Name: 175867-01-3|trans-4-(2-Methoxyethoxy)cyclohexanamine|97%
Brand: Ambeed
SKU: A178536
Price: 31.0 USD
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1
[ 1700637-43-9 ]
[ 175867-01-3 ]
[ 1700637-55-3 ]

Yield	Reaction Conditions	Operation in experiment
87.3 mg	With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one; acetonitrile at 180℃; for 10h; Microwave irradiation;

Reference： [1]Haffner, Curt D.; Becherer, J. David; Boros, Eric E.; Cadilla, Rodolfo; Carpenter, Tiffany; Cowan, David; Deaton, David N.; Guo, Yu; Harrington, Wallace; Henke, Brad R.; Jeune, Michael R.; Kaldor, Istvan; Milliken, Naphtali; Petrov, Kim G.; Preugschat, Frank; Schulte, Christie; Shearer, Barry G.; Shearer, Todd; Smalley, Terrence L.; Stewart, Eugene L.; Stuart, J. Darren; Ulrich, John C. [Journal of Medicinal Chemistry, 2015, vol. 58, # 8, p. 3548 - 3571]

2
[ 1799917-40-0 ]
[ 175867-01-3 ]

Yield	Reaction Conditions	Operation in experiment
87%	Stage #1: trans-N,N-dibenzyl-4-(2-methoxyethoxy)cyclohexanamine hydrochloride salt With sodium hydroxide In tert-butyl methyl ether; water for 0.0833333h; Stage #2: With 10 wt% Pd(OH)2 on carbon; hydrogen In ethanol at 20℃; for 4.33h;	C C. (trans)-4-(2-Methoxyethoxy)cyclohexanamine (Intermediate 39B) (19.7 g, 50.5 mmol) in water (150 mL) was stirred until near solution was achieved. TBME (150 mL) was added, then 1 N NaOH (50 mL) was added slowly over 5 minutes (internal temp stayed steady at ambient without external cooling). The layers were separated, and the aqueous phase was extracted with TBME (30 mL). The combined TBME layers were washed with brine, dried over MgS04, filtered and concentrated chasing with EtOH. The resulting light amber oil was dissolved in EtOH (150 mL), and purged with N2. Pd(OH)2 on activated charcoal (1 .6 g, 10-20% Pd; -50% water as stabilizer) was added, and the stirred mixture was evacuated and purged with N2 and then with H2, and stirred under H2 atmosphere at room temperature, monitoring uptake with a Buchi Pressflow apparatus. After 3 h of rapid stirring, the reaction appeared to be slowing down, so the reaction vessel was evacuated and purged with N2, and charged with an additional amount of Pd(OH)2 (1 .62 g), and hydrogenolysis was continued for an additional 80 min. The vessel was evacuated and purged with N2, and the reaction mixture was filtered through a millipore filter pad containing Celite. The filtrate was concentrated to afford the title compound as a nearly colorless oil (7.6 g, 87%). 1H NMR (400 MHz, CD3SOCD3) δ 0.94-1 .18 (m, 4 H), 1 .68-1 .76 (m, 2 H), 1 .85-1 .93 (m, 2 H), 2.46-2.55 (m, 1 H), 3.1 1 -3.20 (m, 1 H), 3.23 (s, 3 H), 3.37-3.42 (m, 2 H), 3.47-3.51 (m, 2 H).
	Multi-step reaction with 2 steps 1: sodium hydroxide; tert-butyl methyl ether / water 2: hydrogen; nitrogen; 10 wt% Pd(OH)2 on carbon / ethanol / 3 h

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2018/69863, 2018, A1 Location in patent: Page/Page column 150
[2]Haffner, Curt D.; Becherer, J. David; Boros, Eric E.; Cadilla, Rodolfo; Carpenter, Tiffany; Cowan, David; Deaton, David N.; Guo, Yu; Harrington, Wallace; Henke, Brad R.; Jeune, Michael R.; Kaldor, Istvan; Milliken, Naphtali; Petrov, Kim G.; Preugschat, Frank; Schulte, Christie; Shearer, Barry G.; Shearer, Todd; Smalley, Terrence L.; Stewart, Eugene L.; Stuart, J. Darren; Ulrich, John C. [Journal of Medicinal Chemistry, 2015, vol. 58, # 8, p. 3548 - 3571]

3
[ 902152-75-4 ]
[ 175867-01-3 ]

Yield	Reaction Conditions	Operation in experiment
92%	With palladium hydroxide on carbon; hydrogen In ethanol at 20℃; for 14h;	3 Step 3: (1r,4r)-4-(2-Methoxyethoxy)cyclohexan-1-amine Under hydrogen, a mixture of (1r,4r)-N,N-dibenzyl-4-(2-methoxyethoxy)cyclohexan-1-amine (60.0 g, 169.7 mmol, 1 eq) and Pd(OH)2 on carbon (10.0 g, 71.2 mmol, 0.42 eq) in EtOH (600 mL) was stirred for 14 h at RT. The solids were filtered out. The filtrate was concentrated under vacuum to afford the title compound (27 g, 92%) as a yellow oil. LCMS: [M+H]+ 174.1.
92%	With palladium hydroxide on carbon; hydrogen In ethanol at 20℃; for 14h;	Step 3: (1r,4r)-4-(2-Methoxyethoxy)cyclohexan-1-amine Under hydrogen, a mixture of (1r,4r)-N,N-dibenzyl-4-(2-methoxyethoxy)cyclohexan- 1-amine (60.0 g, 169.7 mmol, 1 eq) and Pd(OH)2 on carbon (10.0 g, 71.2 mmol, 0.42 eq) in EtOH (600 mL) was stirred for 14 h at RT. The solids were filtered out. The filtrate was concentrated under vacuum to afford the title compound (27 g, 92%) as a yellow oil. LCMS: [M+H]+ 174.1.
92%	With palladium hydroxide on carbon; hydrogen In ethanol at 20℃; for 14h;	Step 3: (1r,4r)-4-(2-Methoxyethoxy)cyclohexan-1-amine Under hydrogen, a mixture of (1r,4r)-N,N-dibenzyl-4-(2-methoxyethoxy)cyclohexan- 1-amine (60.0 g, 169.7 mmol, 1 eq) and Pd(OH)2 on carbon (10.0 g, 71.2 mmol, 0.42 eq) in EtOH (600 mL) was stirred for 14 h at RT. The solids were filtered out. The filtrate was concentrated under vacuum to afford the title compound (27 g, 92%) as a yellow oil. LCMS: [M+H]+ 174.1.

79%	With 20 weight% Pd(OH)2/C; hydrogen In ethanol at 20℃; for 24h;
25 g	With palladium hydroxide on carbon; nitrogen; hydrogen In ethanol for 3h;

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC - US2021/32251, 2021, A1 Location in patent: Paragraph 0431
[2]Current Patent Assignee: RIBON THERAPEUTICS INC - WO2022/165114, 2022, A1 Location in patent: Page/Page column 40-41
[3]Current Patent Assignee: RIBON THERAPEUTICS INC - WO2022/165114, 2022, A1 Location in patent: Page/Page column 40-41
[4]Lagu, Bharat; Wu, Xinyuan; Kulkarni, Santosh; Paul, Rakesh; Becherer, J. David; Olson, Lyndsay; Ravani, Stella; Chatzianastasiou, Athanasia; Papapetropoulos, Andreas; Andrzejewski, Sylvia [Journal of Medicinal Chemistry, 2022, vol. 65, # 13, p. 9418 - 9446]
[5]Haffner, Curt D.; Becherer, J. David; Boros, Eric E.; Cadilla, Rodolfo; Carpenter, Tiffany; Cowan, David; Deaton, David N.; Guo, Yu; Harrington, Wallace; Henke, Brad R.; Jeune, Michael R.; Kaldor, Istvan; Milliken, Naphtali; Petrov, Kim G.; Preugschat, Frank; Schulte, Christie; Shearer, Barry G.; Shearer, Todd; Smalley, Terrence L.; Stewart, Eugene L.; Stuart, J. Darren; Ulrich, John C. [Journal of Medicinal Chemistry, 2015, vol. 58, # 8, p. 3548 - 3571]

4
[ 175867-01-3 ]
[ CAS Unavailable ]
[ 2222514-75-0 ]

Yield	Reaction Conditions	Operation in experiment
73%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In ethyl acetate; N,N-dimethyl-formamide	58 (fra/7s)-3-(Benzord1thiazol-4-yloxy)-A/-((fra/7s)-4-(2- methoxyethoxy)cvclohexyl)cvclobutanecarboxamide To a DMF (1 .5 mL) solution of (frans)-3-(benzo[d]thiazol-4-yloxy)cyclobutanecarboxylic acid (Intermediate 25) (50 mg, 0.20 mmol), (frans)-4-(2-methoxyethoxy)cyclohexanamine (Intermediate 39) (42 mg, 0.24 mmol) and N,N-diisopropylethylamine (0.09 mL, 0.5 mmol) was added, dropwise, a 50% solution of T3P in ethyl acetate (255 mg, 0.40 mmol). The reaction was stirred 1 h, diluted with water and MeOH, and loaded onto a semi-prep HPLC (NH4OH as modifier) to afford partially pure product which was purified by silica gel chromatography, eluting with a 10-70% 3:1 EtOAc:EtOH in hexanes gradient to afford the title compound as a white solid (59 mg, 73% yield). 1H NMR (400 MHz, CDCI3) δ 0.94-1 .17 (m, 2 H), 1 .25-1 .46 (m, 2 H), 1 .87- 2.09 (m, 4 H), 2.48-2.61 (m, 2 H), 2.67-2.76 (m, 2 H), 2.85-2.97 (m, 1 H), 3.1 1 -3.24 (m, 1 H), 3.30 (s, 3 H), 3.41 -3.48 (m, 2 H), 3.50-3.59 (m, 2 H), 3.64-3.83 (m, 1 H), 5.06-5.15 (m, 1 H), 5.28 (d, J = 8 Hz, 1 H), 6.70 (d, J = 8 Hz, 1 H), 7.26 (m, 1 H), 7.44 (d, J = 8 Hz, 1 H), 8.83 (s, 1 H); LC-MS (LC-ES) M+H = 405.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2018/69863, 2018, A1 Location in patent: Page/Page column 311

5
[ 175867-01-3 ]
[ 7693-46-1 ]
[ 2222518-70-7 ]

Yield	Reaction Conditions	Operation in experiment
72%	With sodium hydrogencarbonate In acetonitrile at 0 - 20℃; for 1h;	Intermediate 65: 4-Nitrophenyl ((trans)-4-(2- methoxyethoxy)cyclohexyl)carbamate To 4-nitrophenyl chloroformate (326 mg, 1 .62 mmol) in acetonitrile (5 mL) at 0 °C was slowly added (irans)-4-(2-methoxyethoxy)cyclohexanamine (Intermediate 39) (200 mg, 1 .15 mmol) in acetonitrile (5 mL). After 30 min, sodium bicarbonate (194 mg, 2.31 mmol) was added, and the mixture was allowed to warm to room temperature. After 1 h, the solvent was removed in vacuo, and the residue was purified on silica gel, eluting with a 0%-60% EtOAc in hexanes gradient to give the title compound as a white solid (280 mg, 72%). 1H NMR (400 MHz, CD3SOCD3) δ 1 .15-1 .32 (m, 4 H), 1 .82-1 .89 (m, 2 H), 1 .90-2.03 (m, 2 H), 2.51 (dt, J = 4, 2 Hz, 1 H), 3.21 -3.24 (m, 1 H), 3.24 (s, 3 H), 3.39-3.45 (m, 2 H), 3.49-3.56 (m, 2 H), 7.36-7.43 (m, 2 H), 8.04 (d, J = 8 Hz, 1 H), 8.24-8.31 (m, 2 H); LC-MS (LC-ES) M+H = 339.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2018/69863, 2018, A1 Location in patent: Page/Page column 178

