Name: 959958-25-9|5-Bromo-6-chloropyridine-2-carboxylic acid|95%
Brand: Ambeed
SKU: A172558
Price: 35.0 USD
Availability: InStock
Rating: 95 (30 reviews)

1
[ 374-01-6 ]
[ 959958-25-9 ]
5-bromo-6-(1,1,1-trifluoropropan-2-yloxy)picolinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: 5-bromo-6-chloropyridine-2-carboxylic acid With potassium hydroxide In dimethyl sulfoxide for 0.25h; Stage #2: 1,1,1-trifluoroisopropanol In dimethyl sulfoxide at 20℃; for 24h;	13.a a) 5-Bromo-6-(l,l,l-trifluoropropan-2-yloxy)picolinic acid a) 5-Bromo-6-(l,l,l-trifluoropropan-2-yloxy)picolinic acid 5-Bromo-6-chloropicolinic acid (5 g, 21.1 mmol; CAN 959958-25-9) was dissolved in DMSO (100 mL) to give a colorless solution. To this solution potassium hydroxide (4.75 g, 84.6 mmol) was added. The reaction mixture turned into a white suspension which was stirred for 15 min. Then l,l,l-trifluoropropan-2-ol (2.41 g, 1.92 mL, 21.1 mmol) was added. The mixture was stirred for 1 d at ambient temp., poured onto ice- water/ IN HC1 (200 mL) and extracted with EtOAc (2 x 400 mL). The organic layers were washed with ice- water/brine (200 mL), combined and dried over Na2S04 and concentrated in vacuo to give the title compound (6.9 g, quant.) as orange solid. MS (EI): m/e = 312.3 [M-H]~.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2014/86806, 2014, A1 Location in patent: Page/Page column 57

2
[ 513-44-0 ]
[ 959958-25-9 ]
5-bromo-6-(isobutylthio)picolinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With caesium carbonate In dimethyl sulfoxide at 150℃; for 24h;	6.a a) 5-Bromo-6-(isobutylthio)picolinic acid a) 5-Bromo-6-(isobutylthio)picolinic acid 5-Bromo-6-chloropicolinic acid (2 g, 8.46 mmol; CAN 959958-25-9), 2-methylpropane-l- thiol (915 mg, 1.1 mL, 10.2 mmol) and cesium carbonate (6.89 g, 21.1 mmol) were suspended in DMSO (100 mL). The reaction mixture was heated to 150 °C and stirred for 1 d and was poured onto ice- water/ IN HC1 (100 mL). The aqueous layer was extracted with EtOAc (2x250 mL). The combined extracts were washed with ice-water/brine (100 mL), dried over Na2S04 and concentrated in vacuo to give the title compound (2.49 g, 51 ) as an orange solid which was used in the next step without further purification. MS (EI): m/e = 288.4 [M-H]~.
51%	With caesium carbonate In dimethyl sulfoxide at 150℃; for 24h;	36.a a) 5-Bromo-6-(isobutylthio)picolinic acid a) 5-Bromo-6-(isobutylthio)picolinic acid 5-Bromo-6-chloropicolinic acid (2 g, 8.46 mmol; CAN 959958-25-9), 2-methylpropane-1- thiol (915 mg, 1.1 mL, 10.2 mmol) and cesium carbonate (6.89 g, 21.1 mmol) were suspended in DMSO (100 mL). The reaction mixture was heated to 150 °C and stirred for 1 d and was poured onto ice-water/iN HC1 (100 mL). The aqueous layer was extracted5 with EtOAc (2x250 mL). The combined extracts were washed with ice-water/brine (100 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound (2.49 g, 51%) as an orange solid which was used in the next step without further purification. MS (El): mle = 288.4 [M-H].

