Name: 173435-41-1|Methyl 3-amino-2-chloroisonicotinate|98%
Brand: Ambeed
SKU: A506193
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1
[ 55279-30-6 ]
methyl 3-amino-2-chloropyridine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With hydrogenchloride; dihydrogen peroxide; at 20℃; for 3h;Cooling with ice;	To a solution of <strong>[55279-30-6]methyl 3-aminopyridine-4-carboxylate</strong> (30.4 g, 0.2 mol) in concentrated HC1 was added H202 (24.9 g, 0.22 mol) dropwise at ice-bath temperature, and the mixture was stirred at rt for 1 h. Aq. Na2S2O3 (10 mL) was added, and the precipitate was filtered. The filtrate was adjusted to pH=8 using aq. NaHCO3, and the solution was extracted with EA, dried and concentrated in vacuo. The crude was purified by silica gel chromatography (20: 1: 1 PE:EA:DCM) to give 18.3 g (50%) of the title compound as an off-white solid. ?H NMR (400 MHz, CDC13): oe 7.69 (d, J= 5.2 Hz, 1H), 7.58 (d, J= 5.2 Hz, 1H), 6.18 (br. s., 2H), 3.91 (s, 3H). [M+H] Calc?d for C7H7C1N202, 187; Found, 187.

Reference： [1]Patent: WO2014/151106,2014,A1 .Location in patent: Paragraph 00191
[2]Journal of Heterocyclic Chemistry,2001,vol. 38,p. 99 - 104

2
[ 103698-10-8 ]
methyl 3-amino-2-chloropyridine-4-carboxylate [ No CAS ]

Reference： [1]Journal of Heterocyclic Chemistry,2001,vol. 38,p. 99 - 104

3
[ 118-52-5 ]
[ 55279-30-6 ]
methyl 3-amino-2-chloropyridine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In 1,1,2,2-tetrachloroethylene;	4. Preparation of Methyl 3-Amino-2-chloroisonicotinate A mixture of 18 g (118 mmol) of methyl 3-aminoisonicotinate and 12 g (60 mmol) of <strong>[118-52-5]1,3-dichloro-5,5-dimethylhydantoin</strong> in 1500 mL of tetrachloroethylene was warmed slowly to 80 C. with stirring and held there for 3 hours. The solution was then cooled, filtered, washed with dilute aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a dark oil. This oil was purified by careful column chromatography to give 6.7 g (30 percent of theory) of the title compound as a colorless solid melting at 91-92 C. Elemental Analysis C7 H7 ClN2 O2 Calc.: %C, 45.1; %H, 3.78; %N, 15.0 Found: %C, 45.2; %H, 3.94; %N, 15.1 1 H NMR CDCl3: 7.7 (d, 1H, J=5.1); 7.6 (d, 1H, J=5.1); 6.2 (br, 2H); 3.9 (s, 3H); 13 C NMR CDCl3: 166.7, 141.9, 139.0, 134.7, 122.8, 116.5, 52.3.
	In 1,1,2,2-tetrachloroethylene;	44. Preparation of Methyl 3-Amino-2-chloroisonicotinate A mixture of 18 g (118 mmol) of methyl 3-aminoisonicotinate and 12 g (60 mmol) of <strong>[118-52-5]1,3-dichloro-5,5-dimethylhydantoin</strong> in 1500 mL of tetrachloroethylene was warmed slowly to 80 C. with stirring and held there for 3 hours. The solution was then cooled, filtered, washed with dilute aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a dark oil. This oil was purified by careful column chromatography to obtain 6.7 g (30 percent of theory) of the title compound as a colorless solid melting at 91-92 C. Elemental Analysis C7 H7 ClN2 O2 Calc.: %C, 45.1; %H, 3.78; %N, 15.0 Found: %C, 45.2; %H, 3.94; %N, 15.1 1 H NMR CDCl3: 7.7 (d, 1H, J=5.1); 7.6 (d, 1H, J=5.1); 6.2 (br, 2H); 3.9 (s, 3H); 13 C NMR CDCl3: 166.7, 141.9, 139.0, 134.7, 122.8, 116.5, 52.3.
	In 1,1,2,2-tetrachloroethylene;	4. Preparation of Methyl 3-Amino-2-chloroisonicotinate A mixture of 18 g (118 mmol) of methyl 3-aminoisonicotinate and 12 g (60 mmol) of <strong>[118-52-5]1,3-dichloro-5,5-dimethylhydantoin</strong> in 1500 mL of tetrachloroethylene was warmed slowly to 80 C. with stirring and held there for 3 hours. The solution was then cooled, filtered, washed with dilute aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain a dark oil. This oil was purified by careful column chromatography to give 6.7 g (30 percent of theory) of the title compound as a colorless solid melting at 91-92 C. Elemental Analysis C7 H7 ClN2 O2 Calc.: %C, 45.1; %H, 3.78; %N, 15.0 Found: %C, 45.2; %H, 3.94; %N, 15.1 1 H NMR CDCl3: 7.7 (d, 1H, J=5.1); 7.6 (d, 1H, J=5.1; 6.2 (br, 2H); 3.9 (s, 3H); 13 C NMR CDCl3: 166.7, 141.9, 139.0, 134.7, 122.8, 116.5, 52.3.

Reference： [1]Patent: US5461161,1995,A
[2]Patent: US5571775,1996,A
[3]Patent: US5614469,1997,A

4
[ 446285-73-0 ]
[ 173435-41-1 ]
[ 1629171-74-9 ]

Yield	Reaction Conditions	Operation in experiment
76%	With Pd-118 In N,N-dimethyl-formamide at 130℃; for 3h; Inert atmosphere;	68B Preparation 68B: methyl 3 -amino-2-( 1-methyl-i H-imidazol-4-yl)pyridine-4-carboxylate A mixture of methyl 3-amino-2-chloropyridine-4-carboxylate (1.0 g, 5.4 mmol), i-methyl-4-tributylatannanyl-1H-imidazole (2.0 g, 5.4 mmol) and Pd-118 (400 mg, 0.54 mmol) in DMF (10 mL) was stirred under N2 at 130 °C for 3 h. The solution was concentrated in vacuo and the residue was purified by silica gel chromatography (5% MeOH:DCM) to give 1.3 g (76%) of the title compound. 1H NMR (400 MHz, CDCl3): ö 3.78 (3H, s), 3.92 (3H, s), 7.30-7.36 (2H, m), 7.65 (1H, d, J= 2.0 Hz), 7.81 (1H, d, J= 6.4 Hz), 8.25 (2H, s).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2014/151106, 2014, A1 Location in patent: Paragraph 00192

5
[ 115-19-5 ]
[ 173435-41-1 ]
[ 1630925-06-2 ]

Yield	Reaction Conditions	Operation in experiment
81%	With dichloro bis(acetonitrile) palladium(II); potassium carbonate; XPhos In acetonitrile at 80℃; for 16h; Inert atmosphere;	4 [0011 5j Methyl 3 -amino-2-chloroisonicotinate (186mg, 1 mmol), PdC12(CH3CN)2(5.2 mg, 0.02 mmol), X-Phos (19 mg, 0.04 mmol), K2C03(278 mg, 2.0 mmol), and 2-methyl-3-butyn-2-ol(130 mg, 1.2 mmol) in CH3CN (2 mL) was purged with N2 for 2 mm.The reaction was allowed to stir at 80 °C for 16 hrs. The reaction was concentrated in vacuoand purified by column chromatography (0-50% gradient of EtOAc/Hex) to afford methyl3 -amino-2-(3 -hydroxy-3 -methylbut- 1 -yn- 1 -yl)pyridine-4-carboxylate (191mg, 81%).[M+H] calc’d for C,2H,4N203, 235; found 235.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2014/164708, 2014, A1 Location in patent: Paragraph 00115

6
[ CAS Unavailable ]
[ 173435-41-1 ]
[ 1630925-98-2 ]

Yield	Reaction Conditions	Operation in experiment
26%	With potassium phosphate; Pd(t-Bu₃P)2; magnesium sulfate; acetic acid In N,N-dimethyl acetamide at 140℃; for 16h; Inert atmosphere; Sealed tube;	91 Example 91: methyl 2-( 1 -benzofuran-2-yl)- 1 H-pyrrolo [3 ,2-b]pyridine-7-carboxylate [00212j A mixture containing methyl 3-amino-2-chloroisonicotinate (372 mg, 2mmol), 2-benzofuranyl methyl ketone (960 mg, 6 mmol), MgSO4 (120 mg, 1 mmol), andAcOH (150 iL, 3mmol) in DMA was purged with N2 for 10 mi Pd(tBu3P)2 (101 mg, 0.2mmol) and K3P04 (552 mg, 2.6 mmol) were added and the reaction sealed and heated at 140°C for 16 hrs. The reaction mixture was taken up in EtOAc and washed successively withwater (2X), brine, and dried with N2S04. The organic layers were concentrated in vacuo andthe residue purified by column chromatography to afford the title compound (152 mg, 26%)as a yellow solid. ‘H NMR (400 MHz, DMSO-d6) ö ppm 4.33 (s, 2 H), 6.24 (s, 1 H), 7.31 -7.44 (m, 2 H), 7.49 (d,J5.31 Hz, 1H), 7.66 (s, 1 H), 8.39 (d,J=4.55 Hz, 1 H), 11.43 (br. s.,1 H), 13.70 (br. s., 1 H). [M+H] Calc’d for C,7H,2N203, 293; Found, 293.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2014/164708, 2014, A1 Location in patent: Paragraph 00212