6
[ 175867-01-3 ]
[ 2597937-68-1 ]
[ 2597935-77-6 ]

Yield	Reaction Conditions	Operation in experiment
33.6%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1h;	268.7 Step 7:2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-7-methyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide A solution of 2-(1H-imidazol-1-yl)-7-methyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxylic acid (55.0 mg, 0.23 mmol, 1 eq), (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (47.0 mg, 0.27 mmol, 1.2 eq), DIEA (87.7 mg, 0.68 mmol, 3 eq), and HATU (128.9 mg, 0.34 mmol, 1.5 eq) in DMF (2 mL) was stirred for 1 h at RT. The resulting solution was quenched with 10 mL of water. The resulting solution was extracted with DCM (320 mL.) The organic layers were combined and concentrated. The crude product was purified by Flash-Prep-HPLC with the following conditions: (Column: YMC-Actus Triart C18 ExRS, 30150 mm, 5 μm. Mobile Phase A: Water (10 mM NH4HCO3), Mobile Phase B: ACN. Flow rate:60 mL/min; Gradient: 29% B to 53% B in 8 min; 254/220 nm) to afford the title compound (30.3 mg, 33.6% yield) as a white solid. LCMS: [M+H]+ 399.15. 1H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 9.00 (s, 1H), 8.87 (d, J=8.6 Hz, 1H), 8.23 (s, 1H), 7.83 (s, 1H), 7.13 (s, 1H), 3.95-3.80 (m, 1H), 3.60-3.53 (m, 2H), 3.48-3.41 (m, 2H), 3.30-3.26 (m, 1H), 3.25 (s, 3H), 2.31 (s, 3H), 2.11-2.05 (m, 2H), 1.90-1.81 (m, 2H), 1.66-1.60 (m, 2H), 1.31-1.21 (m, 2H).

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC - US2021/32251, 2021, A1 Location in patent: Paragraph 0896

7
[ CAS Unavailable ]
[ 175867-01-3 ]
[ 2597936-41-7 ]
[ 2597933-19-0 ]

Yield	Reaction Conditions	Operation in experiment
7%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; triethylamine In dimethyl sulfoxide at 90℃; for 6h;	9.3 Step 3: 5-(1H-Imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-1H-indole-7-carboxamide A solution of 7-bromo-5-(1H-imidazol-1-yl)-2-methyl-1H-indole (200 mg, 0.72 mmol, 1.0 eq), Int-B1 (502 mg, 2.9 mmol, 4.0 eq), TEA (146.6 mg, 1.45 mmol, 2.0 eq), and Pd(dppf)Cl2 (53 mg, 0.072 mmol, 0.1 eq) in DMSO (2 mL) was stirred for 6 h at 90° C. under CO (2 atm) atmosphere. The reaction was quenched with water. The resulting solution was extracted with 3*30 mL of EtOAc. The organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (80 mg) was purified by Prep-HPLC eluting with ACN/H2O to afford the title compound (20 mg, 7%) as a white solid. LCMS: [M+H]+ 397.20. 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.35 (d, J=7.7 Hz, 1H), 8.17 (s, 1H), 7.75 (d, J=10.7 Hz, 2H), 7.70 (s, 1H), 7.12 (s, 1H), 6.25 (s, 1H), 3.87 (dd, J=7.7, 4.0 Hz, 1H), 3.58-3.53 (m, 2H), 3.46-3.41 (m, 2H), 3.303.28 (m, 1H), 3.25 (s, 3H), 2.44 (s, 3H), 2.06 (d, J=12.2 Hz, 2H), 1.95 (d, J=12.6 Hz, 2H), 1.42 (q, J=11.8 Hz, 2H), 1.26 (q, J=11.8 Hz, 2H).

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC - US2021/32251, 2021, A1 Location in patent: Paragraph 0507

8
[ 175867-01-3 ]
[ 2597936-29-1 ]
[ 2597936-30-4 ]

Yield	Reaction Conditions	Operation in experiment
26%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 3h;	1.2 Step 2: 5-(1H-Imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxamide A mixture of 6-imidazol-1-yl-3-(2-trimethylsilylethoxymethyl)benzimidazole-4-carboxylic acid (200 mg, 0.56 mmol, 1 eq), Int-B1 (97 mg, 0.56 mmol, 1 eq), HATU (318 mg, 0.84 mmol, 1.5 eq) and DIPEA (108 mg, 0.84 mmol, 1.5 eq) in DMF (5 mL) was stirred at RT for 3 h. After diluting with EtOAc (20 mL), the organic phase was washed with brine (5 mL*3). After concentration, the mixture was purified by silica gel chromatography (DCM:MeOH, 20:1) to give the title compound (75 mg, 0.15 mmol, 26% yield). LCMS: [M+H]+ 514.4.

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC - US2021/32251, 2021, A1 Location in patent: Paragraph 0473

9
[ 175867-01-3 ]
[ 2597936-00-8 ]
[ 2597936-34-8 ]

Yield	Reaction Conditions	Operation in experiment
35%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 25℃;	4.1 Step 1: 5-Bromo-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-7-carboxamide To a solution of Int-A1 (100 mg, 0.27 mmol, 1 eq), HOBt (44 mg, 0.32 mmol, 1.2 eq), EDC (50 mg, 0.32 mmol, 1.2 eq) in DMF (2 mL) was added Int-B1 (51 mg, 0.30 mmol, 1.1 eq), and the mixture was stirred at 25° C. overnight. The mixture was diluted with water (25 mL) and extracted with EtOAc (20 mL*3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether:EtOAc, 1:1) to afford the title compound (50 mg, 0.095 mmol, 35% yield) as a brown oil. LCMS: [M+H]+ 528.2.

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC - US2021/32251, 2021, A1 Location in patent: Paragraph 0483

10
[ 175867-01-3 ]
[ 2597936-02-0 ]
[ 2597933-17-8 ]

Yield	Reaction Conditions	Operation in experiment
64%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 35℃; for 2h;	7 Example 7 2-(1H-Imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide A solution of Int-A2 (23 g, 100 mmol, 1.0 eq), Int-B1 (19.1 g, 110 mmol, 1.1 eq), HATU (57.2 g, 150 mmol, 1.5 eq), and DIPEA (32.4 g, 250 mmol, 2.5 eq) in DMF (500 mL) was stirred at 35° C. for 2 h. The reaction was quenched with water and extracted with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by prep-HPLC eluting with ACN/H2O to afford the title compound (24.8 g, 64 mmol, 64% yield) as a white solid. LCMS: [M+H]+ 385.15; 1H NMR (300 MHz, DMSO-d6) δ 12.08 (s, 1H), 8.98 (s, 1H), 8.96-8.89 (m, 1H), 8.23 (s, 1H), 8.03 (t, J=4.0 Hz, 1H), 7.13 (s, 1H), 6.71 (d, J=3.1 Hz, 1H), 3.99-3.85 (m, 1H), 3.59-3.56 (m, 2H), 3.47-3.42 (m, 2H), 3.33-3.30 (m, 1H), 3.26 (s, 3H), 2.09-1.99 (m, 2H), 1.91-1.83 (m, 2H), 1.71-1.55 (m, 2H), 1.45-1.21 (m, 2H).

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC - US2021/32251, 2021, A1 Location in patent: Paragraph 0495-0496

11
[ 175867-01-3 ]
[ 1448259-10-6 ]
[ 1937268-24-0 ]

Yield	Reaction Conditions	Operation in experiment
59%	Stage #1: 5-iodo-1H-indole-7-carboxylic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Stage #2: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine In N,N-dimethyl-formamide at 0 - 20℃; for 2.5h;	1.7 Step 7: 5-iodo-N-((lr,4r)-4-(2-methoxyethoxy) cyclohexyl)-lH-indole-7-carboxamide To a stirred solution of 5-Iodo-lH-indole-7-carboxylic acid (1.78 g, 6.2 mmol) in DMF (10 mL) were added DIPEA (1.4 mL, 8.0 mmol) and HATU (2.80 g, 7.4 mmol) at 0 °C. After stirring for 5 min a solution of (lr,4r)-4-(2-methoxyethoxy)cyclohexan-l -amine (1.27 g, 7.4 mmol) in DMF (2.5 mL) was added at same temperature. Further reaction was stirred at RT for 2.5 h. The reaction mixture was monitored by TLC and quenched with water (25 mL). The resulting suspension was extracted with EtOAc (3 x 25 mL). The combined organic layer was washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4 and solvent was evaporated under vacuum. The resulting crude product was purified by column chromatography (100-200 mesh silica gel, 10-50% EtOAc in petroleum ether) to afford the title compound Yield: 59% (1.62 g, White solid). Further 100 mg taken for trituration with ether to get more purity to submit for assay. 1HNMR (400 MHz, DMSO-d6): δ 11.25 (s, 1H), 8.41 (d, J = 7.6 Hz, 1H), 8.07 (s, 1H), 7.92 (s, 1H), 7.33 (s, 1H), 6.44 (s, 1H), 3.87-3.82 (m, 1H), 3.56-3.53 (m, 2H), 3.44-3.42 (m, 2H), 3.22-3.23 (m, 4H), 2.05-2.02 (m, 2H), 1.99-1.88 (m, 2H), 1.46-1.37 (m, 2H), 1.28-1.23 (m, 2H). LCMS: (Method A) 443.0 (M+H)
59%	Stage #1: 5-iodo-1H-indole-7-carboxylic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Inert atmosphere; Stage #2: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine In N,N-dimethyl-formamide at 0 - 20℃; for 2.5h; Inert atmosphere;
56%	With N-ethyl-N,N-diisopropylamine; O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate In N,N-dimethyl-formamide at 20℃; for 6h;	6.1 Step 1: 5-Iodo-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-indole-7-carboxamide A solution of 5-iodo-1H-indole-7-carboxylic acid, prepared in Example 5, Step 2 (844 mg, 2.94 mmol, 1 eq), Int-B1 (611 mg, 3.53 mmol, 1.2 eq), DIPEA (1.33 mL, 7.64 mmol, 2.6 eq), HATU (1.34 g, 3.53 mmol, 1.2 eq) in DMF (15 mL) was stirred at RT for 6 h. The mixture was concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc (3*60 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column (petroleum ether:EtOAc, 3:1, v/v) to afford the title compound (740 mg, 1.67 mmol, 56% yield) as a gray solid. LCMS: [M+H]+ 443.2.

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2021/87087, 2021, A1 Location in patent: Page/Page column 30; 34
[2]Lagu, Bharat; Wu, Xinyuan; Kulkarni, Santosh; Paul, Rakesh; Becherer, J. David; Olson, Lyndsay; Ravani, Stella; Chatzianastasiou, Athanasia; Papapetropoulos, Andreas; Andrzejewski, Sylvia [Journal of Medicinal Chemistry, 2022, vol. 65, # 13, p. 9418 - 9446]
[3]Current Patent Assignee: RIBON THERAPEUTICS INC - US2021/32251, 2021, A1 Location in patent: Paragraph 0493

12
[ 175867-01-3 ]
[ 2597936-38-2 ]
[ 2597936-39-3 ]

Yield	Reaction Conditions	Operation in experiment
41.7%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃;	8.4 Step 4: 5-Iodo-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carboxamide A mixture of 5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-7-carboxylic acid, (280 mg, 0.67 mmol, 1.0 eq), Int-B1 (231.9 mg, 1.34 mmol, 2.0 eq), HATU (509.0 mg, 1.34 mmol, 2.0 eq), and DIPEA (259.5 mg, 2.01 mmol, 3.0 eq) in DMF (5 mL) was stirred overnight at RT. The mixture was concentrated and purified by flash chromatography on silica gel eluting with MeOH in DCM (0-10%) to afford the title compound (160 mg, 41.7% yield) as a yellow oil. LCMS: [M+H]+ 574.15.