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2014/86806, 2014, A1 Location in patent: Page/Page column 52-53
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2014/86705, 2014, A1 Location in patent: Page/Page column 58; 59

3
[ 97-99-4 ]
[ 959958-25-9 ]
[ 1415899-56-7 ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: 5-bromo-6-chloropyridine-2-carboxylic acid With potassium hydroxide In dimethyl sulfoxide at 20℃; for 0.25h; Stage #2: Tetrahydrofurfuryl alcohol In dimethyl sulfoxide at 20℃; for 24h;	166.a 5-Bromo-6-chloropicolinic acid (200 mg, 846 μmol; CAN 959958-25-9) and powdered potassium hydroxide (190 mg, 3.38 mmol) were combined with DMSO (1.93 mL) to give a colorless solution which was stirred for 15 min at ambient temperature before tetrahydro-2-furanmethanol (130 mg, 123 μl, 1.27 mmol, CAN 97-99-4) was added, and stirring continued for 1 day at ambient temperature. The reaction mixture was poured into a mixture of ice-water and 1 M NaOH, and extracted with t-butylmethyl ether (2×25 mL) and washed with ice-water/brine. The water phases were combined acidified with ice/1 N HCl and extracted with isopropyl acetate (2×30 mL). The organic layers were washed with ice-water/brine (2×30 mL), dried with Na2SO4 and concentrated in vacuo to give the title compound (254 mg, 99%) as light brown oil; MS (ESI): 301.8 [M-H]-.
99%	Stage #1: 5-bromo-6-chloropyridine-2-carboxylic acid With potassium hydroxide In dimethyl sulfoxide at 20℃; for 0.25h; Stage #2: Tetrahydrofurfuryl alcohol In dimethyl sulfoxide at 20℃; for 24h; Stage #3: With hydrogenchloride In water	166.a 5-Bromo-6-chloropicolinic acid (200 mg, 846 μηιο; CAN 959958-25-9) and powdered potassium hydroxide (190 mg, 3.38 mmol) were combined with DMSO (1.93 mL) to give a colorless solution which was stirred for 15 min at ambient temperature before tetrahydro- 2-furanmethanol (130 mg, 123 μ, 1.27 mmol, CAN 97-99-4) was added, and stirring continued for 1 day at ambient temperature. The reaction mixture was poured into a mixture of ice-water and 1 M NaOH, and extracted with t-butylmethyl ether (2x 25 mL) and washed with ice- water/brine. The water phases were combined acidified with ice/1 N HC1 and extracted with isopropyl acetate (2 x 30 mL). The organic layers were washed with ice-water/brine (2 x 30 mL), dried with Na2S04 and concentrated in vacuo to give the title compound (254 mg, 99%) as light brown oil; MS (ESI): 301.8 [M-H]
99%	Stage #1: 5-bromo-6-chloropyridine-2-carboxylic acid With potassium hydroxide In dimethyl sulfoxide at 20℃; for 0.25h; Stage #2: Tetrahydrofurfuryl alcohol In dimethyl sulfoxide at 20℃; for 24h;	4.a a) 5-Bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid a) 5-Bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid 5-Bromo-6-chloropicolinic acid (200 mg, 846 μιηο; CAN 959958-25-9) and powdered potassium hydroxide (190 mg, 3.38 mmol) were combined with DMSO (1.93 mL) to give a colorless solution which was stirred for 15 min at ambient temperature before tetrahydro- 2-furanmethanol (130 mg, 123 μ, 1.27 mmol, CAN 97-99-4) was added, and stirring continued for 1 day at ambient temperature. The reaction mixture was poured into a mixture of ice- water and 1 M NaOH, and extracted with i-butylmethyl ether (2 x 25 mL) and washed with ice-water/brine. The water phases were combined acidified with ice/1 N HC1 and extracted with isopropyl acetate (2 x 30 mL). The organic layers were washed with ice-water/brine (2 x 30 mL), dried with Na2S04 and concentrated in vacuo to give the title compound (254 mg, 99%) as light brown oil; MS (ESI): 301.8 [M-H]~.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2012/316147, 2012, A1 Location in patent: Page/Page column 99
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2012/168350, 2012, A1 Location in patent: Page/Page column 199; 200
[3]Current Patent Assignee: ROCHE HOLDING AG - WO2014/86806, 2014, A1 Location in patent: Page/Page column 48