7
[ 107-19-7 ]
[ 173435-41-1 ]
[ 1630925-12-0 ]

Yield	Reaction Conditions	Operation in experiment
18%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In acetonitrile at 40℃; for 16h; Inert atmosphere;	9 [00121j Methyl 3-amino-2-chloroisonicotinate (1.04 g, 5.64 mmol), propargyl alcohol (393 iL, 6.76 mmol), Pd(PPh3)2Cl2 (198 mg, 0.28 mmol), Cul (28 mg, 0.14 mmol), and TEA (2.84 g, 28.18 mmol) were combined in acetonitrile (20 mL). The reaction was purged with nitrogen for 2 mm and then was stirred at 40 °C for 16 hrs. The reaction was concentrated in vacuo and the residue suspended in dichloromethane and filtered. The filtrate was concentrated in vacuo and the residue purified by silica gel chromatography (PE/EA = 3/1 1/1) to afford methyl 3-amino-2-(3-hydroxyprop-1-yn-1-yl)pyridine-4- carboxylate (200 mg, 18%). ‘H NMR (300 MHz, DMSO-d6): ö 3.86 (3H, s), 4.39 (2H, d, J = 8.0 Hz), 5.42 (1H, t, J 8.0 Hz), 6.24 (2H, s), 7.55 (1H, d, J= 6.4 Hz), 7.81 (1H, d, J= 5.6 Hz). [M+H] Calc’d for C,0H,0N203, 207; Found, 207.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2014/164708, 2014, A1 Location in patent: Paragraph 00121

8
[ 536-74-3 ]
[ 173435-41-1 ]
[ 1630925-03-9 ]

Yield	Reaction Conditions	Operation in experiment
77%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In N,N-dimethyl-formamide at 100℃; for 16h; Inert atmosphere;	2 [001 12j Methyl 3 -amino-2-chloroisonicotinate (187 mg, 1.0 mmol), Pd(PPh3)2C12 (35 mg, 0.05 mmol), Cul (38 mg, 0.20 mmol), TEA (278 iL,2.0 mmol) and phenylacetylene (130 mg, 1.2 mmol) were suspended in DMF (2mL). N2 was bubbled into the reaction for 2 mm and it was allowed to stir at 100 °C for 16 hrs. The reaction was concentrated in vacuo and purified by column chromatography (0-50% gradient of EtOAc/Hex) to afford methyl 3-amino-2-(phenylethynyl)pyridine-4-carboxylate (195 mg, 77%) as a brown foam. [M+H] calc’d for C,4H,0N202, 239; found 239.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2014/164708, 2014, A1 Location in patent: Paragraph 00112

9
[ 1569308-28-6 ]
[ 173435-41-1 ]
[ 1569308-65-1 ]

Yield	Reaction Conditions	Operation in experiment
194 mg	Stage #1: methyl 3-amino-2-chloropyridine-4-carboxylate With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 0.166667h; Stage #2: With manganese(IV) oxide In tetrahydrofuran; toluene at 50℃; Stage #3: 6-chloro-2-(3-fluoropyridin-2-yl)chromane-7-amine Further stages;	54.A A) 2-chloro-4-(((6-chloro-2-(3-fluoropyridin-2-yl)-3,4-dihydro-2H-chromen-7-yl)amino)methyl)pyridin-3-amine To a suspension of lithium aluminum hydride (244 mg) in THF (10.0 mL) was added dropwise a solution of methyl 3-amino-2-chloroisonicotinate (300 mg) in THF (6.0 mL) at 0°C, and the mixture was stirred at 0°C for 10 min. To the reaction mixture was added sodium sulfate decahydrate, and the insoluble material was filtered off with celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in THF (4.0 mL) and toluene (12.0 mL), manganese dioxide (IV) (704 mg) was added, and the mixture was stirred at 50°C overnight. The reaction mixture was cooled to room temperature, and the insoluble material was filtered off by using celite. The filtrate was concentrated under reduced pressure. To a solution of the residue in toluene (7.7 mL) was added 6-chloro-2-(3-fluoropyridin-2-yl)chromane-7-amine (120 mg). p-Toluenesulfonic acid monohydrate (14.6 mg) was added, and the mixture was stirred under a nitrogen atmosphere at 100°C overnight. After cooling to room temperature, the mixture was extracted with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The extract was washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. To a suspension of lithium aluminum hydride (117 mg) in THF (5.0 mL) was added dropwise a solution of the residue in THF (2.0 mL) at 0°C, and the mixture was stirred at 0°C for 15 min. To the reaction mixture was added sodium sulfate decahydrate, and the insoluble material was filtered off with celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (194 mg). 1H NMR (300 MHz, CDCl3) δ 2.10-2.23 (1H, m), 2.30-2.46 (1H, m), 2.71-2.84 (1H, m), 2.86-3.01 (1H, m), 4.17-4.24 (2H, m), 4.27-4.36 (1H, m), 4.46 (2H, s), 5.36-5.45 (1H, m), 6.26 (1H, s), 7.01-7.07 (2H, m), 7.27-7.34 (1H, m), 7.44 (1H, ddd, J = 9.8, 8.3, 1.4 Hz), 7.77 (1H, d, J = 4.9 Hz), 8.47 (1H, dt, J = 4.4, 1.4 Hz).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2889291, 2015, A1 Location in patent: Paragraph 0409

10
methyl 3-amino-2-chloropyridine-4-carboxylate [ No CAS ]
[ 58483-94-6 ]

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 515 - 519
Angew. Chem.,2019,vol. 131,p. 525 - 529,5
[2]Journal of Medicinal Chemistry,2016,vol. 59,p. 1388 - 1409

11
[ 173435-41-1 ]
[ 342899-34-7 ]

Yield	Reaction Conditions	Operation in experiment
86%	With ammonia In methanol at 30℃; for 48h; Autoclave;	1 Step 1 A mixture of methyl 3-amino-2-chloroisonicotinate (1) (180 g, 0.96 mol) and methanol (1.2 L) in an autoclave was purged with ammonia gas until saturation. The mixture was stirred at 30° C. for 48 hours. An aliquot of the crude reaction mixture was analyzed by LC-MS and showed that the reaction was finished. The mixture was concentrated and gave the give crude product which was triturated with EtOAc (200 mL), filtered, and the cake was collected and dried in a vacuum to afford 3-amino-2-chloropyridine-4-carboxamide (2) as a white solid (142 g, 86% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.68 (s, 1H), 7.62 (d, J=5.0 Hz, 1H), 7.51 (d, J=5.0 Hz, 1H), 6.77 (s, 2H). LCMS (ESI) m/z 172, 174 (M+H).
76.14%	With ammonia In methanol at 20 - 25℃; for 48h;	1.3 third step: preparation of 3-amino-2-chloroisonicotinamide (intermediate 1-c) The raw material methyl 3-amino-2-chloroisonicotinate (3 g, 16.1 mmol) was dissolved in 7 molar ammonia gas methanol solution (120 mL), and stirred at room temperature (20-25° C.) for 2 days. After the reaction was detected by TLC, the crude product was directly concentrated to obtain the crude product, 15 ml of ethyl acetate was added, and 15°C was beaten for 10 minutes, and 2.1 g of white solid, namely 3-amino-2-chloroisonicotinamide, was obtained by filtration, with a yield of 76.14%.
	Multi-step reaction with 2 steps 1.1: lithium hydroxide monohydrate; sodium hydroxide / methanol / 0.75 h / 20 °C 1.2: pH 5.5 2.1: thionyl chloride; N,N-dimethyl-formamide / 2 h / Inert atmosphere; Reflux 2.2: 20 °C / Cooling with ice

	Multi-step reaction with 2 steps 1: sodium hydroxide 2: thionyl chloride; ammonium hydroxide
	Multi-step reaction with 2 steps 1: sodium hydroxide; methanol; lithium hydroxide monohydrate / 2 h / 25 - 30 °C 2: 1,1′-carbonyldiimidazole / acetonitrile / 1 h / 20 - 30 °C

Reference： [1]Current Patent Assignee: PFIZER INC - US2019/233440, 2019, A1 Location in patent: Paragraph 0170; 0171
[2]Current Patent Assignee: CSPC PHARMACEUTICAL GROUP LIMITED - WO2021/254493, 2021, A1 Location in patent: Page/Page column 37-38
[3]Bavetsias, Vassilios; Lanigan, Rachel M.; Ruda, Gian Filippo; Atrash, Butrus; McLaughlin, Mark G.; Tumber, Anthony; Mok, N. Yi; Le Bihan, Yann-Vaï; Dempster, Sally; Boxall, Katherine J.; Jeganathan, Fiona; Hatch, Stephanie B.; Savitsky, Pavel; Velupillai, Srikannathasan; Krojer, Tobias; England, Katherine S.; Sejberg, Jimmy; Thai, Ching; Donovan, Adam; Pal, Akos; Scozzafava, Giuseppe; Bennett, James M.; Kawamura, Akane; Johansson, Catrine; Szykowska, Aleksandra; Gileadi, Carina; Burgess-Brown, Nicola A.; Von Delft, Frank; Oppermann, Udo; Walters, Zoe; Shipley, Janet; Raynaud, Florence I.; Westaway, Susan M.; Prinjha, Rab K.; Fedorov, Oleg; Burke, Rosemary; Schofield, Christopher J.; Westwood, Isaac M.; Bountra, Chas; Müller, Susanne; Van Montfort, Rob L. M.; Brennan, Paul E.; Blagg, Julian [Journal of Medicinal Chemistry, 2016, vol. 59, # 4, p. 1388 - 1409]
[4]Vazquez-Rodriguez, Saleta; Wright, Miranda; Rogers, Catherine M.; Cribbs, Adam P.; Velupillai, Srikannathasan; Philpott, Martin; Lee, Henry; Dunford, James E.; Huber, Kilian V. M.; Robers, Matthew B.; Vasta, James D.; Thezenas, Marie-Laetitia; Bonham, Sarah; Kessler, Benedikt; Bennett, James; Fedorov, Oleg; Raynaud, Florence; Donovan, Adam; Blagg, Julian; Bavetsias, Vassilios; Oppermann, Udo; Bountra, Chas; Kawamura, Akane; Brennan, Paul E. [Angewandte Chemie - International Edition, 2019, vol. 58, # 2, p. 515 - 519][Angew. Chem., 2019, vol. 131, p. 525 - 529,5]
[5]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2020/239999, 2020, A1