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC - US2021/32251, 2021, A1 Location in patent: Paragraph 0501

13
[ 175867-01-3 ]
[ 2597936-46-2 ]
[ 2597933-20-3 ]

Yield	Reaction Conditions	Operation in experiment
20%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1h;	10.6 Step 6: 5-(1H-Imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamide A solution of 5-(1H-imidazol-1-yl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid (15 mg, 0.066 mmol, 1 eq), Int-B1 (11.4 mg, 0.066 mmol, 1 eq), HATU (25 mg, 0.066 mmol, 1.0 eq) and DIPEA (17 mg, 0.13 mmol, 2.0 eq) in DMF (1 mL) was stirred for 1 h at RT. The resulting mixture was purified by C18 reverse phase eluting with CH3CN/H2O to afford the title compound (5 mg, 20%) as a white solid. LCMS: 384.25 [M+H]+. 1H NMR (400 MHz, CD3OD-d4) δ 8.52 (d, J=1.3 Hz, 1H), 7.94 (d, J=1.4 Hz, 1H), 7.83 (s, 1H), 7.74 (d, J=3.3 Hz, 1H), 7.19 (t, J=1.2 Hz, 1H), 6.69 (d, J=3.3 Hz, 1H), 4.02-3.98 (m, 1H), 3.70-3.61 (m, 2H), 3.59-3.51 (m, 2H), 3.46-3.38 (m, 4H), 2.21-2.08 (m, 4H), 1.59-1.34 (m, 4H).

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC - US2021/32251, 2021, A1 Location in patent: Paragraph 0514

14
[ 175867-01-3 ]
[ 2597936-52-0 ]
[ 2597933-22-5 ]

Yield	Reaction Conditions	Operation in experiment
23%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.666667h;	12.6 Step 6: 5-(1H-Imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamide A solution of 5-(1H-imidazol-1-yl)-1H-pyrrolo[2,3-c]pyridine-7-carboxylic acid (35 mg, 0.15 mmol, 1.0 eq), Int-B1 (32 mg, 0.18 mmol, 1.2 eq), HATU (58 mg, 0.15 mmol, 1.0 eq) and DIPEA (39.6 mg, 0.31 mmol, 2.0 eq) in DMF (5 mL) was stirred for 40 min at RT. The resulting mixture was quenched with water and extracted with 3*10 mL EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified with C18 reverse phase chromatography eluting with H2O/CH3CN to afford the title compound (13 mg, 23%) as a white solid. LCMS (ESI, m/z): 384.20[M+H]+. 1H NMR (300 MHz, Methanol-d4) δ8.71 (d, J=1.4 Hz, 1H), 8.02-7.99 (m, 2H), 7.71 (dd, J=3.1, 1.2 Hz, 1H), 7.17 (d, J=1.5 Hz, 1H), 6.71 (dd, J=3.2, 1.2 Hz, 1H), 4.08-3.97 (m, 1H), 3.74-3.62 (m, 2H), 3.60-3.51 (m, 2H), 3.44-3.36 (m, 4H), 2.27-1.94 (m, 4H), 1.73-1.54 (m, 2H), 1.52-1.26 (m, 2H).

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC - US2021/32251, 2021, A1 Location in patent: Paragraph 0526

15
[ 175867-01-3 ]
[ 2597936-55-3 ]
[ 2597933-23-6 ]

Yield	Reaction Conditions	Operation in experiment
47%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1h;	13.6 Step 6: N-((1r,4r)-4-(2-Methoxyethoxy)cyclohexyl)-2-methyl-5-(thiazol-5-yl)-1H-benzo[d]imidazole-7-carboxamide A solution of 2-methyl-5-(thiazol-5-yl)-1H-benzo[d]imidazole-7-carboxylic acid (105 mg, 0.41 mmol, 1.0 eq), Int-B1 (84 mg, 0.47 mmol, 1.2 eq), DIPEA (157 mg, 1.22 mmol, 3.0 eq), and HATU (231 mg, 0.61 mmol, 1.5 eq) in DMF (3.5 mL) was stirred for 1 h at RT. The reaction was then quenched with the addition of 0.1 mL of ethanolamine. The crude product was purified by C18 reverse phase chromatography eluting with H2O/CH3CN to afford the title compound (80 mg, 47%) as a white solid. LCMS: [M+H]+ 415.20. 1HNMR (400 MHz, DMSO-d6) δ: 12.69 (s, 1H), 9.75 (s, 1H), 9.08 (d, J=0.7 Hz, 1H), 8.34 (d, J=0.8 Hz, 1H), 8.00 (d, J=1.7 Hz, 1H), 7.92 (d, J=1.7 Hz, 1H), 3.89-3.85 (m, 1H), 3.59-3.51 (m, 2H), 3.50-3.40 (m, 2H), 3.36-3.30 (m, 1H), 3.26 (s, 3H), 2.59 (s, 3H), 2.01 (d, J=9.0 Hz, 4H), 1.47-1.27 (m, 4H).

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC - US2021/32251, 2021, A1 Location in patent: Paragraph 0533

16
[ 175867-01-3 ]
[ 2597936-59-7 ]
[ 2597936-60-0 ]

Yield	Reaction Conditions	Operation in experiment
75%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1h;	14.6 Step 6: 2-(1H-Imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine-6-carboxamide A solution of 2-(1H-imidazol-1-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purine-6-carboxylic acid (120 mg, 0.33 mmol, 1.0 eq), Int-B1 (69 mg, 0.40 mmol, 1.2 eq), HATU (165 mg, 0.43 mmol, 1.3 eq) and DIPEA (86 mg, 0.67 mmol, 2.0 eq) in DMF (2 mL) was stirred at RT for 1 h. After concentration, the crude product was purified by prep-HPLC to give the title compound (130 mg, 75% yield) as a white solid. LCMS: [M+H]+ 516.30.

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC - US2021/32251, 2021, A1 Location in patent: Paragraph 0540

17
[ 175867-01-3 ]
[ 2597936-69-9 ]
[ 2597933-26-9 ]

Yield	Reaction Conditions	Operation in experiment
43%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.666667h;	16.7 Step 7: 5-(1H-Imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide To a solution of 5-(1H-imidazol-1-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxylic acid (65 mg, 0.28 mmol, 1.0 eq), HATU (108 mg, 0.28 mmol, 1.0 eq) and DIPEA (73 mg, 0.57 mmol, 2.0 eq) in DMF (5.0 mL) was added Int-B1 (49.1 mg, 0.28 mmol, 1.0 eq). The resulting solution was stirred for 40 min at RT. The resulting mixture was quenched with water and extracted with 3*20 mL of EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by C18 reverse phase eluting with H2O/ACN to afford the title compound (46.9 mg, 43%) as a white solid. LCMS (ESI, m/z): 385.25 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ13.85 (s, 1H), 8.93 (d, J=1.3 Hz, 1H), 8.74 (d, J=8.7 Hz, 1H), 8.37 (dd, J=2.8, 1.0 Hz, 2H), 8.23 (s, 1H), 7.16 (s, 1H), 4.05-3.79 (m, 1H), 3.57 (dd, J=5.9, 3.7 Hz, 2H), 3.44 (dd, J=5.9, 3.7 Hz, 2H), 3.34-3.30 (m, 4H), 2.08 (d, J=12.3 Hz, 2H), 1.90 (d, J=11.9 Hz, 2H), 1.64 (m, 2H), 1.29 (m, 2H).

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC - US2021/32251, 2021, A1 Location in patent: Paragraph 0557

18
[ 175867-01-3 ]
[ 2597936-76-8 ]
[ 2597933-27-0 ]

Yield	Reaction Conditions	Operation in experiment
26%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.666667h;	17.8 Step 8 N-((1r,4r)-4-(2-Methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxamide A solution of 5-(thiazol-5-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylic acid (20 mg, 0.08 mmol, 1.0 eq), Int-B1 (14 mg, 0.081 mmol, 1.0 eq), HATU (31 mg, 0.081 mmol, 1.0 eq) and DIPEA (32 mg, 0.24 mmol, 3.0 eq) in DMF (0.5 mL) was stirred for 40 min at RT, and the resulting solution was purified by C18 reverse phase eluting with H2O/ACN to afford the title compound (8.4 mg, 26%) as a white solid. LCMS (ESI, m/z): 402.25 [M+H]+.H NMR (300 MHz, Methanol-d4) δ 9.11 (d, J=9.1 Hz, 1H), 8.58 (s, 1H), 8.45 (d, J=9.1 Hz, 1H), 8.38 (d, J=4.5 Hz, 1H), 4.06-3.99 (m, 1H), 3.69-3.66 (m, 2H), 3.57-3.54 (m, 2H), 3.42-3.32 (m, 4H), 2.28-2.12 (m, 4H), 1.59-1.41 (m, 4H).

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC - US2021/32251, 2021, A1 Location in patent: Paragraph 0566

19
[ 175867-01-3 ]
[ 2597936-83-7 ]
[ 2597936-84-8 ]

Yield	Reaction Conditions	Operation in experiment
84%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1h;	19.8 Step 8: tert-Butyl ((5-(1H-imidazol-1-yl)-7-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)carbamoyl)-1H-indol-2-yl)methyl)carbamate A mixture of 2-((tert-butoxycarbonylamino)methyl)-5-(1H-imidazol-1-yl)-1H-indole-7-carboxylic acid (100 mg, 0.28 mmol, 1.0 eq), DIPEA (108 mg, 0.84 mmol, 3 eq), HATU (129 mg, 0.34 mmol, 1.2 eq) and Int-B1 (59 mg, 0.34 mmol, 1.2 eq) in DMF (1.0 mL) was stirred at RT for 1 h. The crude product was purified by C18 reverse phase chromatography eluting with H2O/CH3CN to afford the title compound (120 mg, 84%) as a white solid. LCMS: [M+H]+ 512.28.

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC - US2021/32251, 2021, A1 Location in patent: Paragraph 0581

20
[ 175867-01-3 ]
[ 2597936-93-9 ]
[ 2597933-31-6 ]

Yield	Reaction Conditions	Operation in experiment
25%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.666667h;	21.9 Step 9: N-((1r,4r)-4-(2-Methoxyethoxy)cyclohexyl)-5-(thiazol-5-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxamide To a solution of 5-(thiazol-5-yl)-1H-pyrazolo[3,4-c]pyridine-7-carboxylic acid (14 mg, 0.057 mmol, 1.00 eq), DIPEA (22 mg, 0.17 mmol, 3.00 eq) and HATU (22 mg, 0.057 mmol, 1.00 eq) in DMF (0.5 mL) was added in Int-B1 (11 mg, 0.063 mmol, 1.10 eq). The resulting solution was stirred for 40 min at RT. The reaction was quenched with H2O and extracted with 3*10 mL EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by C18 reverse phase chromatography eluting with CH3CN/H2O to afford the title compound (6 mg, 25%) as a white solid. LCMS (ESI, m/z): 402.10 [M+H]+. 1H NMR (400 MHz, CD3OD-d4) δ 9.03 (d, J=0.7 Hz, 1H), 8.56 (d, J=0.7 Hz, 1H), 8.46 (s, 1H), 8.30 (s, 1H), 4.03 (ddt, J=11.1, 7.4, 3.9 Hz, 1H), 3.71-3.64 (m, 2H), 3.60-3.53 (m, 2H), 3.49-3.34 (m, 1H), 3.40 (s, 3H), 2.21-2.10 (m, 4H), 1.68-1.55 (m, 2H), 1.52-1.39 (m, 2H).

