-nitropyridin-2-amine (127mg, 0.6mmol), DIPEA (5.5eq) were taken in IPA and heated at 60oC for 15h when a yellow precipitate appeared. The precipitate was filtered, washed well with IPA and dried to afford the desired product, (198mg, 34%).

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2013/116291, 2013, A1 Location in patent: Page/Page column 191

50
[ 662116-67-8 ]
[ 1443626-56-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 60 °C 2: acetic acid; iron / tetrahydrofuran / 4 h / 30 °C 3: ammonium acetate / ethanol / 70 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2013/116291, 2013, A1

51
[ 662116-67-8 ]
[ 1449503-43-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 60 °C 2: acetic acid; iron / tetrahydrofuran / 4 h / 30 °C 3: ammonium acetate / ethanol / 80 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2013/116291, 2013, A1

52
[ 662116-67-8 ]
[ 1449503-73-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 60 °C 2: acetic acid; iron / tetrahydrofuran / 4 h / 30 °C 3: ammonium acetate; N-ethyl-N,N-diisopropylamine / ethanol / 18 h / 70 °C

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2013/116291, 2013, A1

53
[ 662116-67-8 ]
[ 1449504-46-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 24 h / 60 °C 2: hydrogen / methanol / 2 h

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2013/116291, 2013, A1

54
[ 662116-67-8 ]
(1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide trifluoroacetic acid salt [ No CAS ]
[ 1443996-00-6 ]

Yield	Reaction Conditions	Operation in experiment
95%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 60℃;	Synthesis of (lS,2S,3R.4R)-3-(2-Amino-5-chloro-3-nitro-pyridin-4-ylamino)- bicyclor2.2.11hept-5-ene-2-carboxylic acid amide (Compound 1 - X=C1) 4,5-Dichloro-3- nitro-pyridin-2-ylamine (l.Olg, 4.86 mmol) and (lS,2S,3R,4R)-3-Amino- bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide trifluoroacetic acid salt (1.5g, 5.5 mmol) were combined with Ν,Ν-diisopropylethylamine (3.3g, 26 mmol) in isopropanol(15 mL) and heated at 60°C overnight. The reaction was permitted to cool to room temperature and the orange solid which had formed was isolated by filtration. The solid was washed with 3 mL cold isopropanol and was dried in an air stream to afford 1.493g (95%) of the desired product. NMR (d-chloroform): 7.82 (br s, IH), 6.54 (br s, 2H), 6.29 (m, IH), 6.23 (m, IH), 5.71 (br s, IH), 5.47 (br s, IH), 4.30 (m, IH), 3.09 (s, IH), 2.80 (s, IH), 2.56 (d, J=7 Hz, IH), 2.44 (d, J=10 Hz, IH), 1.71 (d, J=9 Hz, IH). MS: 323.94 (M+H). HPLC retention time: 1.75 minutes (G Method).

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2013/116291, 2013, A1 Location in patent: Page/Page column 62

55
[ 662116-67-8 ]
(R)-N-(piperidin-3-ylmethyl)methanesulfonamide trifluoroacetic acid [ No CAS ]
(R)-N-((1-(2-amino-5-chloro-3-nitropyridin-4-yl)piperidin-3-yl)methyl)methanesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.150 g	With N-ethyl-N,N-diisopropylamine In dichloromethane; isopropyl alcohol at 45℃; for 24h; Inert atmosphere;

Reference： [1]Bavetsias, Vassilios; Faisal, Amir; Crumpler, Simon; Brown, Nathan; Kosmopoulou, Magda; Joshi, Amar; Atrash, Butrus; Pérez-Fuertes, Yolanda; Schmitt, Jessica A.; Boxall, Katherine J.; Burke, Rosemary; Sun, Chongbo; Avery, Sian; Bush, Katherine; Henley, Alan; Raynaud, Florence I.; Workman, Paul; Bayliss, Richard; Linardopoulos, Spiros; Blagg, Julian [Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9122 - 9135]