12
methyl 3-amino-2-chloropyridine-4-carboxylate [ No CAS ]
[ 84341-13-9 ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 1388 - 1409
[2]Patent: US2019/233440,2019,A1

13
[ 1257237-31-2 ]
[ 173435-41-1 ]
[ 1876471-17-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: 1-[(3R)-3-methylmorpholin-4-yl]ethan-1-one With trichlorophosphate In 1,2-dichloro-ethane at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: methyl 3-amino-2-chloropyridine-4-carboxylate at 20 - 80℃;	b methyl 2-ch loro-3-[1-((R)-3-methylmorpholin-4-yl)eth-(E)-ylideneamino]isonicotinate Under argon and at a temperature of 0°C, 17.1 ml (188 mmol) of phosphorus oxychloride wereadded to a solution of 9.00 g (62.8 mmol) of 1-[(R)-3-methylmorpholin-4-yl]ethanone in 78 ml ofabsolute 1,2-dichloroethane. The yellow solution was stirred at room temperature for 30 mm.11.7 g (62.8 mmol) of methyl 3-amino-2-chloroisonicotinate were then added. The mixture wasstirred at 80°C for 1 h, at room temperature overnight and on the next day at 80°C for another5 h. The 1,2-dichloroethane was distilled off. For work-up, the mixture was taken up in 200 ml ofdichloromethane and 100 ml of water, sodium carbonate was added slowly and a little at a timewith vigorous stirring (pH = 9) and the mixture was extracted three times with in each case 250 mlof dichloromethane. The combined organic phases were dried over sodium sulphate and thenconcentrated to dryness under reduced pressure. In this manner, methyl 2-chloro-3-[1-((R)-3-methylmorpholin-4-yl)eth-(E)-ylideneamino]isonicotinate was obtained in a yield of 19.5 g (100%of theory) as a brown oil which was used without further purification in the next step. ‘H NMR(400 MHz, CDCI3): 6 [ppm] = 1.37 (3H), 1.78 (3H), 3.35 (1H); 3.58 (1H), 3.72-3.75 (3H), 3.83 (3H),3.95 (1H), 4.28 (1H), 7.52 (1H), 8.01 (1H). LC-MS (method 1): Rt = 0.23 mm; MS (ESI/APCIpos) m/z = 312.2 [M+H]+.

Reference： [1]Current Patent Assignee: POLI NUTRI ALIMENTOS SA; BAYER AG - WO2016/20320, 2016, A1 Location in patent: Page/Page column 90

14
[ 24424-99-5 ]
[ 173435-41-1 ]
[ 1876472-04-6 ]

Yield	Reaction Conditions	Operation in experiment
52%	With dmap In tetrahydrofuran at 20℃; for 16h; Inert atmosphere;	62.a methyl 3-tert-butoxycarbonylamino-2-chloroisonicotinate Under argon and at room temperature, 1.92 g (8.7 mmol) of di-tert-butyl dicarbonate and 244 mg (2 mmol) of 4-dimethylaminopyridine were added to a solution of 1.49 g (8 mmol) of methyl 3- amino-2-chloroisonicotinate in 20 ml of dry tetrahydrofuran. The mixture was stirred at roomtemperature for 16 h. For work-up, the reaction mixture was adjusted to pH 7 using 2N hydrochloric acid. The resulting precipitated solid was filtered off with suction and washed with 10 ml of water. In this manner, methyl 3-tert-butoxycarbonylamino-2-chloroisonicotinate was obtained in a yield of 1.2 g (52% of theory) as a colourless solid. This solid was a mixture of the product and the double Boc protected compound. The mixture was used for the next step withoutfurther purification.

Reference： [1]Current Patent Assignee: POLI NUTRI ALIMENTOS SA; BAYER AG - WO2016/20320, 2016, A1 Location in patent: Page/Page column 200; 201

15
[ 1257237-46-9 ]
[ 173435-41-1 ]
[ 1876471-22-5 ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: 1-((S)-3-methylmorpholin-4-yl)ethanone With trichlorophosphate In 1,2-dichloro-ethane at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: methyl 3-amino-2-chloropyridine-4-carboxylate In 1,2-dichloro-ethane at 80℃; for 5h;	b methyl 2-ch loro-3-[l-((S)-3-methylmorpholin-4-yl)eth-(E)-ylideneamino]isonicotinate Under argon and at a temperature of 0°C, 18.3 ml of (197 mmol) of phosphorus oxychloride were added to a solution of 9.39 g (65.6 mmol) of 1-((S)-3-methylmorpholin-4-yl)ethanone in 83 ml of absolute 1,2-dichloroethane. The yellow solution was stirred at room temperature for 30 mm. 12.37 g (65.6 mmol) of methyl 3-amino-2-chloroisonicotinate were then added. The mixture was stirred at 80°C for 5 h. The 1,2-dichloroethane was distilled off. For work-up, the mixture was taken up in 200 ml of dichloromethane and 100 ml of water, with vigorous stirring, by slowlyadding, a little at a time, solid sodium carbonate, the pH was adjusted to pH = 9 and the mixture was then extracted three times with in each case 250 ml of dichloromethane. The combined organic phases were dried over sodium sulphate and then concentrated under reduced pressure. In this manner, methyl 2-chloro-3-[1-((S)-3-methylmorpholin-4-yl)eth-(E)- ylideneamino]isonicotinate was obtained in a yield of 19.2 g (94% of theory) as a brown oil whichwas reacted further without further purification. ‘H NMR (400 MHz, CDCI3): 6 [ppm] = 1.37 (3H),1.78 (3H), 3.35 (1H); 3.58 (1H), 3.72-3.75 (3H), 3.83 (3H), 3.95 (1H), 4.28 (1H), 7.52 (1H), 8.01 (1H). LC-MS (method 1): R = 0.23 mm; MS (ESI/APCIpos) m/z = 312.2 [M÷H].

Reference： [1]Current Patent Assignee: POLI NUTRI ALIMENTOS SA; BAYER AG - WO2016/20320, 2016, A1 Location in patent: Page/Page column 93; 94

16
[ 1696-20-4 ]
methyl 3-amino-2-chloropyridine-4-carboxylate [ No CAS ]
methyl 2-chloro-3-[1-morpholin-4-yleth-(E)-ylideneamino]isonicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	Stage #1: 4-acetylmorpholine With trichlorophosphate In 1,2-dichloro-ethane at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: methyl 3-amino-2-chloropyridine-4-carboxylate In 1,2-dichloro-ethane at 80℃; for 3h;	a methyl-2-chloro-3-[i-morpholin-4-yleth-(E)-ylideneamino]isonicotinate Under argon and at a temperature of 0°C, 2.44 ml (25.40 mmol) of phosphorus oxychioride were added to a solution of 2.17 ml (18.8 mmol) of N-acetylmorpholine in 12 ml of absolute dichloroethane. The yellow solution was stirred at room temperature for 30 mm. 1.75 g(9.39 mmol) of methyl 3-amino-2-chloroisonicotinate were then added. The mixture was stirred at 80°C for 3 h. Dichloroethane was distilled off. Without work-up, the residue was purified by column chromatography [Puriflash silica gel 60 (80 g, 30 im); ethyl acetate/methanol 1:1, (300 ml)]. In this manner, methyl 2-chloro-3-[1-morpholin-4-yleth-(E)-ylideneamino]isonicotinate was obtained in a yield of 2.5 g (89% of theory) as a yellow oil. ‘H NMR (400 MHz, CDCI3): 6[ppm] = 1.79-1.84 (2H), 2.14 (3H), 3.66-67 (4H), 3.88-3.91 (4H), 3.93 (3H), 7.77 (1H), 8.56 (2H).