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC - US2021/32251, 2021, A1 Location in patent: Paragraph 0598

21
[ 175867-01-3 ]
[ 2090149-31-6 ]
[ 2597936-05-3 ]

Yield	Reaction Conditions	Operation in experiment
58%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 25℃; for 2h;	3 Step 3: 2-Chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide A solution of 2-chloro-5H-pyrrolo[3,2-d]pyrimidine-4-carboxylic acid (2.3 g, 11.64 mmol, 1.0 eq), DIPEA (4.49 g, 34.74 mmol, 2.9 eq), HATU (5.30 g, 13.94 mmol, 1.2 eq) and Int B1 (2.40 g, 13.85 mmol, 1.2 eq) in DMF (20 mL) was stirred for 2 h at 25° C. The reaction was quenched with water and extracted with 3*100 mL of dichloromethane. The organic layers were combined, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by re-crystallization from MeOH to afford the title compound (2.4 g, 58% yield) as a yellow solid. LCMS: [M+H]+ 353.13.

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC - US2021/32251, 2021, A1 Location in patent: Paragraph 0418

22
[ 175867-01-3 ]
[ 1369497-72-2 ]
[ 2597937-23-8 ]

Yield	Reaction Conditions	Operation in experiment
88%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1h;	41.5 Step 5: 5-Bromo-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)benzo[d]isothiazole-7-carboxamide A mixture of 5-bromobenzo[d]isothiazole-7-carboxylic acid (1.28 g, 4.96 mmol, 1.00 eq), Int-B1 (945 mg, 5.46 mmol, 1.10 eq), HATU (2.64 g, 6.94 mmol, 1.40 eq), DIPEA (2.56 g, 19.84 mmol, 4.00 eq) in DMF (15 mL) was stirred at RT for 1 h. The reaction was quenched with water and extracted with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated. The crude product was applied onto a silica gel column eluting with (EtOAc:petroleum ether, 1:1) to afford the title compound (1.8 g, 88% yield) as a white solid. LCMS: [M+H]+ 413.1, 415.1.

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC - US2021/32251, 2021, A1 Location in patent: Paragraph 0685

23
[ 175867-01-3 ]
[ 2597937-32-9 ]
[ 2597934-18-2 ]

Yield	Reaction Conditions	Operation in experiment
45%	With trimethylaluminum In n-heptane; toluene at 80℃; for 1.5h;	108.4 Step 4. 2-(JH-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxamide A solution of ethyl 2-(1H-imidazol-1-yl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-4-carboxylate (100.00 mg, 0.369 mmol, 1.00 equiv), (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (70.25 mg, 0.405 mmol, 1.10 equiv), and AlMe3 (1M in n-heptane, 1.1 mL, 1.106 mmol, 3 equiv) in toluene (6 mL) was stirred at 80° C. for 1.5 h. The reaction was quenched with MeOH. The solids were filtered and the filtrate was concentrated. The crude product was purified by reverse phase column eluting with ACN/H2O (2/3) followed by lyophilization to afford the title compound (66 mg, 45% yield) as a white solid. LCMS: [M+H]+ 399.3. 1H NMR (300 MHz, DMSO-d6) δ11.94 (s, 1H), 8.93 (s, 1H), 8.85 (d, J=8.6 Hz, 1H), 8.20 (t, J=1.4 Hz, 1H), 7.11 (d, J=1.2 Hz, 1H), 6.45 (s, 1H), 4.01-3.82 (m, 1H), 3.57 (dd, J=5.9, 3.7 Hz, 2H), 3.44 (dd, J=5.9, 3.7 Hz, 2H), 3.30-3.28 (m, 1H), 3.26 (s, 3H), 2.56 (s, 3H), 2.11-2.02 (m, 2H), 1.90-1.81 (m, 2H), 1.76-1.55 (m, 2H), 1.35-1.25 (m, 2H).

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC - US2021/32251, 2021, A1 Location in patent: Paragraph 0720-0721

24
[ 175867-01-3 ]
[ 2597937-56-7 ]
[ 2597935-08-3 ]

Yield	Reaction Conditions	Operation in experiment
60%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1.5h;	198.7 Step 7: 5-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)thieno[2,3-c]pyridine-7-carboxamide A solution of 5-(1H-imidazol-1-yl)thieno[2,3-c]pyridine-7-carboxylic acid (100 mg, 0.41 mmol, 1 equiv), (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (70.6 mg, 0.41 mmol, 1 equiv), DIEA (158.1 mg, 1.22 mmol, 3 equiv), and HATU (186.04 mg, 0.49 mmol, 1.2 equiv) in DMF (3.0 mL) was stirred for 1.5 h at RT. The crude product was purified by reverse phase column eluting with MeCN/H2O (38/62) to afford the title compound (99.7 mg, 60%). LCMS: [M+H]+ 401.20. 1H NMR (300 MHz, DMSO-d6) δ: δ 8.98 (s, 1H), 8.80 (d, J=8.7 Hz, 1H), 8.45 (d, s, 1H), 8.27 (dd, J=9.3, 3.5 Hz, 2H), 7.57 (d, J=5.5 Hz, 1H), 7.16 (s, 1H), 3.90-3.88 (m, 1H), 3.60-3.51 (m, 2H), 3.48-3.39 (m, 2H), 3.31-3.26 (m, 4H), 2.12-2.06 (m, 2H), 1.92-1.81 (m, 2H) 1.75-1.52 (m, 2H), 1.35-1.1 (m, 2H).

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC - US2021/32251, 2021, A1 Location in patent: Paragraph 0835

25
[ 175867-01-3 ]
[ 2641484-98-0 ]
[ 2641484-99-1 ]

Yield	Reaction Conditions	Operation in experiment
77%	Stage #1: 6-bromo-7-fluoro-1H-indole-4-carboxylic acid With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Inert atmosphere; Stage #2: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine In N,N-dimethyl-formamide at 0 - 20℃; for 16h; Inert atmosphere;
68.3%	Stage #1: 6-bromo-7-fluoro-1H-indole-4-carboxylic acid With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide for 0.0833333h; Inert atmosphere; Stage #2: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine In N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere;	55.5 Step 5: 6-bromo-7-fluoro-N-((lr,4r)-4-(2-methoxyethoxy)cyclohexyl)-lH-indole-4- carboxamide To a stirred solution of 6-bromo-7-fluoro-lH-indole-4-carboxylic acid (210 mg, 0.81 mmol) in DMF (5 mL) at 0 °C EDC.HC1 (233 mg, 1.21 mmol, HOBt (164 mg, 1.21 mmol) and TEA (0.29 mL, 2.03 mmol) were added under nitrogen atmosphere. Then after 5 min (lr,4r)-4-(2- methoxyethoxy)cyclohexan-l -amine (169 mg, 0.97 mmol) in DMF was added at same temperature. Further reaction was stirred for another 16 h at RT. After completion of reaction, the reaction mixture was quenched with ice cold water (50 mL) and then extracted with EtOAc (100 mL). The resulting organic solution was washed with brine solution (50 mL), water (50 mL), dried over Na2SO4, and concentrated under vacuum to get crude product. The resulting crude residue was purified by flash chromatography on Biotage Isolera (100-200 mesh silica gel, 50% - 80% EtOAc in petroleum ether) to get title compound. Yield: 68.3% (230 mg, yellow solid). 1H NMR (400 MHz, DMSO-d6): δ 11.99 (s, 1H), 8.18 (d, J = 7.6 Hz, 1H), 7.62-7.60 (m, 1H), 7.55-7.51 (m, 1H), 6.91 (s, 1H), 3.75-3.70 (m, 1H), 3.53-3.50 (m, 2H), 3.42-3.40 (m, 2H), 3.25-3.16 (m, 4H), 2.20-1.86 (m, 4H), 1.39-1.22 (m, 4H). LCMS: (Method C) 415.1 (M+H)

Reference： [1]Lagu, Bharat; Wu, Xinyuan; Kulkarni, Santosh; Paul, Rakesh; Becherer, J. David; Olson, Lyndsay; Ravani, Stella; Chatzianastasiou, Athanasia; Papapetropoulos, Andreas; Andrzejewski, Sylvia [Journal of Medicinal Chemistry, 2022, vol. 65, # 13, p. 9418 - 9446]
[2]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2021/87087, 2021, A1 Location in patent: Page/Page column 103; 105

26
[ 175867-01-3 ]
[ 1360956-97-3 ]
[ 2641485-01-8 ]

Yield	Reaction Conditions	Operation in experiment
66%	Stage #1: 6-bromo-3-cyano-1H-indole-4-carboxylic acid With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In tetrahydrofuran; dichloromethane at 20℃; for 0.0833333h; Inert atmosphere; Stage #2: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine In dichloromethane at 20℃; for 16h; Inert atmosphere;
35%	With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; triethylamine In tetrahydrofuran; dichloromethane at 20℃; for 12h;	56.3 Step 3: 6-bromo-3-cyano-N-((lr,4r)-4-(2-methoxyethoxy)cyclohexyl)-lH-indole-4- carboxamide To a stirred solution of 6-bromo-3-cyano-lH-indole-4-carboxylic acid (200 mg, 0.75 mmol) in THF:DCM (1:1, 4 mL), were added EDC.HC1 (187 mg, 0.97 mmol), HOBt (152 mg, 1.12 mmol) and NEt3 (0.3 mL, 2.25 mmol) followed by (lr,4r)-4-(2-methoxyethoxy)cyclohexan- 1-amine (156 mg, 0.9 mmol) at RT and stirred for 12 h. After completion of reaction, the reaction mixture was concentrated and to the resulting crude water (10 mL) and extracted with DCM (3 x 20 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The resulting crude residue was purified by flash chromatography on Biotage Isolera (230-400 mesh silica gel, 0-5% methanol in DCM) to afford the title compound. Yield: 35% (110 mg, yellow solid). 1H NMR 400 MHz, DMSO-d6: δ 12.5 (s, 1H), 8.41 (d, / = 7.6 Hz, 1H), 8.34 (s, 1H), 7.81 (d, J = 1.6 Hz, 1H), 7.41 (d, J = 1.6 Hz, 1H), 3.74-3.73 (m, 1H), 3.55-3.52 (m, 2H), 3.44-3.41 (m, 2H), 3.28-3.22 (m, 4H), 2.02-1.98 (m, 4H), 1.36-1.23 (m, 4H). LCMS: (Method C) 420.0 (M-H)

Reference： [1]Lagu, Bharat; Wu, Xinyuan; Kulkarni, Santosh; Paul, Rakesh; Becherer, J. David; Olson, Lyndsay; Ravani, Stella; Chatzianastasiou, Athanasia; Papapetropoulos, Andreas; Andrzejewski, Sylvia [Journal of Medicinal Chemistry, 2022, vol. 65, # 13, p. 9418 - 9446]
[2]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2021/87087, 2021, A1 Location in patent: Page/Page column 106-108

27
[ 1167056-92-9 ]
[ 175867-01-3 ]
[ 2641485-04-1 ]

Yield	Reaction Conditions	Operation in experiment
37%	Stage #1: 6-chloro-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 20℃; for 0.0833333h; Stage #2: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine In dichloromethane at 20℃; for 16h;	58.2 Step 2: 6-chloro-N-((lr,4r)-4-(2-methoxyethoxy)cyclohexyl)-lH-pyrrolo[2,3-b]pyridine-4- carboxamide To a stirred solution of 6-chloro-lH-pyrrolo[2,3-b]pyridine-4-carboxylic acid (0.3 g, 1.52 mmol) in DCM (10 mL) at RT were added TEA (0.64 mL, 4.56 mmol), EDC-HC1 (0.437 g, 2.28 mmol) and HOBt (0.309 g, 2.28 mmol). After stirring for 5 min at RT, (lr,4r)-4-(2- methoxyethoxy)cyclohexan-l -amine (0.396 g, 2.28 mmol) was added and the reaction mixture was stirred at RT for 16 h. After completion (monitored by TLC), the reaction mixture was diluted with water (10 mL) and the resulting suspension was extracted with DCM (2 x 10 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The resulting crude residue was purified by flash chromatography on Biotage Isolera (60-120 mesh silica gel, eluent: 3% MeOH in DCM) to afford the title compound. Yield: 37% (0.2 g, off white solid). LCMS: (Method C) 352.2 (M+H)

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2021/87087, 2021, A1 Location in patent: Page/Page column 111-112

28
[ 175867-01-3 ]
[ 2641485-07-4 ]
[ 2641485-08-5 ]

Yield	Reaction Conditions	Operation in experiment
62%	Stage #1: 5-chloro-1H-pyrrolo[2,3-c]pyridine-7-carboxylic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Inert atmosphere; Stage #2: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine In N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere;	59.6 Step 6 : 5-chloro-N-((lr,4r)-4-(2-methoxyethoxy)cyclohexyl)-lH-pyrrolo[2,3-c]pyridine- 7-carboxamide To a stirred solution of 5-chloro-lH-pyrrolo[2,3-c]pyridine-7-carboxylic acid (845 mg, 4.29 mmol) in DMF (10 mL) at 0 °C, HATU (1.11 g, 6.44 mmol) followed by DIPEA (1.98 mL, 10.74 mmol) were added under nitrogen atmosphere and the stirring was continued at 0 °C for 5 min. Then (lr,4r)-4-(2-methoxyethoxy)cyclohexan-l -amine (1.11 g, 6.44 mmol) was added the reaction mixture was stirred for 16 h at RT. After completion (the starting material was consumed according to TLC), the reaction mixture was diluted with water (100 mL) and then extracted with EtOAc (200 mL). The resulting organic solution was washed with water (2 x 50 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum. The resulting crude residue was purified by grace chromatography using silica gel (100-200 mesh, 50%-70% EtOAc in pet ether) to get the title compound. Yield: 62% (935 mg, brown solid). LCMS: (Method C) 352.0 (M+H).