56
[ 662116-67-8 ]
(S)-N-methyl-N-(piperidin-3-ylmethyl)methanesulfonamide trifluoroacetic acid [ No CAS ]
(S)-N-((1-(2-amino-5-chloro-3-nitropyridin-4-yl)piperidin-3-yl)methyl)-N-methylmethanesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.12 g	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 45℃; for 20h;

Reference： [1]Bavetsias, Vassilios; Faisal, Amir; Crumpler, Simon; Brown, Nathan; Kosmopoulou, Magda; Joshi, Amar; Atrash, Butrus; Pérez-Fuertes, Yolanda; Schmitt, Jessica A.; Boxall, Katherine J.; Burke, Rosemary; Sun, Chongbo; Avery, Sian; Bush, Katherine; Henley, Alan; Raynaud, Florence I.; Workman, Paul; Bayliss, Richard; Linardopoulos, Spiros; Blagg, Julian [Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9122 - 9135]

57
[ 662116-67-8 ]
[ 103-67-3 ]
N4-benzyl-5-chloro-N4-methyl-3-nitropyridine-2,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 60℃; for 18h;

Reference： [1]Bavetsias, Vassilios; Faisal, Amir; Crumpler, Simon; Brown, Nathan; Kosmopoulou, Magda; Joshi, Amar; Atrash, Butrus; Pérez-Fuertes, Yolanda; Schmitt, Jessica A.; Boxall, Katherine J.; Burke, Rosemary; Sun, Chongbo; Avery, Sian; Bush, Katherine; Henley, Alan; Raynaud, Florence I.; Workman, Paul; Bayliss, Richard; Linardopoulos, Spiros; Blagg, Julian [Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9122 - 9135]

58
[ 662116-67-8 ]
[ 14121-97-2 ]
4-((2-amino-5-chloro-3-nitropyridin-4-yl)oxy)-N-phenylbenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	Stage #1: 4-hydroxybenzanilide With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.333333h; Inert atmosphere; Stage #2: 4,5-dichloro-3-nitropyridin-2-ylamine In N,N-dimethyl-formamide at 20℃; for 1.25h; Inert atmosphere;

Reference： [1]Bavetsias, Vassilios; Faisal, Amir; Crumpler, Simon; Brown, Nathan; Kosmopoulou, Magda; Joshi, Amar; Atrash, Butrus; Pérez-Fuertes, Yolanda; Schmitt, Jessica A.; Boxall, Katherine J.; Burke, Rosemary; Sun, Chongbo; Avery, Sian; Bush, Katherine; Henley, Alan; Raynaud, Florence I.; Workman, Paul; Bayliss, Richard; Linardopoulos, Spiros; Blagg, Julian [Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9122 - 9135]

59
[ 662116-67-8 ]
4-hydroxy-N-(pyridin-3-yl)benzamide [ No CAS ]
4-(2-amino-5-chloro-3-nitropyridin-4-yloxy)-N-(pyridin-3-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 80℃; for 5.25h; Inert atmosphere;

Reference： [1]Bavetsias, Vassilios; Faisal, Amir; Crumpler, Simon; Brown, Nathan; Kosmopoulou, Magda; Joshi, Amar; Atrash, Butrus; Pérez-Fuertes, Yolanda; Schmitt, Jessica A.; Boxall, Katherine J.; Burke, Rosemary; Sun, Chongbo; Avery, Sian; Bush, Katherine; Henley, Alan; Raynaud, Florence I.; Workman, Paul; Bayliss, Richard; Linardopoulos, Spiros; Blagg, Julian [Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9122 - 9135]

60
[ 662116-67-8 ]
(R)-N-(pyrrolidin-3-ylmethyl)acetamide trifluoroacetic acid [ No CAS ]
(S)-N-((1-(2-amino-5-chloro-3-nitropyridin-4-yl)pyrrolidin-3-yl)-methyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.205 g	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 45℃; for 20h;

Reference： [1]Bavetsias, Vassilios; Faisal, Amir; Crumpler, Simon; Brown, Nathan; Kosmopoulou, Magda; Joshi, Amar; Atrash, Butrus; Pérez-Fuertes, Yolanda; Schmitt, Jessica A.; Boxall, Katherine J.; Burke, Rosemary; Sun, Chongbo; Avery, Sian; Bush, Katherine; Henley, Alan; Raynaud, Florence I.; Workman, Paul; Bayliss, Richard; Linardopoulos, Spiros; Blagg, Julian [Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9122 - 9135]