Reference： [1]Current Patent Assignee: BAYER AG; POLI NUTRI ALIMENTOS SA - WO2016/20320, 2016, A1 Location in patent: Page/Page column 85; 86

17
[ 120226-28-0 ]
[ 173435-41-1 ]
[ 1876471-26-9 ]

Yield	Reaction Conditions	Operation in experiment
58%	Stage #1: 1-[(3R,5S)-3,5-dimethylmorpholin-4-yl]ethanone With trichlorophosphate In 1,2-dichloro-ethane at 0 - 20℃; for 0.5h; Stage #2: methyl 3-amino-2-chloropyridine-4-carboxylate In 1,2-dichloro-ethane at 80℃; for 6h;	b methyl 2-ch loro-3-[(E)-{1-[(3R,55)-3,5-dimethylmorpholin-4-yl]ethylidene}amino] isonicotinate 1-[(3R,5S)-3,5-Dimethylmorpholin-4-yl]ethanone (0.54 g, 3.4 mmol, 2.3 eq.) was solubilized in DCE(2.7 mL) and the reaction mixture was cooled to 0°C. POd3 (0.46 mL, 4.3 mmol, 3.3 eq.) was added slowly and the reaction was warmed up to rt. After 30 minutes, methyl 3-amino-2- chloroisonicotinate (0.28 g, 1.5 mmol, 1 eq.) was added in one portion and the mixture was stirred at 80°C. After 6 hours, the reaction was cooled to room temperature and the solvent was removed under reduced pressure. The crude mixture was diluted with CH2CI2 and washed threetimes with sat. NaHCO3. The organic phase was dried (MgSO4) and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (gradient: 100% hexane to 100% EtOAc). The desired product was obtained in 58% yield (0.28 g). ‘H NMR (400 MHz, DMSOd 5) 6 ppm: 1.29 (3H), 1.33 (3H), 1.77 (3H), 3.56 (2H), 3.72 (2H), 3.77 (3H), 4.06 - 4.24 (2H), 7.56 (1H), 8.01 (1H). LC-MS (Method 3): m/z: [M÷H] = 326, R = 0.85 mm.
58%	Stage #1: 1-[(3R,5S)-3,5-dimethylmorpholin-4-yl]ethanone With trichlorophosphate In 1,2-dichloro-ethane at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: methyl 3-amino-2-chloropyridine-4-carboxylate In 1,2-dichloro-ethane at 80℃; for 6h; Inert atmosphere;

Reference： [1]Current Patent Assignee: POLI NUTRI ALIMENTOS SA; BAYER AG - WO2016/20320, 2016, A1 Location in patent: Page/Page column 98
[2]Lücking, Ulrich; Wortmann, Lars; Wengner, Antje M.; Lefranc, Julien; Lienau, Philip; Briem, Hans; Siemeister, Gerhard; Bömer, Ulf; Denner, Karsten; Schäfer, Martina; Koppitz, Marcus; Eis, Knut; Bartels, Florian; Bader, Benjamin; Bone, Wilhelm; Moosmayer, Dieter; Holton, Simon J.; Eberspächer, Uwe; Grudzinska-Goebel, Joanna; Schatz, Christoph; Deeg, Gesa; Mumberg, Dominik; Von Nussbaum, Franz [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7293 - 7325]

18
[ 1876471-29-2 ]
[ 173435-41-1 ]
[ 1876471-30-5 ]

Yield	Reaction Conditions	Operation in experiment
18%	Stage #1: 1-[(3R,5R)-3,5-dimethylmorpholin-4-yl]ethanone With trichlorophosphate In 1,2-dichloro-ethane at 0 - 20℃; for 0.5h; Stage #2: methyl 3-amino-2-chloropyridine-4-carboxylate In 1,2-dichloro-ethane at 20℃; for 48h;	b methyl 2-ch Ioro-3-[(E)-{1-[(3R,5R)-3,5-dimethylmorpholin-4-yI]ethylidene}amino] isonicotinate 1-[(3R,5R)-3,5-Dimethylmorpholin-4-yl]ethanone (0.70 g, 4.4 mmol, 2.3 eq.) was solubilized inDCE (10 mL) and the reaction mixture was cooled to 0°C. P0C13 (0.59 mL, 6.4 mmol, 3.3 eq.) was added slowly and the reaction was warmed up to rt. After 30 minutes, methyl 3-amino-2-chloroisonicotinate (0.36 g, 1.9 mmol, 1 eq.) was added in one portion and the mixture wasstirred at rt. After 48 hours, the reaction was quenched with sat. NaHCO3 and extracted three times with CH2CI2. The organic phase was dried (MgSO4) and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (gradient: 100% hexane to 100% EtOAc). The desired product was obtained in 18% yield (0.12 g). ‘H NMR (400 MHz, DMSO5 d6) 6 ppm: 1.26 (3H), 1.33 (3H), 1.79 (3H), 3.55 (2H), 3.77 (3H), 3.89 - 4.00 (4H), 7.54 - 7.58 (1H),8.02 -8.06 (1H).
18%	Stage #1: 1-[(3R,5R)-3,5-dimethylmorpholin-4-yl]ethanone With trichlorophosphate In 1,2-dichloro-ethane at 0 - 20℃; for 0.5h; Stage #2: methyl 3-amino-2-chloropyridine-4-carboxylate In 1,2-dichloro-ethane at 20℃; for 48h;

Reference： [1]Current Patent Assignee: POLI NUTRI ALIMENTOS SA; BAYER AG - WO2016/20320, 2016, A1 Location in patent: Page/Page column 99; 100
[2]Lücking, Ulrich; Wortmann, Lars; Wengner, Antje M.; Lefranc, Julien; Lienau, Philip; Briem, Hans; Siemeister, Gerhard; Bömer, Ulf; Denner, Karsten; Schäfer, Martina; Koppitz, Marcus; Eis, Knut; Bartels, Florian; Bader, Benjamin; Bone, Wilhelm; Moosmayer, Dieter; Holton, Simon J.; Eberspächer, Uwe; Grudzinska-Goebel, Joanna; Schatz, Christoph; Deeg, Gesa; Mumberg, Dominik; Von Nussbaum, Franz [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7293 - 7325]

19
[ 173435-41-1 ]
[ 1876471-12-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: trichlorophosphate / 1,2-dichloro-ethane / 0.5 h / 0 - 20 °C / Inert atmosphere 1.2: 3 h / 80 °C 2.1: lithium hexamethyldisilazane / N,N-dimethyl-formamide / 3 h / 0 - 20 °C / Inert atmosphere 3.1: caesium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / 1,4-dioxane / 16 h / 80 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1.1: trichlorophosphate / 1,2-dichloro-ethane / 0.5 h / 20 °C / Inert atmosphere 1.2: 3 h / 80 °C / Inert atmosphere 2.1: lithium hexamethyldisilazane / N,N-dimethyl-formamide; tetrahydrofuran / 3 h / 0 - 20 °C / Inert atmosphere 3.1: caesium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / 1,4-dioxane / 16 h / 80 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: POLI NUTRI ALIMENTOS SA; BAYER AG - WO2016/20320, 2016, A1
[2]Lücking, Ulrich; Wortmann, Lars; Wengner, Antje M.; Lefranc, Julien; Lienau, Philip; Briem, Hans; Siemeister, Gerhard; Bömer, Ulf; Denner, Karsten; Schäfer, Martina; Koppitz, Marcus; Eis, Knut; Bartels, Florian; Bader, Benjamin; Bone, Wilhelm; Moosmayer, Dieter; Holton, Simon J.; Eberspächer, Uwe; Grudzinska-Goebel, Joanna; Schatz, Christoph; Deeg, Gesa; Mumberg, Dominik; Von Nussbaum, Franz [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7293 - 7325]

20
[ 173435-41-1 ]
[ 1876471-13-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: trichlorophosphate / 1,2-dichloro-ethane / 0.5 h / 0 - 20 °C / Inert atmosphere 1.2: 3 h / 80 °C 2.1: lithium hexamethyldisilazane / N,N-dimethyl-formamide / 3 h / 0 - 20 °C / Inert atmosphere 3.1: caesium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / 1,4-dioxane / 16 h / 80 °C / Inert atmosphere 4.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / 20 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: trichlorophosphate / 1,2-dichloro-ethane / 0.5 h / 20 °C / Inert atmosphere 1.2: 3 h / 80 °C / Inert atmosphere 2.1: lithium hexamethyldisilazane / N,N-dimethyl-formamide; tetrahydrofuran / 3 h / 0 - 20 °C / Inert atmosphere 3.1: caesium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / 1,4-dioxane / 16 h / 80 °C / Inert atmosphere 4.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: POLI NUTRI ALIMENTOS SA; BAYER AG - WO2016/20320, 2016, A1
[2]Lücking, Ulrich; Wortmann, Lars; Wengner, Antje M.; Lefranc, Julien; Lienau, Philip; Briem, Hans; Siemeister, Gerhard; Bömer, Ulf; Denner, Karsten; Schäfer, Martina; Koppitz, Marcus; Eis, Knut; Bartels, Florian; Bader, Benjamin; Bone, Wilhelm; Moosmayer, Dieter; Holton, Simon J.; Eberspächer, Uwe; Grudzinska-Goebel, Joanna; Schatz, Christoph; Deeg, Gesa; Mumberg, Dominik; Von Nussbaum, Franz [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7293 - 7325]

21
[ 173435-41-1 ]
[ 1876471-86-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: trichlorophosphate / 1,2-dichloro-ethane / 0.5 h / 0 - 20 °C / Inert atmosphere 1.2: 3 h / 80 °C 2.1: lithium hexamethyldisilazane / N,N-dimethyl-formamide / 3 h / 0 - 20 °C / Inert atmosphere 3.1: caesium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / 1,4-dioxane / 16 h / 80 °C / Inert atmosphere 4.1: potassium carbonate / acetonitrile / 7 h / 85 °C
	Multi-step reaction with 4 steps 1.1: trichlorophosphate / 1,2-dichloro-ethane / 0.5 h / 20 °C / Inert atmosphere 1.2: 3 h / 80 °C / Inert atmosphere 2.1: lithium hexamethyldisilazane / N,N-dimethyl-formamide; tetrahydrofuran / 3 h / 0 - 20 °C / Inert atmosphere 3.1: caesium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ / 1,4-dioxane / 16 h / 80 °C / Inert atmosphere 4.1: potassium carbonate / acetonitrile / 7 h / 85 °C