4
[ 422-05-9 ]
[ 959958-25-9 ]
5-bromo-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%	With potassium <i>tert</i>-butylate In tetrahydrofuran; N,N-dimethyl-formamide at 140℃; for 96h;	84.a a) 5-Bromo-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid a) 5-Bromo-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid To a solution of 6-chloro-5-bromo-pyridine-2-carboxylic acid (CAN 959958-25-9, 1.7 g, 7.19 mmol) in DMF (90 mL) and THF (30 mL) was added potassium iert-butoxide (2.02 g, 18.0 mmol) and 2,2,3, 3,3-pentafluoropropan-l-ol (5.73 mL, 57.5 mmol). The mixture was stirred at 140 °C for 4 days, cooled and poured into ice-water (100 mL). 2 M Hydrochloric acid (15 mL) was added to adjust the pH to 2-3 and the mixture was extracted with TBME, organic layers were washed twice with water, pooled, dried with Na2S04, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, ethyl acetate / n-heptane gradient) to give the title compound (548 mg, 22%) as light-brown solid; LC-MS (UV peak area, ESI) 100%, 347.9306 [M-H-].
22%	With potassium <i>tert</i>-butylate In tetrahydrofuran; N,N-dimethyl-formamide at 140℃; for 96h; Cooling with ice;	49.a a) 5-Bromo-6-(2,2,3 ,3 ,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid a) 5-Bromo-6-(2,2,3 ,3 ,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid To a solution of 6-chloro-5-bromo-pyridine-2-carboxylic acid (CAN 959958-25-9, 1.7 g, 7.19 mmol) in DMF (90 mL) and THF (30 mL) was added potassium tert-butoxide (2.02 g, 18.0 mmol) and 2,2,3,3,3-pentafluoropropan-1-ol (5.73 mL, 57.5 mmol). The mixture was stilTed at 140 °C for 4 days, cooled and poured into ice-water (100 mL). 2 MHydrochloric acid (15 mL) was added to adjust the pH to 2-3 and the mixture was extracted with TBME, organic layers were washed twice with water, pooled, dried with Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, ethyl acetate / n-heptane gradient) to give the title compound (548 mg, 22%) as light-brown solid; LC-MS (UV peak area, ESI) 100%, 347.9306 EM-Hi.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2014/86806, 2014, A1 Location in patent: Page/Page column 95-96
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2014/86705, 2014, A1 Location in patent: Paragraph 49.a

5
[ 959958-25-9 ]
5-cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide; tetrahydrofuran / 96 h / 140 °C / Cooling with ice 2: palladium diacetate; tricyclohexylphosphine; potassium phosphate / toluene; water / 22 h / 100 °C / Cooling with ice
	Multi-step reaction with 2 steps 1: potassium <i>tert</i>-butylate / N,N-dimethyl-formamide; tetrahydrofuran / 96 h / 140 °C 2: tricyclohexylphosphine; potassium phosphate; palladium diacetate / toluene; water / 22 h / 100 °C

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2014/86705, 2014, A1
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2014/86806, 2014, A1

6
[ 959958-25-9 ]
methyl 5-bromo-6-(isobutylthio)picolinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: caesium carbonate / dimethyl sulfoxide / 24 h / 150 °C 2: sulfuric acid / 24 h / 80 °C
	Multi-step reaction with 2 steps 1: caesium carbonate / dimethyl sulfoxide / 24 h / 150 °C 2: sulfuric acid / methanol / 24 h / 80 °C

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2014/86806, 2014, A1
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2014/86705, 2014, A1

7
[ 959958-25-9 ]
methyl 5-bromo-6-(isobutylsulfonyl)picolinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: caesium carbonate / dimethyl sulfoxide / 24 h / 150 °C 2: sulfuric acid / methanol / 24 h / 80 °C 3: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 24 h / 0 - 20 °C / Cooling with ice
	Multi-step reaction with 3 steps 1: caesium carbonate / dimethyl sulfoxide / 24 h / 150 °C 2: sulfuric acid / 24 h / 80 °C 3: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 24 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2014/86705, 2014, A1
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2014/86806, 2014, A1