61
[ 662116-67-8 ]
4-hydroxy-N-(3-methylisoxazol-5-yl)benzamide [ No CAS ]
4-(2-amino-5-chloro-3-nitropyridin-4-yloxy)-N-(3-methylisoxazol-5-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: 4-hydroxy-N-(3-methylisoxazol-5-yl)benzamide With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide for 0.5h; Inert atmosphere; Stage #2: 4,5-dichloro-3-nitropyridin-2-ylamine In N,N-dimethyl-formamide at 80℃; for 1h; Inert atmosphere;

Reference： [1]Bavetsias, Vassilios; Faisal, Amir; Crumpler, Simon; Brown, Nathan; Kosmopoulou, Magda; Joshi, Amar; Atrash, Butrus; Pérez-Fuertes, Yolanda; Schmitt, Jessica A.; Boxall, Katherine J.; Burke, Rosemary; Sun, Chongbo; Avery, Sian; Bush, Katherine; Henley, Alan; Raynaud, Florence I.; Workman, Paul; Bayliss, Richard; Linardopoulos, Spiros; Blagg, Julian [Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9122 - 9135]

62
[ 662116-67-8 ]
4-hydroxy-N-(pyridin-4-yl)benzamide [ No CAS ]
4-(2-amino-5-chloro-3-nitropyridin-4-yloxy)-N-(pyridin-4-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	Stage #1: 4-hydroxy-N-(pyridin-4-yl)benzamide With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.333333h; Inert atmosphere; Stage #2: 4,5-dichloro-3-nitropyridin-2-ylamine In N,N-dimethyl-formamide at 20℃; for 2h; Inert atmosphere;

Reference： [1]Bavetsias, Vassilios; Faisal, Amir; Crumpler, Simon; Brown, Nathan; Kosmopoulou, Magda; Joshi, Amar; Atrash, Butrus; Pérez-Fuertes, Yolanda; Schmitt, Jessica A.; Boxall, Katherine J.; Burke, Rosemary; Sun, Chongbo; Avery, Sian; Bush, Katherine; Henley, Alan; Raynaud, Florence I.; Workman, Paul; Bayliss, Richard; Linardopoulos, Spiros; Blagg, Julian [Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9122 - 9135]

63
[ 662116-67-8 ]
[ 33901-20-1 ]
4-(2-amino-5-chloro-3-nitropyridin-4-yloxy)-N-benzylbenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	Stage #1: N-benzyl-4-hydroxybenzamide With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.333333h; Inert atmosphere; Stage #2: 4,5-dichloro-3-nitropyridin-2-ylamine In N,N-dimethyl-formamide at 20℃; for 1.5h; Inert atmosphere;

Reference： [1]Bavetsias, Vassilios; Faisal, Amir; Crumpler, Simon; Brown, Nathan; Kosmopoulou, Magda; Joshi, Amar; Atrash, Butrus; Pérez-Fuertes, Yolanda; Schmitt, Jessica A.; Boxall, Katherine J.; Burke, Rosemary; Sun, Chongbo; Avery, Sian; Bush, Katherine; Henley, Alan; Raynaud, Florence I.; Workman, Paul; Bayliss, Richard; Linardopoulos, Spiros; Blagg, Julian [Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9122 - 9135]

64
[ 662116-67-8 ]
[ 478929-28-1 ]
(4-(2-amino-5-chloro-3-nitropyridin-4-yloxy)phenyl)(pyrrolidin-1-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	Stage #1: (4-hydroxyphenyl)(pyrrolidin-1-yl)methanone With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.333333h; Inert atmosphere; Stage #2: 4,5-dichloro-3-nitropyridin-2-ylamine In N,N-dimethyl-formamide at 20℃; for 1.58333h; Inert atmosphere;