Reference： [1]Current Patent Assignee: POLI NUTRI ALIMENTOS SA; BAYER AG - WO2016/20320, 2016, A1
[2]Lücking, Ulrich; Wortmann, Lars; Wengner, Antje M.; Lefranc, Julien; Lienau, Philip; Briem, Hans; Siemeister, Gerhard; Bömer, Ulf; Denner, Karsten; Schäfer, Martina; Koppitz, Marcus; Eis, Knut; Bartels, Florian; Bader, Benjamin; Bone, Wilhelm; Moosmayer, Dieter; Holton, Simon J.; Eberspächer, Uwe; Grudzinska-Goebel, Joanna; Schatz, Christoph; Deeg, Gesa; Mumberg, Dominik; Von Nussbaum, Franz [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7293 - 7325]

22
[ 173435-41-1 ]
[ 1876471-11-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: trichlorophosphate / 1,2-dichloro-ethane / 0.5 h / 0 - 20 °C / Inert atmosphere 1.2: 3 h / 80 °C 2.1: lithium hexamethyldisilazane / N,N-dimethyl-formamide / 3 h / 0 - 20 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1.1: trichlorophosphate / 1,2-dichloro-ethane / 0.5 h / 20 °C / Inert atmosphere 1.2: 3 h / 80 °C / Inert atmosphere 2.1: lithium hexamethyldisilazane / N,N-dimethyl-formamide; tetrahydrofuran / 3 h / 0 - 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: POLI NUTRI ALIMENTOS SA; BAYER AG - WO2016/20320, 2016, A1
[2]Lücking, Ulrich; Wortmann, Lars; Wengner, Antje M.; Lefranc, Julien; Lienau, Philip; Briem, Hans; Siemeister, Gerhard; Bömer, Ulf; Denner, Karsten; Schäfer, Martina; Koppitz, Marcus; Eis, Knut; Bartels, Florian; Bader, Benjamin; Bone, Wilhelm; Moosmayer, Dieter; Holton, Simon J.; Eberspächer, Uwe; Grudzinska-Goebel, Joanna; Schatz, Christoph; Deeg, Gesa; Mumberg, Dominik; Von Nussbaum, Franz [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7293 - 7325]

23
[ 173435-41-1 ]
[ 1876471-42-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: trichlorophosphate / 1,2-dichloro-ethane / 0.5 h / 0 - 20 °C / Inert atmosphere 1.2: 3 h / 80 °C 2.1: lithium hexamethyldisilazane / N,N-dimethyl-formamide / 3 h / 0 - 20 °C / Inert atmosphere 3.1: caesium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)CH₂Cl₂ / 1,4-dioxane / 16 h / 80 °C / Inert atmosphere 4.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / 20 °C / Inert atmosphere 5.1: caesium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)CH₂Cl₂ / 1,4-dioxane / 2 h / 90 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1.1: trichlorophosphate / 1,2-dichloro-ethane / 0.5 h / 20 °C / Inert atmosphere 1.2: 3 h / 80 °C / Inert atmosphere 2.1: lithium hexamethyldisilazane / N,N-dimethyl-formamide; tetrahydrofuran / 3 h / 0 - 20 °C / Inert atmosphere 3.1: caesium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)CH₂Cl₂ / 1,4-dioxane / 16 h / 80 °C / Inert atmosphere 4.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 16 h / 20 °C / Inert atmosphere 5.1: caesium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)CH₂Cl₂ / 1,4-dioxane / 2 h / 90 °C / Inert atmosphere; Microwave irradiation

Reference： [1]Current Patent Assignee: POLI NUTRI ALIMENTOS SA; BAYER AG - WO2016/20320, 2016, A1
[2]Lücking, Ulrich; Wortmann, Lars; Wengner, Antje M.; Lefranc, Julien; Lienau, Philip; Briem, Hans; Siemeister, Gerhard; Bömer, Ulf; Denner, Karsten; Schäfer, Martina; Koppitz, Marcus; Eis, Knut; Bartels, Florian; Bader, Benjamin; Bone, Wilhelm; Moosmayer, Dieter; Holton, Simon J.; Eberspächer, Uwe; Grudzinska-Goebel, Joanna; Schatz, Christoph; Deeg, Gesa; Mumberg, Dominik; Von Nussbaum, Franz [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7293 - 7325]

24
[ 173435-41-1 ]
[ 395083-14-4 ]
[ 1889268-12-5 ]

Yield	Reaction Conditions	Operation in experiment
77%	With palladium diacetate; caesium carbonate; triphenylphosphine In tetrahydrofuran; water for 16h; Reflux; Inert atmosphere;	4 Methyl 3-amino-2-isopropenylisonicotinate Methyl 3-amino-2-isopropenylisonicotinate A mixture of methyl 3-amino-2-chloroisonicotinate (3.0 g, 16.1 mmol), potassium isopropenyltrifluoroborate (2.35 g, 16.1 mmol), cesium carbonate (11.6 g, 35.5 mmol), triphenylphosphine (210 mg) and palladium acetate (150 mg) in THF/H2O (50 mL, v/v=5/1) was heated to reflux 16 h under N2 atmosphere. The mixture was extracted with EtOAc (30 mL*3). The combined organic layers were dried over sodium sulfate and concentrated to dryness. The residue was purified by chromatography on silica gel (EtOAc:PE=1:4) to give the titled compound (2.40 g, 77%) as yellow solids.

Reference： [1]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); Sumitomo Pharma (in: Sumitomo Chemical); SUMITOMO CHEMICAL COMPANY LIMITED - US2016/83400, 2016, A1 Location in patent: Paragraph 0205; 0207

25
[ 69271-42-7 ]
methyl 3-amino-2-chloropyridine-4-carboxylate [ No CAS ]
methyl 2-(1-methyl-1H-indazol-3-yl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%		Methyl 3-amino-2-chloropyridine-4-carboxylate (186 mg, 1.0 mmol), 1-(1 -methyl- lH-indazol-3-yl)ethanone (348 mg, 2.0 mmol), MgS04(120 mg), and acetic acid (85 mu, 1.5 mmol) were combined in DMA (3 mL), and the reaction mixture was purged with nitrogen for 10 min. Pd(PtBu3)2(50 mg, 0.1 mmol) and K P04(276 mg, 1.3 mmol) were added. The reaction vessel was sealed and heated at 120 C for 16 h. The reaction was concentrated and purified by prep-HP LC (20-65% ACN/water with 0.1% formic acid) to give 36 mg (12%) of the title compound. [M+H] Calc'd for CnHi4N402, 307; Found, 307.

Reference： [1]Patent: WO2016/44138,2016,A1 .Location in patent: Paragraph 00155

26
[ 173435-41-1 ]
[ 1066-54-2 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In acetonitrile at 40℃; Inert atmosphere;	Preparation la: Methyl 3-amino-2-eth nylpyridine-4-carboxylate A mixture of methyl 3-amino-2-chloropyridine-4-carboxylate (1.86 g, 10 mmol), TMS-acetylene (1.18 g, 12 mmol), Pd(PPh3)2Cl2(350 mg, 0.50 mmol), Cul (48 mg, 0.25 mmol), TEA (5.05 g, 50 mmol) and acetonitrile (50 mL) was purged with nitrogen and stirred at 40 °C overnight. Solvent was removed and the residue was dissolved in dichloromethane and filtered. The filtrate was concentrated and re-dissolved in THF (10 mL). The mixture was cooled 0 °C and TBAF (1M, 0.35 mL) was added dropwise, and the reaction stirred 30 min.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2016/44138, 2016, A1 Location in patent: Paragraph 00111

27
[ 173435-41-1 ]
[ 1002129-57-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: methyl 3-amino-2-chloropyridine-4-carboxylate With lithium aluminium tetrahydride In tetrahydrofuran at -20 - 0℃; for 0.5h; Stage #2: With magnesium sulfate; ammonium chloride In methanol for 0.25h;	4-(Difluoromethyl)-2-methylpyri din-3 -amine Lithium aluminium hydride [16853-85-3] (0.2 g, 5.14 mmol) was added to a stirred solution of methyl 3-amino-2-chloroisonicotinate [173435-41-1] (1 g, 4.29 mmol) in dry THF (10 mL) at -20 °C. The mixture was stirred at 0°C for 30 min. NLLCl (800 mg), MeOH (5 mL) and MgSCL were added and the mixture was stirred 15 min. The mixture was filtered and concentrated in vacuo. The crude was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 3.5/96.5). The desired fractions were collected and concentrated in vacuo to yield (3 -amino-2-chloropyridin-4-yl)m ethanol as a white solid (704 mg, 100%).
96%	With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 0.5h;	10.1 Step 1 Methyl 3-amino-2-chloroisonicotinate 10a (5 g, 26.88 mmol) was dissolved in 100 mL of tetrahydrofuran, the mixture was cooled to 0° C., and lithium aluminum hydride (2.05 g, 53.76 mmol) was added in batches. After stirring at room temperature for 30 minutes, the reaction was quenched with sodium sulfate decahydrate, the reaction solution was filtered and concentrated under reduced pressure to obtain (3-amino-2-chloropyridin-4-yl)methanol 10b (4.1 g, yellow solid) with a yield of 96%. MS m/z (ESI): 159.3 [M+1].
96%	With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 0.5h;	10.1 Step 1 Methyl 3-amino-2-chloroisonicotinate 10a (5 g, 26.88 mmol) was dissolved in 100 mL of tetrahydrofuran, the mixture was cooled to 0° C., and lithium aluminum hydride (2.05 g, 53.76 mmol) was added in batches. After stirring at room temperature for 30 minutes, the reaction was quenched with sodium sulfate decahydrate, the reaction solution was filtered and concentrated under reduced pressure to obtain (3-amino-2-chloropyridin-4-yl)methanol 10b (4.1 g, yellow solid) with a yield of 96%. MS m/z (ESI): 159.3 [M+1].