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2021/87087, 2021, A1 Location in patent: Page/Page column 113-114; 117

29
[ 175867-01-3 ]
[ 2641485-11-0 ]
[ 2641485-12-1 ]

Yield	Reaction Conditions	Operation in experiment
54%	Stage #1: 5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine In N,N-dimethyl-formamide at 20℃; for 18h;	60.6 Step 6: 5-chloro-N-( ( lr,4r)-4-( 2-methoxy ethoxy )cyclohexyl)-l-( ( 2-( trimethylsilyl)ethoxy )methyl)-lH-pyrrolo[3,2-b Jpyridine- 7 -carboxamide To a stirred solution of 5-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrolo[3,2- b]pyridine-7-carboxylic acid (0.71 g, 2.17 mmol) in DMF (5 mL) were added DIPEA (0.84 g, 6.53 mmol), EDC.HC1 (0.62 g, 3.26 mmol) and HOBt (0.44 g, 3.26 mmol) at RT. After stirring for 5 min, a solutions of (lr,4r)-4-(2-methoxyethoxy)cyclohexan-l -amine (0.45 g, 2.61 mmol) was added and the reaction mixture was stirred at RT for 18 h. After completion (monitored by TLC) the reaction mixture was diluted with water (30 mL) and the resulting suspension was extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and the solvent was evaporated under vacuum to afford the title compound. Yield: 54% (0.41 g, yellow solid). 1H NMR (400 MHz, DMSO-d6): δ 8.69 (d, J = 7.6 Hz, 1H), 7.94 (d, J = 3.2 Hz, 1H), 7.16 (s, 1H), 6.67 (d, J = 3.2 Hz, 1H), 5.59 (s, 2H), 3.77-3.71 (m, 1H), 3.55-3.52 (m, 2H), 3.44-3.41 (m, 2H), 3.28-3.23 (m, 6H), 2.02-1.94 (m, 4H), 1.35-1.23 (m, 4H), 0.74 (t, J = 8.4 Hz, 2H), - 0.09 (s, 9H). LCMS: (Method C) 482.2 (M+H).
54%	Stage #1: 5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Inert atmosphere; Stage #2: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine In N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere;

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2021/87087, 2021, A1 Location in patent: Page/Page column 118-119; 122
[2]Lagu, Bharat; Wu, Xinyuan; Kulkarni, Santosh; Paul, Rakesh; Becherer, J. David; Olson, Lyndsay; Ravani, Stella; Chatzianastasiou, Athanasia; Papapetropoulos, Andreas; Andrzejewski, Sylvia [Journal of Medicinal Chemistry, 2022, vol. 65, # 13, p. 9418 - 9446]

30
[ 175867-01-3 ]
[ 2641484-64-0 ]
[ 2641484-07-1 ]

Yield	Reaction Conditions	Operation in experiment
18%	Stage #1: 5-(thiazol-4-yl)-1H-indole-7-carboxylic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Stage #2: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h;	5.3 Step 3.N-((lr,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(thiazol-4-yl)-lH-indole-7- carboxamide To a stirred solution of 5-(thiazol-4-yl)-lH-indole-7-carboxylic acid (80 mg, 0.327 mmol) in DMF (3 mF) were added DIPEA (54.9 mg, 0.426 mmol) and HATU (149.5 mg, 0.393 mmol) at 0 °C. After stirring for 5 min a solution of (lr, 4r)-4-(2-methoxyethoxy) cyclohexan-1- amine (62.3 mg, 0.360 mmol) in DMF (0.5 mF) followed by DIPEA (54.9 mg, 0.42 mmol) were added at same temperature. Further reaction was stirred at RT for 16 h. The reaction mixture was monitored by TEC and quenched with water (2.5 mF). The resulting suspension was extracted with DCM (3 x 10 mF). The combined organic layer was washed with water (20 mF), brine (20 mF), dried over anhydrous Na2SO4 and solvent was evaporated under vacuum to get the crude product which was purified by flash chromatography (Biotage Isolera, 230-400 mesh silica gel eluting with 0-10% MeOH in DCM) to afford the title compound. Further it was purified by Prep-HPLC (Method A). The collected prep. HPLC fraction was concentered under vacuum. The resulting residue was dissolved in DCM and neutralized with 10% NaHCO3 aqueous solution. The organic phase was washed with water, brine, dried over anhydrous Na2SO4 and evaporated to afford the title compound. Yield: 18% (23.94 mg, off white solid). 1H NMR (400 MHz, DMSO-d6): δ 11.14 (s, 1H), 9.20 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 8.0 Hz, 1H), 8.33 (d, J = 0.8 Hz, 1H), 8.23 (d, J = 1.6 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.36 (t, J = 2.8 Hz, 1H), 6.54-6.53 (m, 1H), 3.91-3.84 (m, 1H), 3.56-3.53 (m, 2H), 3.44-3.41 (m, 2H), 3.24-3.25 (m, 4H), 2.06-2.04 (m, 2H), 1.95-1.92 (m,2H), 1.51-1.41 (m, 2H), 1.31-1.24 (m, 2H). LCMS: (Method C) 400.0 (M+H)
18%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere;

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2021/87087, 2021, A1 Location in patent: Page/Page column 37-39
[2]Lagu, Bharat; Wu, Xinyuan; Kulkarni, Santosh; Paul, Rakesh; Becherer, J. David; Olson, Lyndsay; Ravani, Stella; Chatzianastasiou, Athanasia; Papapetropoulos, Andreas; Andrzejewski, Sylvia [Journal of Medicinal Chemistry, 2022, vol. 65, # 13, p. 9418 - 9446]

31
[ 175867-01-3 ]
[ 2641484-67-3 ]
[ 2641484-08-2 ]

Yield	Reaction Conditions	Operation in experiment
37%	Stage #1: 5-(1H-imidazol-2-yl)-1H-indole-7-carboxylic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Stage #2: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h;	6.5 Step 5: 5-(lH-imidazol-2-yl)-N-((lr,4r)-4-(2-methoxyethoxy)cyclohexyl)-lH-indole-7- carboxamide To a stirred solution of 5-(lH-imidazol-2-yl)-lH-indole-7-carboxylic acid (80 mg, 0.352 mmol) in DMF (4 mL) were added DIPEA (59.1 mg, 0.458 mmol) and HATU (160.7 mg, 0.422 mmol) at 0 °C. After stirring for 5 min a solution of (lr, 4r)-4-(2-methoxyethoxy) cyclohexan-1 -amine (73.1 mg, 0.422 mmol) in DMF (1.0 mL) followed by was DIPEA (59.1 mg, 0.45 mmol) were added at same temperature. Further reaction was stirred at RT for 16 h. The reaction mixture was monitored by TLC and quenched with water (2.5 mL). The resulting suspension was extracted with DCM (3 x 10 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and solvent was evaporated under vacuum. The resulting crude product which was purified by flash chromatography (Biotage Isolera, 230-400 mesh silica gel, 0-10% MeOH in DCM) to afford the title compound. Yield: 37% (50.04 mg, off white solid). 1HNMR (400 MHz, DMSO+L): d 12.67 (s, 1H), 11.20 (s, 1H), 8.43 (d, J = 8.0 Hz, 1H), 8.21 (s, 2H), 7.38 (s, 1H), 7.18 (s, 2H), 6.55 (m, 1H), 3.89-3.86 (m, 1H), 3.57-3.54 (m, 2H), 3.45-3.42 (m, 2H), 3.26-3.24 (m, 4H), 2.07-2.04 (m, 2H), 1.94-1.91 (m, 2H), 1.51-1.42 (m, 2H), 1.31-1.23 (m, 2H). LCMS: (Method C) 383.0 (M+H)
37%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere;

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2021/87087, 2021, A1 Location in patent: Page/Page column 39; 41-42
[2]Lagu, Bharat; Wu, Xinyuan; Kulkarni, Santosh; Paul, Rakesh; Becherer, J. David; Olson, Lyndsay; Ravani, Stella; Chatzianastasiou, Athanasia; Papapetropoulos, Andreas; Andrzejewski, Sylvia [Journal of Medicinal Chemistry, 2022, vol. 65, # 13, p. 9418 - 9446]

32
[ 175867-01-3 ]
[ CAS Unavailable ]
[ 2641484-41-3 ]

Yield	Reaction Conditions	Operation in experiment
30%	Stage #1: 6-(thiazol-5-yl)-1H-indole-4-carboxylic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide for 0.0833333h; Stage #2: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine In N,N-dimethyl-formamide at 0 - 20℃; for 16h;	38.3 Step 3: N-((lr,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)-lH-indole-4- carboxamide To a stirred solution of 6-(thiazol-5-yl)-lH-indole-4-carboxylic acid (0.9 g, 3.68 mmol) in DMF (18 mL) at 0 °C, were added DIPEA (1.98 mL, 11.0 mmol) and HATU (1.68 g, 4.42 mmol). After stirring for 5 min, a solution of (lr,4r)-4-(2-methoxyethoxy)cyclohexan-l- amine (0.765 g, 4.42 mmol) was added at 0 °C and the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC. After completion, the reaction mixture was diluted with water (50 mL) and the resulting suspension was extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The resulting crude residue was purified by flash chromatography on Biotage Isolera (230-400 mesh silica gel, eluent: 3% MeOH in DCM) followed by reverse phase purification (Method A). The collected fraction was concentrated under reduced pressure. The residue was diluted with 10% MeOH in DCM (10 mL) and washed with 10% aq. NaHCO3 solution (4 mL), brine solution and water. The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and lyophilized to get the title compound. Yield: 30% (0.447 g, off white solid). 1H NMR (400 MHz, DMSO-d6): δ 11.39 (s, 1H), 9.06 (s, 1H), 8.31 (s, 1H), 8.17 (d, J = 7.6 Hz, 1H), 7.76 (s, 1H), 7.66 (s, 1H), 7.50-7.49 (m, 1H), 6.81 (s, 1H), 3.86-3.84 (m, 1H), 3.56-3.53 (m, 2H), 3.45-3.42 (m, 2H), 3.30-3.26 (m, 4H), 2.05-2.02 (m, 2H), 1.94-1.91 (m, 2H), 1.46- 1.37 (m, 2H), 1.30-1.22 (m, 2H). LCMS: (Method A) 400.0 (M+H)
10.25 g	Stage #1: 6-(thiazol-5-yl)-1H-indole-4-carboxylic acid With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.0333333h; Inert atmosphere; Stage #2: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine In dichloromethane at 20℃; for 16h; Inert atmosphere;