Reference： [1]Bavetsias, Vassilios; Faisal, Amir; Crumpler, Simon; Brown, Nathan; Kosmopoulou, Magda; Joshi, Amar; Atrash, Butrus; Pérez-Fuertes, Yolanda; Schmitt, Jessica A.; Boxall, Katherine J.; Burke, Rosemary; Sun, Chongbo; Avery, Sian; Bush, Katherine; Henley, Alan; Raynaud, Florence I.; Workman, Paul; Bayliss, Richard; Linardopoulos, Spiros; Blagg, Julian [Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9122 - 9135]

65
[ 662116-67-8 ]
N-cyclobutyl-4-hydroxybenzamide [ No CAS ]
4-((2-amino-5-chloro-3-nitropyridin-4-yl)oxy)-N-cyclobutylbenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	Stage #1: N-cyclobutyl-4-hydroxybenzamide With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.333333h; Inert atmosphere; Stage #2: 4,5-dichloro-3-nitropyridin-2-ylamine In N,N-dimethyl-formamide at 20℃; for 1.58333h; Inert atmosphere;

Reference： [1]Bavetsias, Vassilios; Faisal, Amir; Crumpler, Simon; Brown, Nathan; Kosmopoulou, Magda; Joshi, Amar; Atrash, Butrus; Pérez-Fuertes, Yolanda; Schmitt, Jessica A.; Boxall, Katherine J.; Burke, Rosemary; Sun, Chongbo; Avery, Sian; Bush, Katherine; Henley, Alan; Raynaud, Florence I.; Workman, Paul; Bayliss, Richard; Linardopoulos, Spiros; Blagg, Julian [Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9122 - 9135]

66
[ 662116-67-8 ]
[ 114636-31-6 ]
(S)-N-(1-(2-amino-5-chloro-3-nitropyridin-4-yl)pyrrolidin-3-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 45℃; for 18h;

Reference： [1]Bavetsias, Vassilios; Faisal, Amir; Crumpler, Simon; Brown, Nathan; Kosmopoulou, Magda; Joshi, Amar; Atrash, Butrus; Pérez-Fuertes, Yolanda; Schmitt, Jessica A.; Boxall, Katherine J.; Burke, Rosemary; Sun, Chongbo; Avery, Sian; Bush, Katherine; Henley, Alan; Raynaud, Florence I.; Workman, Paul; Bayliss, Richard; Linardopoulos, Spiros; Blagg, Julian [Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9122 - 9135]

67
[ 662116-67-8 ]
[ 131900-62-4 ]
(R)-N-(1-(2-amino-5-chloro-3-nitropyridin-4-yl)pyrrolidin-3-yl)acetamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 9122 - 9135

68
[ 662116-67-8 ]
[ 131900-62-4 ]
(R)-N-(1-(6-chloro-2-(1,3-dimethyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)pyrrolidin-3-yl)acetamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 9122 - 9135

69
[ 662116-67-8 ]
(S)-N-(piperidin-3-ylmethyl)methanesulfonamide trifluoroacetic acid [ No CAS ]
(S)-N-((1-(2-amino-5-chloro-3-nitropyridin-4-yl)piperidin-3-yl)methyl)methanesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.080 g	With N-ethyl-N,N-diisopropylamine In dichloromethane; isopropyl alcohol at 45℃; for 20h; Inert atmosphere;

Reference： [1]Bavetsias, Vassilios; Faisal, Amir; Crumpler, Simon; Brown, Nathan; Kosmopoulou, Magda; Joshi, Amar; Atrash, Butrus; Pérez-Fuertes, Yolanda; Schmitt, Jessica A.; Boxall, Katherine J.; Burke, Rosemary; Sun, Chongbo; Avery, Sian; Bush, Katherine; Henley, Alan; Raynaud, Florence I.; Workman, Paul; Bayliss, Richard; Linardopoulos, Spiros; Blagg, Julian [Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9122 - 9135]