8
[ 959958-25-9 ]
5-cyclopropyl-6-(1,1,1-trifluoropropan-2-yloxy)picolinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: potassium hydroxide / dimethyl sulfoxide / 0.25 h 1.2: 24 h / 20 °C 2.1: caesium carbonate; palladium diacetate; catacxium A / toluene; water / 24 h / 120 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2014/86806, 2014, A1

9
[ 374-01-6 ]
[ 959958-25-9 ]
5-bromo-6-(1,1,1-trifluoropropan-2-yloxy)picolinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: 5-bromo-6-chloropyridine-2-carboxylic acid With potassium hydroxide In dimethyl sulfoxide for 0.25h; Stage #2: 1,1,1-trifluoroisopropanol In dimethyl sulfoxide at 20℃; for 24h;	33.a a) 5-Bromo-6- (1,1,1 -trifluoropropan-2-yloxy)picolinic acid a) 5-Bromo-6- (1,1,1 -trifluoropropan-2-yloxy)picolinic acid 5-Bromo-6-chloropicolinic acid (5 g, 21.1 mmol; CAN 959958-25-9) was dissolved in DMSO (100 mL) to give a colorless solution. To this solution potassium hydroxide (4.7515 g, 84.6 mmol) was added. The reaction mixture turned into a white suspension which was stilTed for 15 mm. Then 1,1,1-trifluoropropan-2-ol (2.41 g, 1.92 mL, 21.1 mmol) was added. The mixture was stirred for 1 d at ambient temp., poured onto ice-water 1 N HC1 (200 mL) and extracted with EtOAc (2 x 400 mL). The organic layers were washed with ice-water/brine (200 mL), combined and dried over Na2SO4 and concentrated in vacuo to20 give the title compound (6.9 g, quant.) as orange solid. MS (El): mle = 312.3 [M-H].

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2014/86705, 2014, A1 Location in patent: Page/Page column 56

10
[ 78-83-1 ]
[ 959958-25-9 ]
[ 74-88-4 ]
methyl 5-bromo-6-isobutoxypicolinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-methyl-propan-1-ol; 5-bromo-6-chloropyridine-2-carboxylic acid With sodium hydride In N,N-dimethyl-formamide; mineral oil at 90℃; for 1h; Inert atmosphere; Stage #2: methyl iodide In N,N-dimethyl-formamide; mineral oil at 90℃; for 0.0833333h;	1.I I) methyl 5-bromo-6-isobutoxypicolinate I) methyl 5-bromo-6-isobutoxypicolinate 2-Methyl-1-propanol (1.48 mL) was added to a suspension of 60% sodium hydride (958 mg) in DMF (30 mL) at room temperature. 5-Bromo-6-chloropicolinic acid (entire amount) obtained in Example 1, step H, was added to the reaction mixture at room temperature. The reaction mixture was stirred under a nitrogen atmosphere at 90°C for 1 hr. Iodomethane (2.49 mL) was added to the reaction mixture, and the mixture was stirred at 90°C for 5 min. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give a crude product of the title compound (698 mg) as a pale-yellow oil.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2816032, 2014, A1 Location in patent: Paragraph 0270

11
[ 30766-11-1 ]
[ 959958-25-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: trifluoroacetic anhydride; urea; dihydrogen peroxide / acetonitrile / 0.5 h / 0 °C 2: thionyl chloride / 1 h / 0 °C / Reflux 3: trichlorophosphate / 0.17 h / 90 °C 4: sodium hydroxide; water / tetrahydrofuran; methanol / 0.5 h / 20 °C

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2816032, 2014, A1

12
[ 959741-37-8 ]
[ 959958-25-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: thionyl chloride / 1 h / 0 °C / Reflux 2: trichlorophosphate / 0.17 h / 90 °C 3: sodium hydroxide; water / tetrahydrofuran; methanol / 0.5 h / 20 °C