85%

With lithium aluminium tetrahydride In tetrahydrofuran at -20 - 0℃; for 0.5h; Inert atmosphere;

213.213.A 213A) (3-Amino-2-chloropyridin-4-yl)methanol To a solution of methyl 3-amino-2-chloroisonicotinate (0.4 g, 2.144 mmol in THF (5 mL) at -20° C. was added) LAH (2.57 mL, 2.57 mmol) under a nitrogen atmosphere. The mixture was then stirred at 0° C. for 30 min. Ammonium chloride (200 mg) was added and after stirred for 15 min. silica gel (3 mL) was added to the reaction mixture and concentrated in vacuo. The crude was dry loaded over a 3 mL silical gel plug and eluted with 10% MeOH in DCM to give (3-amino-2-chloropyridin-4-yl)methanol (290 mg, 1.829 mmol, 85% yield) as a white flaky solid. HPLC: RT=0.44 min (H2O/ACN with 0.05% TFA, Waters Acquity SDS BEH C18, 2.1×50 mm, 1.7-μm particles, gradient=1.8 min, wavelength=220 nm); MS (ES): m/z=159 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.61 (d, J=4.6 Hz, 1H), 7.18 (d, J=4.6 Hz, 1H), 5.40 (t, J=5.5 Hz, 1H), 5.24 (s, 2H), 4.43 (d, J=5.5 Hz, 2H)

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2021/123294, 2021, A1 Location in patent: Page/Page column 48
[2]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - US2021/386721, 2021, A1 Location in patent: Paragraph 0284-0285
[3]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - US2021/386721, 2021, A1 Location in patent: Paragraph 0284-0285
[4]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2016/176871, 2016, A1 Location in patent: Paragraph 0801-0802

28
[ 173435-41-1 ]
[ 1289046-28-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0.5 h / -20 - 0 °C / Inert atmosphere 2: Dess-Martin periodane / tetrahydrofuran; dichloromethane / 1 h / 20 °C
	Multi-step reaction with 2 steps 1.1: lithium aluminium tetrahydride / tetrahydrofuran / 0.5 h / -20 - 0 °C 1.2: 0.25 h 2.1: Dess-Martin periodane / tetrahydrofuran; dichloromethane
	Multi-step reaction with 2 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0.5 h / 0 - 20 °C 2: manganese(IV) oxide / tetrahydrofuran; dichloromethane / 20 °C

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2016/176871, 2016, A1
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2021/123294, 2021, A1
[3]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - US2021/386721, 2021, A1
[4]Current Patent Assignee: YANGTZE RIVER PHARMACEUTICAL GROUP CO LTD - US2021/386721, 2021, A1

29
[ 2226528-89-6 ]
[ 173435-41-1 ]
[ 2226539-83-7 ]

Yield	Reaction Conditions	Operation in experiment
86%	With C₃₇H₅₆ClPPd; potassium carbonate In acetonitrile at 75℃; for 12h; Inert atmosphere; Sealed tube;

Reference： [1]Horton, John R.; Liu, Xu; Wu, Lizhen; Zhang, Kai; Shanks, John; Zhang, Xing; Rai, Ganesha; Mott, Bryan T.; Jansen, Daniel J.; Kales, Stephen C.; Henderson, Mark J.; Pohida, Katherine; Fang, Yuhong; Hu, Xin; Jadhav, Ajit; Maloney, David J.; Hall, Matthew D.; Simeonov, Anton; Fu, Haian; Vertino, Paula M.; Yan, Qin; Cheng, Xiaodong [Journal of Medicinal Chemistry, 2018, vol. 61, # 7, p. 3193 - 3208]

30
[ 823-96-1 ]
[ 173435-41-1 ]
[ 1227581-39-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane at 100℃; for 1h; Inert atmosphere; Microwave irradiation;	1 Step 1: Methyl 3-amino-2-methylisonicotinate To a solution of methyl 3-amino-2-chloroisonicotinate (2.0 g, 10.7 mmol, 1.0 eq) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (4.0 g, 32.2 mmol, 3.0 eq) in 1,4-dioxane (40 mL) under a N2 atmosphere was added Pd(dppf)Cl2 (1.6 g, 2.1 mmol, 0.2 eq) and K2CO3 (3.0 g, 21.4 mmol, 2.0 eq) and the mixture was heated at 100° C. for 1 h in a microwave. The mixture was cooled to RT, diluted with water (50 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were washed with water (40 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether:EtOAc, 5:1 to 3:1, v/v) to afford the title compound (1.9 g, 100%) as a yellow solid. LCMS: [M+H]+ 167.1.

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC - US2019/194174, 2019, A1 Location in patent: Paragraph 0265

31
[ 173435-41-1 ]
[ 2397623-81-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: palladium [2'-(amino-κN)[1,1'-biphenyl]-2-yl-κC][[5-(diphenylphosphino)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphine-κP](methanesulfonato-κO) / tetrahydrofuran / 0.67 h / 50 °C / Inert atmosphere 2: lithium borohydride; methanol / tetrahydrofuran / 3.5 h / 20 - 40 °C 3: N-ethyl-N,N-diisopropylamine; dmap / dichloromethane / 3 h / 20 °C
	Multi-step reaction with 2 steps 1.1: palladium [2'-(amino-κN)[1,1'-biphenyl]-2-yl-κC][[5-(diphenylphosphino)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphine-κP](methanesulfonato-κO) dichloromethane / tetrahydrofuran / 0.33 h 2.1: lithium borohydride / tetrahydrofuran / 0.25 h / 20 °C 2.2: 18 h / 20 °C 2.3: 20 h / 20 °C

Reference： [1]Current Patent Assignee: AMGEN INC - US2019/375749, 2019, A1
[2]Current Patent Assignee: AMGEN INC - US2019/374542, 2019, A1

32
[ 173435-41-1 ]
[ 77047-87-1 ]
[ 1889268-14-7 ]

Yield	Reaction Conditions	Operation in experiment
72%	With palladium [2'-(amino-κN)[1,1'-biphenyl]-2-yl-κC][[5-(diphenylphosphino)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphine-κP](methanesulfonato-κO) dichloromethane In tetrahydrofuran for 0.333333h;	1 Step 1. Methyl 3-amino-2-isopropylisonicotinate A 250-mL round-bottomed flask was charged with 3-amino-2-chloro-4-(methoxycarbonyl)pyridine (3.09 g, 16.6 mmol, Combi-Block, Inc.), methanesulfonato[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene][2'-amino-1,1'-biphenyl]palladium(ii) dichloromethane adduct (Xantophos G3) (0.862 g, 0.835 mmol,) and THF (50 mL) under argon. 2-Propylzinc bromide (0.5 M in THF, 43.1 mL, 21.5 mmol, Aldrich) was added slowly via addition funnel. The addition funnel was swapped with a Findensor condenser and the mixture was stirred at 50° C. for 20 min. The mixture was cooled to rt then placed in an ice water bath. Water (˜80 mL) and EtOAc (˜50 mL) were added and the mixture was filtered through fine frit glass filter funnel (eluent:EtOAc) to remove insoluble emulsions. The phases were separated and the aqueous phase was extracted with EtOAc (2*50 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated. A chromatographic purification (silica gel, 5-60% EtOAc/heptane) obtained methyl 3-amino-2-isopropylisonicotinate (2.31 g, 11.9 mmol, 72% yield) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.94 (1H, d, J=5.2 Hz), 7.50 (1H, d, J=5.2 Hz), 5.87 (2H, br s), 3.91 (3H, s), 3.08 (1H, dt, J=13.5, 6.7 Hz), 1.32 (6H, d, J=6.8 Hz). m/z (ESI, +ve ion): 195.2 [M+H].
	With palladium [2'-(amino-κN)[1,1'-biphenyl]-2-yl-κC][[5-(diphenylphosphino)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphine-κP](methanesulfonato-κO) In tetrahydrofuran at 50℃; for 0.666667h; Inert atmosphere;	5.1 Step 1: Methyl 3-amino-2-isopropylisonicotinate Step 1: Methyl 3-amino-2-isopropylisonicotinate To a 1-L three necked round-bottomed flask equipped with Findenser condenser was added 3-amino-2-chloro-4-(methoxycarbonyl)pyridine (10.6 g, 56.8 mmol, Combi-Blocks Inc., San Diego, Calif.) and [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (2.69 g, 2.8 mmol, Sigma-Aldrich, St. Louis, Mo.) in tetrahydrofuran (114 ml) under argon. 2-Propylzinc bromide 0.5M in tetrahydrofuran (148 ml, 73.8 mmol, Sigma-Aldrich, St. Louis, Mo.) was added via addition funnel over 4 min. The reaction mixture was then stirred at 50° C. for 40 min. The reaction mixture was cooled with ice water bath. Ice (˜100 g) and Celite (˜100 g) were added with stirring and the mixture was filtered through fine frit glass filter and washed with DCM to remove insoluble emulsions. The two layers were separated, and the aqueous layer was extracted with DCM (3*200 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to afford brown oil. The crude material was purified by chromatography on silica gel eluting with a gradient of 0% to 70% EtOAc in heptane, to provide methyl 3-amino-2-isopropylisonicotinate as yellow oil.