70
[ 662116-67-8 ]
5-chloro-4-(4-(isoxazol-3-ylmethyl)piperazin-1-yl)-3-nitropyridin-2-amine trifluoroacetate [ No CAS ]
5-chloro-4-(4-(isoxazol-3-ylmethyl)piperazin-1-yl)-3-nitropyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
239 mg	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 45℃; for 16h;	3 5-Chloro-4-( 4-(isoxazol-3-ylmethyl)piperazin-1-yl)-3-nitropyridin-2-amine tert-Butyl 4-(isoxazol-3-ylmethyl)piperazine-1-carboxylate (335 mg, 1.24 mmol)was dissolved in dichloromethane (8.5 ml) and trifluoroacetic acid (1.7 ml) was added.The reaction was stirred for 2 h. The solvents were evaporated and the residue wasazeotroped twice with toluene and dried in vacuum over sodium hydroxide for 4.5 h. Thistrifluoroacetate salt was stirred in 2-propanol (9 ml) and 2-amino-3-nitro-4,5-dichloropyridine (202 mg, 0.97 mmol) was added followed by diisopropylethylamine (0.90ml, 666 mg, 5.16 mmol). The reaction was stirred at 45 °C for 16 h. The reaction wascooled to 0-5 °C and the solid was filtered off, washed with 2-propanol (2 x 5 ml) andwith ether (2 x 5 ml) to give the title compound (239 mg, 72%). 1H-NMR (500 MHz,5 DMSO-d6) 2.53 (m, 4H, piperazine C-H), 3.05 (m, 4H, piperazine C-H), 3.66 (s, 2H, NCH2-isoxazole), 6.56 (d, J= 1.6 Hz, 1 H, isoxazole C-H), 6.95 (s, 2H, NH2), 8.06 (s, 1 H,pyridine 6-H), 8.86 (d, J=1.58Hz, 1 H, isoxazole C-H).[00132] LC- MS (ESI, m/z): Rt = 1.33 min- 339 (M+Ht, 35CI isotope.

Reference： [1]Current Patent Assignee: CANCER RESEARCH UK - WO2013/190320, 2013, A1 Location in patent: Paragraph 00131

71
[ 662116-67-8 ]
[ 7006-50-0 ]
N4-(1-benzylpiperidin-4-yl)-5-chloro-N4-methyl-3-nitropyridine-2,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
474 mg	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 80℃; for 20h;	INTERMEDIATE 22 N4-(l-Benzylpiperidin-4-yl)-5-chloro- N4-methyl-3-nitropyridine-2,4-diamine To a slurry of 4,5-dichloro-3-nitropyridine-2-amine (INTERMEDIATE 3, 300 mg, 1.44 mmol) in IPA (6 mL) was added l-benzyl-N-methylpiperidin-4-amine (309 mg, 1.51 mmol) and DIPEA (280 mg, 2.16 mmol, 380 mu). The mixture was stirred at 80 C for 20 h. After cooling the solvent was evaporated and the crude residue dissolved in EtOAc (40 mL). Water (2 mL) and K2CO3 (ca 200 mg) were added, and the mixture was stirred for 10 min. forming clear layers. The aqueous phase was separated and the organic layer was washed with water (5x2 mL), dried over Na2S04, filtered and the filtrate evaporated to furnish 531 mg (98%) of brown-yellow solid. Trituration with diethyl ether (ca 4 mL) furnished 451 mg (83%) of yellow powder. A second crop of the triturated material furnished 23 mg of brown solid, 95% pure. 1H NMR (600 MHz, CD3OD) delta ppm 7.97 (s, 1 H) 7.32 (d, J=4.58 Hz, 4 H) 7.22 - 7.29 (m, 1 H) 3.52 (s, 2 H) 3.47 - 3.55 (m, 1 H) 2.90 - 3.00 (m, 2 H) 2.71 (s, 3 H) 2.03 - 2.12 (m, 2 H) 1.83 - 1.91 (m, 4 H). MS (ESI+) m/z 376, 378 [M+H]+ , chlorine isotopic pattern.