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2816032, 2014, A1

13
5-bromo-2-(methoxycarbonyl)-1^A[5]-pyridin-1-olate [ No CAS ]
[ 959958-25-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: trichlorophosphate / 0.17 h / 90 °C 2: sodium hydroxide; water / tetrahydrofuran; methanol / 0.5 h / 20 °C

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2816032, 2014, A1

14
[ 1214353-79-3 ]
[ 959958-25-9 ]

Yield	Reaction Conditions	Operation in experiment
944 mg	With water; sodium hydroxide; In tetrahydrofuran; methanol; at 20℃; for 0.5h;	H) 5-bromo-6-chloropicolinic acid To a solution of methyl 5-bromo-4-chloropicolinate (1.08 g) in THF (25 mL) and methanol (12.5 mL) was added 1N aqueous sodium hydroxide solution (25 mL), and the mixture was stirred at room temperature for 30 min. 1N Hydrochloric acid was added to the reaction mixture at 0C, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound (944 mg) as a pale-yellow solid.

Reference： [1]Patent: EP2816032,2014,A1 .Location in patent: Paragraph 0269

15
[ 959958-25-9 ]
2-((5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methyl)-1H-isoindole-1,3(2H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 90 °C / Inert atmosphere 1.2: 0.08 h / 90 °C 2.1: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane / toluene / 0.5 h / 100 °C / Inert atmosphere 3.1: lithium aluminium tetrahydride / water; diethyl ether / 1 h / 0 °C 4.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran; toluene / 15 h / 10 - 35 °C

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2816032, 2014, A1

16
[ 959958-25-9 ]
1-(5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methanamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 90 °C / Inert atmosphere 1.2: 0.08 h / 90 °C 2.1: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane / toluene / 0.5 h / 100 °C / Inert atmosphere 3.1: lithium aluminium tetrahydride / water; diethyl ether / 1 h / 0 °C 4.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran; toluene / 15 h / 10 - 35 °C 5.1: hydrazine hydrate / ethanol / 20 h / 10 - 35 °C

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2816032, 2014, A1

17
[ 959958-25-9 ]
ethyl 3-cyclopropyl-3-(6-(((5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methyl)amino)pyrimidin-4-yl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 90 °C / Inert atmosphere 1.2: 0.08 h / 90 °C 2.1: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane / toluene / 0.5 h / 100 °C / Inert atmosphere 3.1: lithium aluminium tetrahydride / water; diethyl ether / 1 h / 0 °C 4.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran; toluene / 15 h / 10 - 35 °C 5.1: hydrazine hydrate / ethanol / 20 h / 10 - 35 °C 6.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 15 h / 70 °C

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2816032, 2014, A1

18
[ 959958-25-9 ]
3-cyclopropyl-3-(6-(((5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methyl)amino)pyrimidin-4-yl)propanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 90 °C / Inert atmosphere 1.2: 0.08 h / 90 °C 2.1: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane / toluene / 0.5 h / 100 °C / Inert atmosphere 3.1: lithium aluminium tetrahydride / water; diethyl ether / 1 h / 0 °C 4.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran; toluene / 15 h / 10 - 35 °C 5.1: hydrazine hydrate / ethanol / 20 h / 10 - 35 °C 6.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 15 h / 70 °C 7.1: sodium hydroxide; water / methanol / 15 h / 50 °C

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2816032, 2014, A1

19
[ 959958-25-9 ]
ethyl 3-cyclopropyl-3-(6-(((5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methyl)(methyl)amino)pyrimidin-4-yl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 90 °C / Inert atmosphere 1.2: 0.08 h / 90 °C 2.1: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane / toluene / 0.5 h / 100 °C / Inert atmosphere 3.1: lithium aluminium tetrahydride / water; diethyl ether / 1 h / 0 °C 4.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran; toluene / 15 h / 10 - 35 °C 5.1: hydrazine hydrate / ethanol / 20 h / 10 - 35 °C 6.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 15 h / 70 °C 7.1: potassium carbonate / N,N-dimethyl-formamide / 17 h / 40 °C 7.2: 1 h / 10 - 35 °C