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2021/87087, 2021, A1 Location in patent: Page/Page column 80-82
[2]Lagu, Bharat; Wu, Xinyuan; Kulkarni, Santosh; Paul, Rakesh; Becherer, J. David; Olson, Lyndsay; Ravani, Stella; Chatzianastasiou, Athanasia; Papapetropoulos, Andreas; Andrzejewski, Sylvia [Journal of Medicinal Chemistry, 2022, vol. 65, # 13, p. 9418 - 9446]

33
[ 175867-01-3 ]
[ 796090-23-8 ]
[ 2725957-06-0 ]

Yield	Reaction Conditions	Operation in experiment
32%	Stage #1: 2-chloro-6-(trifluoromethyl)pyridine-4-carboxylic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine In N,N-dimethyl-formamide at 20℃;	4.1 Step 1: 2-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(trifluoromethyl)isonicotinamide To a stirred solution of 2-chloro-6-(trifluoromethyl)isonicotinic acid (200 mg, 0.888 mmol) in DMF (5 mL) were added HATU (506.6 mg, 1.33 mmol) and DIPEA (0.46 mL, 2.66 mmol) at RT. After stirring for 5 min a solution of (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (230.1 mg, 1.33 mmol) in DMF (0.5 mL) was added at same temperature. Further reaction was stirred at RT for overnight. The reaction mixture was monitored by TLC. Reaction mixture was quenched with water (25 mL). The resulting suspension was extracted with DCM (3 x 25 mL). The combined organic layer was washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4 and solvent was evaporated under vacuum. The resulting crude product which was purified by column chromatography Biotage Isolera (100-200 mesh silica gel eluting with 10-50% EtOAc in pet ether) to afford the title compound. Yield: 32% (109 mg, White solid). 1HNMR (300 MHz, DMSO-d6): δ 8.79 (d, J = 7.2 Hz, 1H), 8.24 (s, 1H), 8.20 (s, 1H), 3.76-3.75 (m, 1H), 3.54-3.52 (m, 2H), 3.47-3.41 (m, 2H), 3.18 (s, 4H), 2.04-2.02 (m, 2H), 1.99-1.91 (m, 2H), 1.87-1.22 (m, 4H). LCMS: (Method C) 379.0 (M-H), Rt.2.278 min.

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2021/207186, 2021, A1 Location in patent: Page/Page column 38-39

34
[ 88912-25-8 ]
[ 175867-01-3 ]
[ 2725957-11-7 ]

Yield	Reaction Conditions	Operation in experiment
77%	Stage #1: 4,6-dichloro-2-pyridinecarboxylic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Stage #2: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine In N,N-dimethyl-formamide at 0 - 20℃; for 16h;	8.1; 10.1; 12.1; 15.1; 16.1; 17.1; 30.1 Step 1: 4,6-dichloro-N-((1r,4r)-4-(2-methoxyethoxy) cyclohexyl)picolinamide To a stirred solution of 4,6-dichloropicolinic acid (3.0 g, 15.62 mmol) in DMF (30 mL) were added DIPEA (8.39 mL,46.87 mmol) and HATU (8.90 g,23.43 mmol) at 0 C. After stirring for 5 min a solution of (1r,4r)-4-(2-methoxyethoxy) cyclohexan-1-amine (3.24 g, 18.75 mmol) in DMF (5.0 mL) was added at same temperature. The reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC. After completion of reaction, it was quenched with water (25 mL). The resulting suspension was extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and solvent was evaporated under vacuum to get crude compound which was purified by column chromatography on Biotage Isolera (100-200 mesh silica gel eluting with 0-60% EtOAc in pet ether) to afford the title compound Yield:77 % (4.2 g, Yellow solid). 1HNMR 300 MHz, DMSO-d6): δ 8.46 (d, J = 8.1 Hz, 1H), 8.01-7.98 (m, 2H),3.76-3.73 (m, 1H), 3.52-3.50 (m, 2H), 3.42-3.40 (m, 2H), 3.23 (s, 4H), 2.00-197 (m, 2H), 1.80-1.76 (m, 2H), 1.55-1.44 (m, 2H), 1.26-1.19 (m, 2H). LCMS: (Method C) 347.0 [M+H], Rt.2.15 min

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2021/207186, 2021, A1 Location in patent: Page/Page column 47-48; 52; 56-57; 63; 66-69; 92-93

35
[ 21190-87-4 ]
[ 175867-01-3 ]
[ 2725957-13-9 ]

Yield	Reaction Conditions	Operation in experiment
69.9%	Stage #1: 6-bromo-pyridine-2-carboxylic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 0.25h; Inert atmosphere; Stage #2: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine In N,N-dimethyl-formamide at 0 - 20℃; for 16h; Inert atmosphere;	9.1 Step 1: 6-bromo-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide To a stirred solution of 6-bromopicolinic acid (415 mg, 2.05 mmol) in DMF (4 mL) was added HATU (1.17 g, 4.46 mmol) followed by DIPEA (0.94 mL, 5.12 mmol) under nitrogen atmosphere at 0 C, the resultant mixture was stirred for 15 min. After 15 min, (1r,4r)-4-(2-methoxyethoxy) cyclohexan-1-amine (533 mg, 3.08 mmol) was added and stirred at RT for 16 h. After completion, the reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (50 mL). The ethyl acetate layer was washed with water (2 x 50 mL) dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give title compound. Yield: 69.9% (510 mg, brown gummy solid). 1H NMR (400 MHz, DMSO-d6): δ 8.32 (d, J = 10.80 Hz, 1H), 8.1-8.00 (m, 1H), 7.95-7.90 (m, 1H), 7.89-7.82 (m, 1H), 3.75-3.70 (m, 1H), 3.53-3.50 (m, 2H), 3.42-3.40 (m, 2H), 3.25-3.16 (m, 4H), 2.20-1.86 (m, 4H), 1.39-1.22 (m, 4H), LCMS: (Method C) 360.0 [M+H], Rt.1.94 min.

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2021/207186, 2021, A1 Location in patent: Page/Page column 50

36
[ 175867-01-3 ]
[ 1060811-25-7 ]
[ 2725957-15-1 ]

Yield	Reaction Conditions	Operation in experiment
43%	Stage #1: 6-bromo-4-chloropicolinic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Stage #2: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine In N,N-dimethyl-formamide at 0 - 20℃;	13.1 Step 1: 6-bromo-4-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide To a stirred solution of 6-bromo-4-chloropicolinic acid (3.0 g, 12.71 mmol) in DMF (30 mL) were added DIPEA (6.60 mL, 38.13 mmol) and HATU (7.23 g, 19.06 mmol) at 0 C. After stirring for 5 min a solution of (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (2.85 g,16.52 mmol) in DMF (2.5 mL) was added at the same temperature. And the reaction mixture was stirred at RT overnight. After completion (monitored by TLC), the reaction mixture was diluted with water (45 mL). The resulting suspension was extracted with EtOAc (3 x 45 mL). The combined organic layer was washed with water (40 mL), brine (40 mL), dried over anhydrous Na2SO4 and the solvent was evaporated under vacuum. The get crude residue was purified by column chromatography on Biotage Isolera (100-200 mesh silica gel eluting with 0-60% EtOAc in pet ether) to afford the title compound. Yield: 43% (2.1 g, Yellow solid). 1H NMR (400 MHz, DMSO-d6): δ 8.44 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 1.6 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 3.78-3.71 (m, 1H), 3.55-3.52 (m, 2H), 3.43-3.41 (m, 2H), 3.24-3.18 (m, 4H), 2.01-198 (m, 2H), 1.81-1.78 (m, 2H), 1.54-1.49 (m, 2H), 1.26-1.21 (m, 2H). LCMS: (Method C) 391.0 [M+H], Rt.2.20 min.

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2021/207186, 2021, A1 Location in patent: Page/Page column 59-60

37
[ 175867-01-3 ]
[ 66572-56-3 ]
[ 2725957-19-5 ]

Yield	Reaction Conditions	Operation in experiment
48.2%	Stage #1: 2-bromoisonicotinic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Inert atmosphere; Stage #2: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine In N,N-dimethyl-formamide at 0 - 20℃; for 16h; Inert atmosphere;	21.1 Step 1: 2-bromo-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide To a stirred solution of 2-bromoisonicotinic acid (510 mg, 2.52 mmol) in DMF (5 mL) at 0 C was added HATU (1.43 g, 3.78 mmol) followed by DIPEA (1.16 mL, 6.30 mmol) under nitrogen atmosphere and stirred for 5 min. After 5 min, (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (656 mg, 3.78 mmol) was added and stirred at RT for 16 h. Upon completion, the reaction mixture was quenched with ice-cold water (20 mL) and extracted with EtOAc (50 mL). The ethyl acetate layer was washed with water (2 x 25 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give title compound. Yield: 48.2% (435 mg, yellow solid). 1H NMR (400 MHz, DMSO-d6): δ 8.59 (d, J = 7.60 Hz, 1H), 8.53 (d, J = 5.20 Hz, 1H), 7.99 (s, 1H), 7.78 (dd, J = 6.40, 1.2 Hz, 1H), 3.84-3.79 (m, 1H), 3.57-3.50 (m, 2H), 3.45-3.40 (m, 2H), 3.30-3.20 (m, 4H), 2.06-2.00 (m, 2H), 1.84-1.80 (m, 2H), 1.61-1.50 (m, 2H),1.30-1.20 (m, 2H), LCMS: (Method A) 357.0 [M+H], Rt.1.86 min.

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2021/207186, 2021, A1 Location in patent: Page/Page column 78

38
[ 324028-95-7 ]
[ 175867-01-3 ]
[ 2725957-22-0 ]

Yield	Reaction Conditions	Operation in experiment
77.05%	Stage #1: 6-chloro-4-methylpyridine-2-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Inert atmosphere; Stage #2: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine In N,N-dimethyl-formamide at 0 - 20℃; for 16h; Inert atmosphere;	29.1 Step 1: 6-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-methylpicolinamide To a stirred solution of 6-chloro-4-methylpicolinic acid (511 mg, 2.97 mmol) in DMF (5 mL) at 0 C was added EDC.HCl (856 mg, 4.46 mmol), HOBt (603 mg, 4.46 mmol) followed by DIPEA (1.37 mL, 7.44 mmol) under nitrogen atmosphere and the resultant mixture was stirred for 5 min. After 5 min, (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (774 mg, 4.46 mmol) was added and stirred at RT for 16 h. After completion, the reaction mixture was quenched with ice-cold water (25 mL) and extracted with EtOAc (50 mL), washed with water (2x20 mL) and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to give title compound. Yield: 77.05% (750 mg, brown solid); 1H NMR (400 MHz, DMSO-d6): δ 11.99 (s, 1H), 8.18 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 16.4 Hz, 1H), 6.91 (s, 1H), 3.75-3.70 (m, 1H), 3.53-3.50 (m, 2H), 3.42-3.40 (m, 2H), 3.25-3.16 (m, 4H), 2.20-1.86 (m, 4H), 1.39-1.22 (m, 4H), LCMS: (Method C) 327.2 [M+H], Rt. 2.10 min.