Reference： [1]Patent: WO2016/124553,2016,A1 .Location in patent: Page/Page column 79

72
[ 662116-67-8 ]
[ 78471-35-9 ]
5-chloro-N⁴-[1-(4-methoxybenzyl)piperidin-4-yl]-3-nitropyridine-2,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 50℃;	INTERMEDIATE 94 5-Chloro- V⁴-[l-(4-methoxybenzyl)piperidin-4-yl]-3-nitropyridine-2,4-diamine INTERMEDIATE 94 5-Chloro- V4-[l-(4-methoxybenzyl)piperidin-4-yl]-3-nitropyridine-2,4-diamine To a slurry of 4,5-dichloro-3-nitropyridine-2-amine (INTERMEDIATE 3, 3.71 g, 17.8 mmol) in z'-PrOH (50 mL) was added l-(4-methoxybenzyl)piperidin-4-amine (INTERMEDIATE 36, 4.00 g, 18.17 mmol) and DIPEA (5.7 mL). The mixture was stirred at 50 °C over night. Monitoring by LCMS indicated full conversion to the title product. The reaction was allowed to cool to room temperature and was centrifuged. The supernatant was separated and the yellow solid was sequentially washed with EtOAc (1x25 mL), MeOH (2x25 mL), EtOAc (30 mL) and then dried in vacuum to furnish 6.70 g (85%) of 99% pure title product as yellow powder. 1H NMR (600 MHz, DMSO-d6) δ ppm 7.87 (s, 1 H) 7.76 (d, J=6.41 Hz, 1 H) 7.57 (br. s., 2 H) 7.19 (d, J=8.55 Hz, 2 H) 6.87 (d, J=8.85 Hz, 2 H) 3.83 (br. s., 1 H) 3.73 (s, 3 H) 3.38 (s, 2 H) 2.67 (d, J=9.46 Hz, 2 H) 2.03 (t, J=10.38 Hz, 2 H) 1.87 (dd, J=13.12, 3.36 Hz, 2 H) 1.49 - 1.57 (m, 2 H). MS (ESI+) m/z 392 [M+H]+.
85%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 50℃;	INTERMEDIATE 25 (0437) 5-Chloro-N4-[1-(4-methoxybenzyl)piperidin-4-yl]-3-nitropyridine-2,4-diamine To a slurry of 4,5-dichloro-3-nitropyridine-2-amine (INTERMEDIATE 3, 3.71 g, 17.8 mmol) in i-PrOH (50 mL) was added 1-(4-methoxybenzyl)piperidin-4-amine (INTERMEDIATE 7, 4.00 g, 18.17 mmol) and DIPEA (5.7 mL). The mixture was stirred at 50 C over night. The reaction was allowed to cool to room temperature and was centrifuged. The supernatant was separated and the yellow solid was sequentially washed with EtOAc (25 mL), MeOH (2x25 mL), EtOAc (30 mL) and then dried in vacuum to furnish 6.70 g (85%) of 99% pure title product as yellow powder.1H NMR (600 MHz, DMSO-d6) δ ppm 7.87 (s, 1 H) 7.76 (d, J=6.41 Hz, 1 H) 7.57 (br. s., 2 H) 7.19 (d, J=8.55 Hz, 2 H) 6.87 (d, J=8.85 Hz, 2 H) 3.83 (br. s., 1 H) 3.73 (s, 3 H) 3.38 (s, 2 H) 2.67 (d, J=9.46 Hz, 2 H) 2.03 (t, J=10.38 Hz, 2 H) 1.87 (dd, J=13.12, 3.36 Hz, 2 H) 1.49 - 1.57 (m, 2 H). MS (ESI+) m/z 392, 394 [M+H]+ , chlorine isotopic pattern.
65%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 70℃; for 12h;	Intermediate 4: 5-Chloro-N4-(1-(4-methoxybenzyl)piperidin-4-yl)-3-nitropyridine-2,4-diamine General method C: in 1-(4-methoxybenzyl) piperidin-4-amine (I-2,5g, 1eq) and 4,5-dichloro-3-nitropyridin-2-amine (I -3,4.8g, 1eq) isopropanol (30ml) suspension was added DIPEA (13ml, 3eq), the mixture was stirred at 70 for 12h. Then cooled to room temperature, the suspension was filtered, and then a small amount of isopropyl alcohol Rinse with propanol, pull dry the filter cake solvent, and dry in vacuo to obtain the yellow target compound 5-chloro-N4-(1-(4-methoxybenzyl)piperidin-4-yl)-3-nitropyridine-2, 4-diamine (I-4, 5.8 g, 65%).