Reference： [1]Current Patent Assignee: AMGEN INC - US2019/374542, 2019, A1 Location in patent: Paragraph 0920-0921
[2]Current Patent Assignee: AMGEN INC - US2019/375749, 2019, A1 Location in patent: Paragraph 0219; 0220

33
[ 1257237-31-2 ]
[ 173435-41-1 ]
[ 2488945-27-1 ]

Yield	Reaction Conditions	Operation in experiment
19.5 g	Stage #1: 1-[(3R)-3-methylmorpholin-4-yl]ethan-1-one With trichlorophosphate In 1,2-dichloro-ethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: methyl 3-amino-2-chloropyridine-4-carboxylate In 1,2-dichloro-ethane at 20 - 80℃; Inert atmosphere;

Reference： [1]Lücking, Ulrich; Wortmann, Lars; Wengner, Antje M.; Lefranc, Julien; Lienau, Philip; Briem, Hans; Siemeister, Gerhard; Bömer, Ulf; Denner, Karsten; Schäfer, Martina; Koppitz, Marcus; Eis, Knut; Bartels, Florian; Bader, Benjamin; Bone, Wilhelm; Moosmayer, Dieter; Holton, Simon J.; Eberspächer, Uwe; Grudzinska-Goebel, Joanna; Schatz, Christoph; Deeg, Gesa; Mumberg, Dominik; Von Nussbaum, Franz [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7293 - 7325]

34
[ 1696-20-4 ]
[ 173435-41-1 ]
[ 2488631-06-5 ]

Yield	Reaction Conditions	Operation in experiment
89%	Stage #1: 4-acetylmorpholine With trichlorophosphate In 1,2-dichloro-ethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: methyl 3-amino-2-chloropyridine-4-carboxylate In 1,2-dichloro-ethane at 80℃; for 3h; Inert atmosphere;

Reference： [1]Lücking, Ulrich; Wortmann, Lars; Wengner, Antje M.; Lefranc, Julien; Lienau, Philip; Briem, Hans; Siemeister, Gerhard; Bömer, Ulf; Denner, Karsten; Schäfer, Martina; Koppitz, Marcus; Eis, Knut; Bartels, Florian; Bader, Benjamin; Bone, Wilhelm; Moosmayer, Dieter; Holton, Simon J.; Eberspächer, Uwe; Grudzinska-Goebel, Joanna; Schatz, Christoph; Deeg, Gesa; Mumberg, Dominik; Von Nussbaum, Franz [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7293 - 7325]

35
[ 1257237-46-9 ]
[ 173435-41-1 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-((S)-3-methylmorpholin-4-yl)ethanone With trichlorophosphate In 1,2-dichloro-ethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: methyl 3-amino-2-chloropyridine-4-carboxylate In 1,2-dichloro-ethane at 20 - 80℃; Inert atmosphere;

Reference： [1]Lücking, Ulrich; Wortmann, Lars; Wengner, Antje M.; Lefranc, Julien; Lienau, Philip; Briem, Hans; Siemeister, Gerhard; Bömer, Ulf; Denner, Karsten; Schäfer, Martina; Koppitz, Marcus; Eis, Knut; Bartels, Florian; Bader, Benjamin; Bone, Wilhelm; Moosmayer, Dieter; Holton, Simon J.; Eberspächer, Uwe; Grudzinska-Goebel, Joanna; Schatz, Christoph; Deeg, Gesa; Mumberg, Dominik; Von Nussbaum, Franz [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7293 - 7325]

36
[ 1396872-47-1 ]
[ 173435-41-1 ]
[ 2488631-07-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)ethanone With trichlorophosphate In 1,2-dichloro-ethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: methyl 3-amino-2-chloropyridine-4-carboxylate In 1,2-dichloro-ethane at 20 - 85℃; Inert atmosphere;

Reference： [1]Lücking, Ulrich; Wortmann, Lars; Wengner, Antje M.; Lefranc, Julien; Lienau, Philip; Briem, Hans; Siemeister, Gerhard; Bömer, Ulf; Denner, Karsten; Schäfer, Martina; Koppitz, Marcus; Eis, Knut; Bartels, Florian; Bader, Benjamin; Bone, Wilhelm; Moosmayer, Dieter; Holton, Simon J.; Eberspächer, Uwe; Grudzinska-Goebel, Joanna; Schatz, Christoph; Deeg, Gesa; Mumberg, Dominik; Von Nussbaum, Franz [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7293 - 7325]

37
[ CAS Unavailable ]
[ 173435-41-1 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]ethanone With trichlorophosphate In 1,2-dichloro-ethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: methyl 3-amino-2-chloropyridine-4-carboxylate In 1,2-dichloro-ethane at 20 - 80℃; Inert atmosphere;

Reference： [1]Lücking, Ulrich; Wortmann, Lars; Wengner, Antje M.; Lefranc, Julien; Lienau, Philip; Briem, Hans; Siemeister, Gerhard; Bömer, Ulf; Denner, Karsten; Schäfer, Martina; Koppitz, Marcus; Eis, Knut; Bartels, Florian; Bader, Benjamin; Bone, Wilhelm; Moosmayer, Dieter; Holton, Simon J.; Eberspächer, Uwe; Grudzinska-Goebel, Joanna; Schatz, Christoph; Deeg, Gesa; Mumberg, Dominik; Von Nussbaum, Franz [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7293 - 7325]

38
[ 2124756-28-9 ]
[ 173435-41-1 ]
[ 2488631-15-6 ]

Yield	Reaction Conditions	Operation in experiment
63%	Stage #1: 1-[(2R)-2-methylmorpholin-4-yl]ethanone With trichlorophosphate In 1,2-dichloro-ethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: methyl 3-amino-2-chloropyridine-4-carboxylate In 1,2-dichloro-ethane at 20 - 85℃; Inert atmosphere;

Reference： [1]Lücking, Ulrich; Wortmann, Lars; Wengner, Antje M.; Lefranc, Julien; Lienau, Philip; Briem, Hans; Siemeister, Gerhard; Bömer, Ulf; Denner, Karsten; Schäfer, Martina; Koppitz, Marcus; Eis, Knut; Bartels, Florian; Bader, Benjamin; Bone, Wilhelm; Moosmayer, Dieter; Holton, Simon J.; Eberspächer, Uwe; Grudzinska-Goebel, Joanna; Schatz, Christoph; Deeg, Gesa; Mumberg, Dominik; Von Nussbaum, Franz [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7293 - 7325]

39
[ 2488631-18-9 ]
[ 173435-41-1 ]
[ 2488631-19-0 ]

Yield	Reaction Conditions	Operation in experiment
35%	Stage #1: 1-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)ethanone With trichlorophosphate In 1,2-dichloro-ethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: methyl 3-amino-2-chloropyridine-4-carboxylate In 1,2-dichloro-ethane at 20 - 80℃; Inert atmosphere;

Reference： [1]Lücking, Ulrich; Wortmann, Lars; Wengner, Antje M.; Lefranc, Julien; Lienau, Philip; Briem, Hans; Siemeister, Gerhard; Bömer, Ulf; Denner, Karsten; Schäfer, Martina; Koppitz, Marcus; Eis, Knut; Bartels, Florian; Bader, Benjamin; Bone, Wilhelm; Moosmayer, Dieter; Holton, Simon J.; Eberspächer, Uwe; Grudzinska-Goebel, Joanna; Schatz, Christoph; Deeg, Gesa; Mumberg, Dominik; Von Nussbaum, Franz [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7293 - 7325]

40
[ 1343073-02-8 ]
[ 173435-41-1 ]
[ 2488631-23-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-(3-ethylmorpholin-4-yl)ethanone With trichlorophosphate In 1,2-dichloro-ethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: methyl 3-amino-2-chloropyridine-4-carboxylate In 1,2-dichloro-ethane at 20 - 80℃; Inert atmosphere;

Reference： [1]Lücking, Ulrich; Wortmann, Lars; Wengner, Antje M.; Lefranc, Julien; Lienau, Philip; Briem, Hans; Siemeister, Gerhard; Bömer, Ulf; Denner, Karsten; Schäfer, Martina; Koppitz, Marcus; Eis, Knut; Bartels, Florian; Bader, Benjamin; Bone, Wilhelm; Moosmayer, Dieter; Holton, Simon J.; Eberspächer, Uwe; Grudzinska-Goebel, Joanna; Schatz, Christoph; Deeg, Gesa; Mumberg, Dominik; Von Nussbaum, Franz [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7293 - 7325]

41
[ 2123563-30-2 ]
[ 173435-41-1 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-[(2S)-2-methylmorpholin-4-yl]ethenone With trichlorophosphate In 1,2-dichloro-ethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: methyl 3-amino-2-chloropyridine-4-carboxylate In 1,2-dichloro-ethane at 20 - 85℃; Inert atmosphere;