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2021/207186, 2021, A1 Location in patent: Page/Page column 90-91

39
[ 175867-01-3 ]
[ 2725957-10-6 ]
[ 2725956-46-5 ]

Yield	Reaction Conditions	Operation in experiment
32%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	6.4 Step 4: N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-pyrazol-4-yl)-2-(thiazol-5-yl)pyrimidine-4-carboxamide To a stirred solution of 6-(1-methyl-1H-pyrazol-4-yl)-2-(thiazol-5-yl)pyrimidine-4-carboxylic acid (150 mg, 0.52 mmol) in DMF (2.5 mL), were added EDC.HCl (150 mg, 0.78 mmol), HOBt (106 mg, 0.78 mmol) and DIPEA (202 mg, 1.56 mmol) and (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (118 mg, 0.68 mmol) at RT and the reaction mixture was stirred overnight at RT. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with brine (10 mL) dried over anhydrous Na2SO4 and concentrated under vacuum. The resulting crude residue was purified by flash chromatography on Biotage Isolera (230-400 mesh silica gel, eluent: 0-5% methanol in DCM) to afford the title compound. Yield: 32% (73 mg, yellow solid).1H NMR (400 MHz, DMSO-d6): δ 9.30 (d, J = 0.4 Hz, 1H), 9.08 (d, J = 0.8 Hz, 1H), 8.70 (s, 1H), 8.6 (d, J = 8.8 Hz, 1H), 8.3 (d, J = 0.4 Hz, 1H), 8.0 (s, 1H), 3.9 (s, 3H), 3.80-3,77 (m, 1H), 3.57-3.55 (m, 2H), 3.45-3.43 (m, 2H), 3.34-3.31 (m, 4H), 2.06-2.04 (m, 2H), 1.89-1.87 (m, 2H), 1.59-1.56 (m, 2H), 1.30-1.24 (m, 2H). LCMS: (Method C) 443.2 (M+H), Rt.1.83 min. HPLC: (Method A) Rt.3.45 min.

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2021/207186, 2021, A1 Location in patent: Page/Page column 42; 44

40
[ 175867-01-3 ]
[ 2725957-27-5 ]
[ 2725957-28-6 ]

Yield	Reaction Conditions	Operation in experiment
52%	Stage #1: 4-bromo-6(1H-imidazol-1-yl)picolinic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine In N,N-dimethyl-formamide at 20℃; for 16h;	37.4; 38.5; 43.4 Step 5: 4-Bromo-6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide To a stirred solution of 4-bromo-6-(1H-imidazol-1-yl)picolinic acid (1.35 g, 5.04 mmol) in DMF (20 mL) were added DIPEA (2.64 mL, 15.10 mmol) and HATU (2.87 g, 7.553 mmol) at RT. After stirring for 5 min, a solution of (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (1.3 g, 7.55 mmol) in DMF (0.5 mL) was added and the reaction mixture was stirred at RT for 16 h. The reaction mixture was monitored by TLC and was diluted with water (25 mL) after completion. The resulting suspension was extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and the solvent was evaporated under vacuum. The crude residue was purified by column chromatography on Biotage Isolera (100-200 mesh silica gel eluting with 060% EtOAc in pet ether) to afford the title compound Yield: 52% (12 g Yellow solid) 1H NMR (300 MHz, DMSO-d6): δ 8.98 (s, 1H), 8.62 (d, J = 8.7 Hz, 1H), 8.39 (d, J = 1.5 Hz, 1H),8.31-8.30 (m, 1H), 8.04 (d, J = 1.5 Hz, 1H), 7.17 (s, 1H), 3.84-3.80 (m, 1H), 3.56-3.50 (m, 2H), 3.44-3.41 (m, 2H), 3.23 (s, 4H), 2.05-2.03 (m, 2H), 1.83-1.80 (m, 2H), 1.62-1.51 (m, 2H), 1.29-1.23 (m, 2H). LCMS: (Method C) 425.0 (M+H), Rt.1.21 min.

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2021/207186, 2021, A1 Location in patent: Page/Page column 109; 111-113; 115-116; 125; 127

41
[ 175867-01-3 ]
[ CAS Unavailable ]
[ 2725956-89-6 ]

Yield	Reaction Conditions	Operation in experiment
55%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere;	50.4 Step 4 : 2-(1H-imidazol-1-yl-d3)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylpyrimidine-4-carboxamide To a stirred solution of sodium 2-(1H-imidazol-1-yl)-6-methylpyrimidine-4-carboxylate (1.0 g, 4.36 mmol) in DMF (10 mL) at RT, DIPEA (0.76 mL, 4.363 mmol), HOBt (885.1 mg, 6.544 mmol), EDC.HCl (1.68 g, 8.726 mmol), and (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (830 mg, 4.80 mmol) were added under nitrogen atmosphere and the reaction mixture was stirred for 16 h at RT. After completion (starting material was consumed according to TLC), the reaction mixture was diluted with water (20 mL) and then extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with brine solution (50 mL), water (50 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum. The crude residue was purified by flash column chromatography on Biotage Isolera using silica gel (230-400 mesh, 5%-100% EtOAc in pet ether) to get the title compound. Yield: 55% (960 mg, Off-white solid).1H NMR (400 MHz, DMSO-d6): δ 8.79 (d, J = 8.8 Hz, 1H), 7.83 (s, 1H), 3.88-3.81 (m, 1H), 3.57-3.54 (m, 2H), 3.44-3.42 (m, 2H), 3.30-3.22 (m, 4H), 2.63 (s, 3 H), 2.06-2.03 (m, 2H), 1.85-1.83 (m, 2H), 1.61-1.51 (m, 2H), 1.31-1.21 (m, 2H). LCMS: (Method C) 363.2 (M+H), Rt.1.02 min. HPLC: (Method A) Rt. 2.34 min. HRMS: C18H25N5O3 (0%), C18H24DN5O3 (0.14%), C18H23D2N5O3 (6.74%), C18H22D3N5O3 (91.95%), C18H21D4N5O3 (1.17%).

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2021/207186, 2021, A1 Location in patent: Page/Page column 138; 140-141

42
[ 88912-21-4 ]
[ 175867-01-3 ]
[ 2725957-45-7 ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: 4-methoxy-6-chloro picolinic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine In N,N-dimethyl-formamide at 20℃;	62.4 Step 4: 6-chloro-4-methoxy-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)picolinamide To a stirred solution of 6-chloro-4-methoxypicolinic acid (0.21 g, 1.12 mmol) in DMF (2 mL) were added DIPEA (0.6 mL, 3.36 mmol) and HATU (0.64 g, 1.68 mmol) at RT. After stirring for 5 min, a solution of (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (0.252 g, 1.45 mmol) was added and the reaction mixture was stirred at RT overnight. After completion (monitored by TLC), the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The resulting crude residue was purified by column chromatography on Biotage Isolera (230-400 mesh silica gel, eluting with 55% EtOAc in petroleum ether) to afford the title compound. Yield: 78% (0.3 g, Pale yellow gum).1H NMR (400 MHz, DMSO-d6): δ 8.30 (d, J = 8.8 Hz, 1H), 7.51-7.50 (m, 1H), 7.31 (d, J = 2.4 Hz, 1H), 3.94 (s, 3H), 3.78-3.71 (m, 1H), 3.55-3.52 (m, 2H), 3.43-3.41 (m, 2H), 3.30-3.21 (m, 4H), 2.01-1.98 (m, 2H), 1.82-1.79 (m, 2H), 1.52-1.48 (m, 2H), 1.27-1.18 (m, 2H). LCMS: (Method C) 343.2 (M+H), Rt.2.01 min.

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2021/207186, 2021, A1 Location in patent: Page/Page column 165; 167

43
[ 25462-85-5 ]
[ 175867-01-3 ]
[ 2725957-31-1 ]

Yield	Reaction Conditions	Operation in experiment
37%	Stage #1: 2-chloro-6-methylpyridine-4-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 0.0833333h; Inert atmosphere; Stage #2: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine In N,N-dimethyl-formamide at 0 - 20℃; for 16h; Inert atmosphere;	46.1 Step 1: 2-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-methylisonicotinamide To a stirred solution of 2-chloro-6-methylisonicotinic acid (210 mg, 1.22 mmol) in DMF (3 mL) at 0 C, EDC.HCl (351.9 mg, 1.83 mmol), HOBt (248 mg, 1.83 mmol) followed by DIPEA (0.53 mL, 3.05 mmol) were added under nitrogen atmosphere and the reaction mixture was stirred at 0 C for 5 min. Then (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (212 mg, 1.22 mmol) was added and the reaction mixture was stirred at RT for 16 h. After completion (starting material was consumed according to TLC), the reaction mixture was diluted with water (30 mL) and then extracted with EtOAc (50 mL). The resulting organic solution was washed with 10% aq. NaHCO3 (15 mL) followed by water (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under vacuum. The resulting crude residue was purified by chromatography using silica gel (100-200 mesh, 50%-70% EtOAc/pet ether) to get the title compound. Yield: 37% (151 mg, yellow solid). LCMS: (Method A) 327.0 (M+H), Rt 2.09 min.

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2021/207186, 2021, A1 Location in patent: Page/Page column 132-133

44
[ 175867-01-3 ]
[ 2725957-38-8 ]
[ 2725956-95-4 ]

Yield	Reaction Conditions	Operation in experiment
36%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0 - 20℃; for 16h; Inert atmosphere;	56.3 Step 3: 6-cyclopropyl-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide To a stirred mixture of 6-cyclopropyl-2-(1H-imidazol-1-yl)pyrimidine-4-carboxylic acid (530 mg, 2.30 mmol) in DMF (17 mL) at 0 C, HATU (1.31 g, 3.45 mmol) and DIPEA (1.0 mL, 5.75 mmol) were added under nitrogen atmosphere followed by (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (498 mg, 2.87 mmol). The reaction mixture was stirred for 16 h at RT. After completion (starting material was consumed according to TLC), the reaction mixture was diluted with water (20 mL) and then extracted with 10% MeOH in DCM (150 mL). The resulting organic solution was washed with 10% NaHCO3 solution (50 mL) followed by water (2 x 25 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The resulting crude product was purified by Grace instrument, reverse phase (Method A). The prep-fraction was concentrated under reduced pressure. The residue was diluted with 10% MeOH/DCM (50 mL) and washed with 10% NaHCO3 solution (15 mL) followed by water (2 x 10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and then lyophilized to get the title compound. Yield: 36% (321.12 mg, off white solid).1H NMR (400 MHz, DMSO-d6): δ 8.90-8.89 (m, 1H), 8.75 (d, J = 8.4 Hz, 1H), 8.17-8.16 (m, 1H), 7.87 (s, 1H), 7.143-7.137 (m, 1H), 3.87-3.79 (m, 1H), 3.57-3.54 (m, 2H), 3.45-3.42 (m, 2H), 3.30-3.23 (m, 4H), 2.41-2.37 (m, 1H), 2.06-2.03 (m, 2H), 1.85-1.80 (m, 2H), 1.58-1.50 (m, 2H), 1.30-1.19 (m, 2H). LCMS: (Method C) 386.1 (M+H), Rt.1.25 min. HPLC: (Method A) Rt.2.61 min.

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2021/207186, 2021, A1 Location in patent: Page/Page column 151; 153

45
[ 175867-01-3 ]
[ 823222-00-0 ]
[ 2725957-18-4 ]

Yield	Reaction Conditions	Operation in experiment
62%	Stage #1: 6-chloro-4-(trifluoromethyl)pyridine-2-carboxylic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine In N,N-dimethyl-formamide at 20℃;	19.5 Step 5: 6-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-(trifluoromethyl)picolinamide To a stirred solution of 6-chloro-4-(trifluoromethyl)picolinic acid (0.5 g, 2.22 mmol) in DMF (10 mL) were added DIPEA (1.19 mL, 6.66 mmol) and HATU (1.26 g, 3.33 mmol) at RT. After stirring for 5 min a solution of (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (0.461 g, 2.66 mmol) was added at same temperature. Further reaction was stirred at RT for overnight. The reaction mixture was monitored by TLC and quenched with water (20 mL). The resulting suspension was extracted with EtOAc (2 x 10 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and solvent was evaporated under vacuum. The resulting crude product which was purified by purified by column chromatography on Biotage Isolera (230-400 mesh silica gel eluting with 16-20%% EtOAc in pet ether) to afford the title compound. Yield: 62% (0.52 g, Yellow gummy solid). LCMS: (Method C) 381.2 [M+H], Rt.2.298 min.