Reference： [1]Current Patent Assignee: KANCERA AB - WO2016/124553, 2016, A1 Location in patent: Page/Page column 101
[2]Current Patent Assignee: KANCERA AB - WO2018/11138, 2018, A1 Location in patent: Page/Page column 77
[3]Current Patent Assignee: LONGTAISHEN PHARMACEUTICAL TECH NANJING; LONGTAISHEN MEDICAL TECH NANJING - CN112574176, 2021, A Location in patent: Paragraph 0223-0226

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(3S)-1-(4-methoxybenzyl)pyrrolidin-3-amine [ No CAS ]
5-chloro-N⁴-[(3S)-1-(4-methoxybenzyl)pyrrolidin-3-yl]-3-nitropyridine-2,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 50℃; for 19h;	INTERMEDIATE 29 (0445) 5-Bromo-N4-(1-ethylpiperidin-4-yl)-3-nitropyridine-2,4-diamine General procedure: To a slurry of 5-bromo-4-chloro-3-nitropyridin-2-amine (INTERMEDIATE 6, 1010 mg, 4.0 mmol) in i-PrOH (15 mL) was added 1-ethylpiperidin-4-amine dihydrochloride (0447) (INTERMEDIATE 15, 805 mg, 4.0 mmol) and DIPEA (1.81 g, 14.0 mmol, 1.81 mL). The mixture was stirred at 50 for 19 h. The reaction was allowed to cool to room temperature, was centrifuged and the supernatant separated. The solid was slurried in EtOAc (200 mL) and washed with sat. Na2CO3 (2x20 mL). The phases were separated and the organic phase was washed with water (3x15 mL) and brine (15 mL), dried over Na2SO4, filtered and evaporated to yield 1.166 g (85%) of pure title product as bright yellow solid.

Reference： [1]Current Patent Assignee: KANCERA AB - WO2018/11138, 2018, A1 Location in patent: Page/Page column 78; 82

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(3S)-1-methylpyrrolidin-3-amine dihydrochloride [ No CAS ]
5-chloro-N⁴-[(3S)-1-methylpyrrolidin-3-yl]-3-nitropyridine-2,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 50℃;	INTERMEDIATE 39 (0464) 5-Chloro-N4-[(3S)-1-methylpyrrolidin-3-yl]-3-nitropyridine-2,4-diamine To a slurry of 4,5-dichloro-3-nitropyridin-2-amine (INTERMEDIATE 3, 1.20 g, 5.78 mmol) in i-PrOH (16 mL) was added (3S)-1-methylpyrrolidin-3-amine dihydrochloride (0466) (INTERMEDIATE 17, 1.00 g, 5.78 mmol) and DIPEA (2.48 g, 19.07 mmol, 3.5 mL). The mixture was stirred at 50 C over night. The mixture was cooled to room temperature and filtered on a G3 glass filter. The solid material was washed with IPA (3x5 mL) and dried in vacuum. The solid was then dissolved in EtOAc (150 mL) and washed with aqueous sat. K2CO3 (2x8 mL), brine (8 mL) and dried (Na2SO4). The organic phase was filtered and the solvent evaporated to furnish 735 mg (53%) of 98% pure title product as yellow solid.1H NMR (600 MHz, DMSO-d6) δ ppm 8.13 (d, J=7.32 Hz, 1 H) 7.86 (s, 1 H) 7.59 (s, 2 H) 4.38 - 4.49 (m, 1 H) 2.71 - 2.77 (m, 1 H) 2.60 (dd, J=9.92, 2.90 Hz, 1 H) 2.52 (d, J=6.00 Hz, 1 H) 2.25 (s, 3 H) 2.17 - 2.24 (m, 2 H) 1.68 - 1.73 (m, 1 H). MS (ESI+) m/z 272 [M+H]+ .