Reference： [1]Lücking, Ulrich; Wortmann, Lars; Wengner, Antje M.; Lefranc, Julien; Lienau, Philip; Briem, Hans; Siemeister, Gerhard; Bömer, Ulf; Denner, Karsten; Schäfer, Martina; Koppitz, Marcus; Eis, Knut; Bartels, Florian; Bader, Benjamin; Bone, Wilhelm; Moosmayer, Dieter; Holton, Simon J.; Eberspächer, Uwe; Grudzinska-Goebel, Joanna; Schatz, Christoph; Deeg, Gesa; Mumberg, Dominik; Von Nussbaum, Franz [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7293 - 7325]

42
[ 1874981-28-8 ]
[ 173435-41-1 ]
[ 2488631-27-0 ]

Yield	Reaction Conditions	Operation in experiment
451 mg	Stage #1: 1-[3-(trifluoromethyl)morpholin-4-yl]ethanone With trichlorophosphate In 1,2-dichloro-ethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: methyl 3-amino-2-chloropyridine-4-carboxylate In 1,2-dichloro-ethane at 20 - 85℃; Inert atmosphere;

Reference： [1]Lücking, Ulrich; Wortmann, Lars; Wengner, Antje M.; Lefranc, Julien; Lienau, Philip; Briem, Hans; Siemeister, Gerhard; Bömer, Ulf; Denner, Karsten; Schäfer, Martina; Koppitz, Marcus; Eis, Knut; Bartels, Florian; Bader, Benjamin; Bone, Wilhelm; Moosmayer, Dieter; Holton, Simon J.; Eberspächer, Uwe; Grudzinska-Goebel, Joanna; Schatz, Christoph; Deeg, Gesa; Mumberg, Dominik; Von Nussbaum, Franz [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7293 - 7325]

43
[ 2271913-55-2 ]
[ 173435-41-1 ]
[ 2488631-31-6 ]

Yield	Reaction Conditions	Operation in experiment
46%	Stage #1: 1-[(3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl]ethanone With trichlorophosphate In 1,2-dichloro-ethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: methyl 3-amino-2-chloropyridine-4-carboxylate In 1,2-dichloro-ethane at 20 - 85℃; Inert atmosphere;

Reference： [1]Lücking, Ulrich; Wortmann, Lars; Wengner, Antje M.; Lefranc, Julien; Lienau, Philip; Briem, Hans; Siemeister, Gerhard; Bömer, Ulf; Denner, Karsten; Schäfer, Martina; Koppitz, Marcus; Eis, Knut; Bartels, Florian; Bader, Benjamin; Bone, Wilhelm; Moosmayer, Dieter; Holton, Simon J.; Eberspächer, Uwe; Grudzinska-Goebel, Joanna; Schatz, Christoph; Deeg, Gesa; Mumberg, Dominik; Von Nussbaum, Franz [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7293 - 7325]

44
[ 2488631-35-0 ]
[ 173435-41-1 ]
[ 2488631-36-1 ]

Yield	Reaction Conditions	Operation in experiment
54%	Stage #1: 1-(2,2,6,6-tetrafluoromorpholin-4-yl)ethanone With trichlorophosphate In 1,2-dichloro-ethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: methyl 3-amino-2-chloropyridine-4-carboxylate In 1,2-dichloro-ethane at 20 - 85℃; Inert atmosphere;

Reference： [1]Lücking, Ulrich; Wortmann, Lars; Wengner, Antje M.; Lefranc, Julien; Lienau, Philip; Briem, Hans; Siemeister, Gerhard; Bömer, Ulf; Denner, Karsten; Schäfer, Martina; Koppitz, Marcus; Eis, Knut; Bartels, Florian; Bader, Benjamin; Bone, Wilhelm; Moosmayer, Dieter; Holton, Simon J.; Eberspächer, Uwe; Grudzinska-Goebel, Joanna; Schatz, Christoph; Deeg, Gesa; Mumberg, Dominik; Von Nussbaum, Franz [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7293 - 7325]

45
[ 1216479-90-1 ]
[ 173435-41-1 ]
[ 2488631-40-7 ]

Yield	Reaction Conditions	Operation in experiment
34%	Stage #1: 1-(3,3-dimethylmorpholin-4-yl)ethanone With trichlorophosphate In 1,2-dichloro-ethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: methyl 3-amino-2-chloropyridine-4-carboxylate In 1,2-dichloro-ethane at 20 - 85℃; Inert atmosphere;

Reference： [1]Lücking, Ulrich; Wortmann, Lars; Wengner, Antje M.; Lefranc, Julien; Lienau, Philip; Briem, Hans; Siemeister, Gerhard; Bömer, Ulf; Denner, Karsten; Schäfer, Martina; Koppitz, Marcus; Eis, Knut; Bartels, Florian; Bader, Benjamin; Bone, Wilhelm; Moosmayer, Dieter; Holton, Simon J.; Eberspächer, Uwe; Grudzinska-Goebel, Joanna; Schatz, Christoph; Deeg, Gesa; Mumberg, Dominik; Von Nussbaum, Franz [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7293 - 7325]

46
[ 1850937-08-4 ]
[ 173435-41-1 ]
[ 2488631-44-1 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-(3-methoxy-3-methylazetidin-1-yl)ethanone With trichlorophosphate In 1,2-dichloro-ethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: methyl 3-amino-2-chloropyridine-4-carboxylate In 1,2-dichloro-ethane at 20 - 85℃; Inert atmosphere;

Reference： [1]Lücking, Ulrich; Wortmann, Lars; Wengner, Antje M.; Lefranc, Julien; Lienau, Philip; Briem, Hans; Siemeister, Gerhard; Bömer, Ulf; Denner, Karsten; Schäfer, Martina; Koppitz, Marcus; Eis, Knut; Bartels, Florian; Bader, Benjamin; Bone, Wilhelm; Moosmayer, Dieter; Holton, Simon J.; Eberspächer, Uwe; Grudzinska-Goebel, Joanna; Schatz, Christoph; Deeg, Gesa; Mumberg, Dominik; Von Nussbaum, Franz [Journal of Medicinal Chemistry, 2020, vol. 63, # 13, p. 7293 - 7325]

47
[ 173435-41-1 ]
[ 1260663-37-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: methanol; sodium hydroxide / 1 h / 20 °C 2: butan-1-ol / 16 h / 130 °C 3: trichlorophosphate; N-ethyl-N,N-diisopropylamine / 2 h / 0 - 110 °C
	Multi-step reaction with 3 steps 1: sodium hydroxide; water / methanol / 1 h / 25 °C 2: 12 h / 140 °C 3: trichlorophosphate; N-ethyl-N,N-diisopropylamine / 12 h / 120 °C

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2020/163193, 2020, A1
[2]Current Patent Assignee: MIRATI THERAPEUTICS, INC. - WO2020/219448, 2020, A1

48
[ 173435-41-1 ]
[ 84341-13-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium hydroxide; lithium hydroxide monohydrate / methanol / 1 h / 25 °C 2: 12 h / 140 °C
	Multi-step reaction with 2 steps 1: ammonia / methanol / 48 h / 20 - 25 °C 2: 16 h / Reflux

Reference： [1]Current Patent Assignee: MIRATI THERAPEUTICS, INC. - WO2020/219448, 2020, A1
[2]Current Patent Assignee: CSPC PHARMACEUTICAL GROUP LIMITED - WO2021/254493, 2021, A1

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	{[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

CAS No. :	173435-41-1	MDL No. :	MFCD03411723
Formula :	C₇H₇ClN₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KSZMBXHYSQDICN-UHFFFAOYSA-N
M.W :	186.60	Pubchem ID :	2762510
Synonyms :

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	44.93
TPSA :	65.21 Å²

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.34 cm/s

Log Po/w (iLOGP) :	1.54
Log Po/w (XLOGP3) :	1.54
Log Po/w (WLOGP) :	1.11
Log Po/w (MLOGP) :	0.35
Log Po/w (SILICOS-IT) :	1.13
Consensus Log Po/w :	1.13

[ CAS No. 173435-41-1 ]

Quality Control of [ 173435-41-1 ]

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Physicochemical Properties

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Medicinal Chemistry

Safety of [ 173435-41-1 ]

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[ 173435-41-1 ] Synthesis Path-Downstream 1~48

Related Functional Groups of
[ 173435-41-1 ]

Chlorides

Esters

Amines

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[ 173435-41-1 ]

Pyridines

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Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Log S (ESOL) :	-2.21
Solubility :	1.16 mg/ml ; 0.00624 mol/l
Class :	Soluble
Log S (Ali) :	-2.52
Solubility :	0.565 mg/ml ; 0.00303 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.36
Solubility :	0.815 mg/ml ; 0.00437 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.78

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H312-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

[ CAS No. 173435-41-1 ]

Quality Control of [ 173435-41-1 ]

Related Doc. of [ 173435-41-1 ]

Product Details of [ 173435-41-1 ]

Calculated chemistry of [ 173435-41-1 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 173435-41-1 ]

Application In Synthesis of [ 173435-41-1 ]

[ 173435-41-1 ] Synthesis Path-Downstream 1~48

Related Functional Groups of [ 173435-41-1 ]

Chlorides

Esters

Amines

Related Parent Nucleus of [ 173435-41-1 ]

Pyridines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 173435-41-1 ]

Related Parent Nucleus of
[ 173435-41-1 ]