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2021/207186, 2021, A1 Location in patent: Page/Page column 72; 74-75

46
[ 149849-93-4 ]
[ 175867-01-3 ]
[ 2725957-21-9 ]

Yield	Reaction Conditions	Operation in experiment
84%	With triethylamine In tetrahydrofuran at 0 - 20℃;	28.2 Step 2: 2-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrimidine-4-carboxamide To a stirred solution of 2-chloropyrimidine-4-carbonyl chloride (1 g, 5.65 mmol) and TEA (2.37 mL, 16.95 mmol) in THF (20 mL) at 0 °C (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (0.977 g, 5.65 mmol) was added at same temperature and stirred at RT for overnight. The reaction mixture was quenched with sat.NaHCO3 solution (20 mL). The resulting suspension was extracted with EtOAc (2 x 25 mL). The combined organic layer was washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4 and solvent was evaporated under vacuum to afford the title compound. Yield: 84% (1.5 g, Pale brown gummy solid). LCMS: (Method C) 314.2 [M+H], Rt.1.615 min.

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2021/207186, 2021, A1 Location in patent: Page/Page column 88-89

47
[ 175867-01-3 ]
[ CAS Unavailable ]
[ 2798957-41-0 ]

Yield	Reaction Conditions	Operation in experiment
44%	Stage #1: 2,6-dichloropyridine-4-carboxylic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine In N,N-dimethyl-formamide at 20℃;	1.1 Step 1: 2,6-dichloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)isonicotinamide To a stirred solution of 2,6-dichloroisonicotinic acid (0.5 g, 2.61 mmol) in DMF (5 mL) at RT were added HATU (1.69 g, 4.45 mmol) and DIPEA (1.07 mL, 7.85 mmol). After stirring for 5 min at RT, (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (589 mg, 3.40 mmol) was added at RT and the reaction mixture was stirred at RT overnight. After completion, the reaction mixture was diluted with water (50 mL) and the resulting solid was filtered and dried to afford the title compound. Yield: 44% (400 mg, white solid).1H NMR (400 MHz, DMSO-d6): δ 8.66 (d, J = 7.6 Hz, 1H), 7.88 (s, 2H), 3.75-3.67 (m, 1H), 3.54-3.51 (m, 2H), 3.43-3.40 (m, 2H), 3.31-3.21 (m, 4H), 2.02-1.99 (m, 2H), 1.88-1.85 (m, 2H), 1.37-1.21 (m, 4H). LCMS: (Method A) 347.1 [M+H], Rt.2.34 min.

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - WO2021/207186, 2021, A1 Location in patent: Page/Page column 32-33

48
[ 175867-01-3 ]
[ 2808338-08-9 ]
[ 2808337-46-2 ]

Yield	Reaction Conditions	Operation in experiment
21%	With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium tertiary butoxide In toluene at 60℃; for 3h; Inert atmosphere;	1.7 Step 7: 6-(1H-imidazol-1-yl)-4-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-1- methylquinolin-2(1H)-one Under an atmosphere of nitrogen, a solution of 4-chloro-6-(1H-imidazol-1-yl)-1- methylquinolin-2(1H)-one (200 mg, 0.77 mmol, 1.0 eq), (1r,4r)-4-(2- methoxyethoxy)cyclohexan-1-amine (Int-B1, 200 mg, 1.16 mmol, 1.5 eq), Pd(OAc)2 (17 mg, 0.077 mmol, 0.10 eq), BINAP (48 mg, 0.077 mmol, 0.10 eq), and t-BuONa (148 mg, 1.54 mmol, 2.0 eq) in toluene (5 mL) was stirred for 3 h at 60 oC . The reaction was then concentrated under vacuum. The crude product was purified by reverse phase column eluting with H2O/ACN (2/1) to afford the title compound (64.7 mg, 21 %) as a white solid. LCMS: [M+H]+ 397.20.1H NMR (300 MHz, DMSO-d6) δ 8.26 (d, J = 0.9 Hz,1H), 8.25 (s,1H), 7.84 (dd, J = 2.4, 9.0 Hz, 1H), 7.78 (t, J = 1.5, 1.2 Hz, 1H), 7.53 (d, J = 9.3 Hz, 1H), 7.14 (s, 1H), 6.55 (d, J = 7.2 Hz, 1H), 5.57 (s, 1H), 3.60 - 3.51 (m, 1H), 3.50 (s, 3H), 3.50 - 3.43 (m, 3H), 3.32 - 3.29 (m, 2H), 3.20 (s, 3H), 2.13 - 2.03 (m, 4H), 1.50 - 1.20 (m, 4H).
21%	With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium tertiary butoxide In toluene at 60℃; for 3h; Inert atmosphere;	1.7 Step 7: 6-(1H-imidazol-1-yl)-4-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-1- methylquinolin-2(1H)-one Under an atmosphere of nitrogen, a solution of 4-chloro-6-(1H-imidazol-1-yl)-1- methylquinolin-2(1H)-one (200 mg, 0.77 mmol, 1.0 eq), (1r,4r)-4-(2- methoxyethoxy)cyclohexan-1-amine (Int-B1, 200 mg, 1.16 mmol, 1.5 eq), Pd(OAc)2 (17 mg, 0.077 mmol, 0.10 eq), BINAP (48 mg, 0.077 mmol, 0.10 eq), and t-BuONa (148 mg, 1.54 mmol, 2.0 eq) in toluene (5 mL) was stirred for 3 h at 60 oC . The reaction was then concentrated under vacuum. The crude product was purified by reverse phase column eluting with H2O/ACN (2/1) to afford the title compound (64.7 mg, 21 %) as a white solid. LCMS: [M+H]+ 397.20.1H NMR (300 MHz, DMSO-d6) δ 8.26 (d, J = 0.9 Hz,1H), 8.25 (s,1H), 7.84 (dd, J = 2.4, 9.0 Hz, 1H), 7.78 (t, J = 1.5, 1.2 Hz, 1H), 7.53 (d, J = 9.3 Hz, 1H), 7.14 (s, 1H), 6.55 (d, J = 7.2 Hz, 1H), 5.57 (s, 1H), 3.60 - 3.51 (m, 1H), 3.50 (s, 3H), 3.50 - 3.43 (m, 3H), 3.32 - 3.29 (m, 2H), 3.20 (s, 3H), 2.13 - 2.03 (m, 4H), 1.50 - 1.20 (m, 4H).

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC - WO2022/165114, 2022, A1 Location in patent: Page/Page column 41; 43
[2]Current Patent Assignee: RIBON THERAPEUTICS INC - WO2022/165114, 2022, A1 Location in patent: Page/Page column 41; 43

49
[ 175867-01-3 ]
[ 2808338-37-4 ]
[ 2808337-56-4 ]

Yield	Reaction Conditions	Operation in experiment
19%	With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium tertiary butoxide In toluene at 75℃; for 2h; Inert atmosphere;	6.1 Step 1: 6-(1H-imidazol-1-yl)-4-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-1-methyl- 1,7-naphthyridin-2(1H)-one Under an atmosphere of nitrogen, a solution of 4-chloro-6-(imidazol-1-yl)-1-methyl- 1,7-naphthyridin-2-one (156 mg, 0.59 mmol, 1.0 eq), (1r,4r)-4-(2- methoxyethoxy)cyclohexan-1-amine (Int-B1, 156 mg, 0.89 mmol, 1.5 eq), Pd(OAc)2 (13.4 mg, 0.060 mmol, 0.10 eq), BINAP (37.3 mg, 0.060 mmol, 0.10 eq), and t-BuONa (115 mg, 1.19 mmol, 2.0 eq) in toluene (2 mL) was stirred for 2 h at 75 oC. The crude product was concentrated under vacuum and purified by reverse phase chromatography eluting with H2O/ACN (65/35). The product was further purified by Prep-HPLC to afford the title compound (44.8 mg, 19 %) as a light yellow solid. LCMS: [M+H]+ 398.10.1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.48 (s, 1H), 8.29 (s, 1H), 7.93 (d, J = 1.4 Hz, 1H), 7.18 (d, J = 1.2 Hz, 1H), 6.67 (d, J = 7.4 Hz, 1H), 5.72 (s, 1H), 3.60-3.50 (m, 5H), 3.48-3.38 (m, 3H), 3.30-3.23 (m, 4H), 2.08 - 2.01 (m, 4H), 1.45-1.30 (m, 4H).
19%	With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium tertiary butoxide In toluene at 75℃; for 2h; Inert atmosphere;	6.1 Step 1: 6-(1H-imidazol-1-yl)-4-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)-1-methyl- 1,7-naphthyridin-2(1H)-one Under an atmosphere of nitrogen, a solution of 4-chloro-6-(imidazol-1-yl)-1-methyl- 1,7-naphthyridin-2-one (156 mg, 0.59 mmol, 1.0 eq), (1r,4r)-4-(2- methoxyethoxy)cyclohexan-1-amine (Int-B1, 156 mg, 0.89 mmol, 1.5 eq), Pd(OAc)2 (13.4 mg, 0.060 mmol, 0.10 eq), BINAP (37.3 mg, 0.060 mmol, 0.10 eq), and t-BuONa (115 mg, 1.19 mmol, 2.0 eq) in toluene (2 mL) was stirred for 2 h at 75 oC. The crude product was concentrated under vacuum and purified by reverse phase chromatography eluting with H2O/ACN (65/35). The product was further purified by Prep-HPLC to afford the title compound (44.8 mg, 19 %) as a light yellow solid. LCMS: [M+H]+ 398.10.1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.48 (s, 1H), 8.29 (s, 1H), 7.93 (d, J = 1.4 Hz, 1H), 7.18 (d, J = 1.2 Hz, 1H), 6.67 (d, J = 7.4 Hz, 1H), 5.72 (s, 1H), 3.60-3.50 (m, 5H), 3.48-3.38 (m, 3H), 3.30-3.23 (m, 4H), 2.08 - 2.01 (m, 4H), 1.45-1.30 (m, 4H).

Reference： [1]Current Patent Assignee: RIBON THERAPEUTICS INC - WO2022/165114, 2022, A1 Location in patent: Page/Page column 49
[2]Current Patent Assignee: RIBON THERAPEUTICS INC - WO2022/165114, 2022, A1 Location in patent: Page/Page column 49

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	175867-01-3	MDL No. :	MFCD28402718
Formula :	C₉H₁₉NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YFUKJAYFLVIFPJ-UHFFFAOYSA-N
M.W :	173.25	Pubchem ID :	45091173
Synonyms :

Num. heavy atoms :	12
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	4
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	48.14
TPSA :	44.48 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) :	-7.12 cm/s

Log Po/w (iLOGP) :	2.45
Log Po/w (XLOGP3) :	0.33
Log Po/w (WLOGP) :	0.92
Log Po/w (MLOGP) :	0.34
Log Po/w (SILICOS-IT) :	0.99
Consensus Log Po/w :	1.01

[ CAS No. 175867-01-3 ]

Quality Control of [ 175867-01-3 ]

Related Doc. of [ 175867-01-3 ]

Product Details of [ 175867-01-3 ]

Calculated chemistry of [ 175867-01-3 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 175867-01-3 ]

Application In Synthesis of [ 175867-01-3 ]

[ 175867-01-3 ] Synthesis Path-Downstream 1~49

Related Functional Groups of
[ 175867-01-3 ]

Aliphatic Cyclic Hydrocarbons

Ethers

Amines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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

Log S (ESOL) :	-0.86
Solubility :	24.0 mg/ml ; 0.139 mol/l
Class :	Very soluble
Log S (Ali) :	-0.83
Solubility :	25.8 mg/ml ; 0.149 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.4
Solubility :	6.88 mg/ml ; 0.0397 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.98

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-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