Reference： [1]Current Patent Assignee: KANCERA AB - WO2018/11138, 2018, A1 Location in patent: Page/Page column 81-82

75
N-(4,5-dichloropyridin-2-yl)nitramide [ No CAS ]
[ 662116-67-8 ]

Yield	Reaction Conditions	Operation in experiment
59%	With sulfuric acid at 40℃; for 2.5h;	INTERMEDIATE 3 (0390) 4,5-Dichloro-3-nitropyridine-2-amine 4,5-Dichloro-N-nitropyridin-2-amine (INTERMEDIATE 2, 20.0 g, 96.2 mmol) was added to 200 mL of conc. H2SO4 at room temperature. After stirring at 40 C for 2.5 h the mixture was cooled to below room temperature and poured onto crushed ice (2 L) while stirring. After the ice had melted, the volume was adjusted to ca.2 L with ice cold water and the yellow precipitate was collected by filtration and washed with ice cold water until neutral pH (3 x 250 mL). The solid was allowed to semi-dry on the filter and was then dissolved in EtOAc (ca.800 mL). The organic phase was washed with 0.25 M NaOH (3x30 mL), water (3x15 mL) and brine (15 mL), dried (Na2SO4), filtered and the solvent evaporated to furnish 11.7 g (59%) of 99% pure title product as yellow solid.1H NMR (600 MHz, CD3OD) δ ppm 8.26 (s, 1 H). MS: (ESI+) m/z 208, 210, 212 [M+H]+ chlorine isotopic pattern.

Reference： [1]Current Patent Assignee: KANCERA AB - WO2018/11138, 2018, A1 Location in patent: Page/Page column 70-71

76
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5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester [ No CAS ]
5-((2-amino-5-chloro-3-nitropyridin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol for 24h; Reflux;	19.2 Step 2) 5-((2-Amino-5-chloro-3-nitropyridin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester To 4,5-dichloro-3-nitropyridin-2-amine(1.50 g, 7.23 mmol) of isopropanol (30.0 mL)Add 5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester to the suspension(3.27g, 14.4mmol)And DIPEA (4.22 g, 32.7 mmol).The reaction system was heated to reflux for 24 hours.After the reaction was completed, it was concentrated under reduced pressure. The residue obtained is passed through a silica gel column Purification by chromatography (DCM/MeOH (v/v) = 100/1)The title compound was obtained as a yellow solid (1.62 g, yield 56%).
56%	With N-ethyl-N,N-diisopropylamine In isopropyl alcohol for 24h; Reflux;	19.2 Step 2) ferf-butyl 5-((2-amino-5-chloro-3-nitropyridin-4-yl amino)hexahydrocvclo- penta[c]pyrrole-2(lH)-carboxylate To a suspension of 4,5-dichloro-3-nitropyridin-2-amine (1.50 g, 7.23 mmol) in z'-PrOH (30.0 mL) were added tert-butyl 5-aminohexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (3.27 g, 14.4 mmol) and DIPEA (4.22 g, 32.7 mmol). The mixture was heated to reflux and stirred for 24 h. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)= 100/1) to afford the title compound as a yellow solid (1.62g, yield 56%).MS (ESI, pos. ion) m/z: 341.9 [M-56+H]+; NMR (600 MHz, CDCh) δ (ppm): 8.79 (s, 1H), 7.83 (s, 1H), 6.73 (s, 2H), 4.72 - 4.62 (m, 1H), 3.54 - 3.46 (m, 2H), 3.41 - 3.27 (m, 2H), 2.71 - 2.63 (m, 2H), 2.53 - 2.46 (m, 2H), 1.49 (s, 9H), 1.47 - 1.43 (m, 2H)

Reference： [1]Current Patent Assignee: CALITOR SCIENCES LLC; SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN108570048, 2018, A Location in patent: Paragraph 0677; 0683-0684
[2]Current Patent Assignee: CALITOR SCIENCES LLC; SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2018/169700, 2018, A1 Location in patent: Paragraph 00364; 00365

77
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3-(5-((6-chloro-2-(1-methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-7-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-3-oxopropanenitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 24 h / Reflux 2: sodium dithionite / ethanol / 85 °C 3: hydrogenchloride / ethyl acetate; dichloromethane / 1 h / 20 °C 4: 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 20 °C
	Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine / isopropyl alcohol / 24 h / Reflux 2: sodium dithionite / ethanol / 85 °C 3: hydrogenchloride / dichloromethane / 1 h / 20 °C 4: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; 1-hydroxy-7-aza-benzotriazole / dichloromethane / 20 °C