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2816032, 2014, A1

20
[ 959958-25-9 ]
3-cyclopropyl-3-(6-(((5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methyl)(methyl)amino)pyrimidin-4-yl)propanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 90 °C / Inert atmosphere 1.2: 0.08 h / 90 °C 2.1: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane / toluene / 0.5 h / 100 °C / Inert atmosphere 3.1: lithium aluminium tetrahydride / water; diethyl ether / 1 h / 0 °C 4.1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran; toluene / 15 h / 10 - 35 °C 5.1: hydrazine hydrate / ethanol / 20 h / 10 - 35 °C 6.1: N-ethyl-N,N-diisopropylamine / acetonitrile / 15 h / 70 °C 7.1: potassium carbonate / N,N-dimethyl-formamide / 17 h / 40 °C 7.2: 1 h / 10 - 35 °C 8.1: sodium hydroxide; water / methanol / 3 h / 50 °C

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2816032, 2014, A1

21
[ 959958-25-9 ]
methyl 5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypicolinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 90 °C / Inert atmosphere 1.2: 0.08 h / 90 °C 2.1: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane / toluene / 0.5 h / 100 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2816032, 2014, A1

22
[ 959958-25-9 ]
(5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 90 °C / Inert atmosphere 1.2: 0.08 h / 90 °C 2.1: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane / toluene / 0.5 h / 100 °C / Inert atmosphere 3.1: lithium aluminium tetrahydride / water; diethyl ether / 1 h / 0 °C

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2816032, 2014, A1

23
[ 959958-25-9 ]
methyl 3-cyclopropyl-3-(3-((5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methoxy)phenyl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 90 °C / Inert atmosphere 1.2: 0.08 h / 90 °C 2.1: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane / toluene / 0.5 h / 100 °C / Inert atmosphere 3.1: lithium aluminium tetrahydride / water; diethyl ether / 1 h / 0 °C 4.1: 1,1'-azodicarbonyl-dipiperidine; tributylphosphine / toluene / 14 h / 10 - 35 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2816032, 2014, A1

24
[ 959958-25-9 ]
3-cyclopropyl-3-(3-((5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methoxy)phenyl)propanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 90 °C / Inert atmosphere 1.2: 0.08 h / 90 °C 2.1: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane / toluene / 0.5 h / 100 °C / Inert atmosphere 3.1: lithium aluminium tetrahydride / water; diethyl ether / 1 h / 0 °C 4.1: 1,1'-azodicarbonyl-dipiperidine; tributylphosphine / toluene / 14 h / 10 - 35 °C / Inert atmosphere 5.1: sodium hydroxide; water / tetrahydrofuran; methanol / 14 h / 10 - 35 °C

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2816032, 2014, A1

25
[ 959958-25-9 ]
ethyl 3-cyclopropyl-3-(6-((5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methoxy)pyrimidin-4-yl)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 90 °C / Inert atmosphere 1.2: 0.08 h / 90 °C 2.1: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane / toluene / 0.5 h / 100 °C / Inert atmosphere 3.1: lithium aluminium tetrahydride / water; diethyl ether / 1 h / 0 °C 4.1: sodium hydride / tetrahydrofuran; mineral oil / 4.5 h / 0 - 50 °C

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2816032, 2014, A1

26
[ 959958-25-9 ]
3-cyclopropyl-3-(6-((5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methoxy)pyrimidin-4-yl)propanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 90 °C / Inert atmosphere 1.2: 0.08 h / 90 °C 2.1: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane / toluene / 0.5 h / 100 °C / Inert atmosphere 3.1: lithium aluminium tetrahydride / water; diethyl ether / 1 h / 0 °C 4.1: sodium hydride / tetrahydrofuran; mineral oil / 4.5 h / 0 - 50 °C 5.1: sodium hydroxide; water / tetrahydrofuran; methanol / 0.5 h / 10 - 35 °C

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP2816032, 2014, A1

27
[ 959958-25-9 ]
5-(4-chloro-2-methylphenyl)-3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methyl-5,6-dihydro-4H-1,2,4-oxadiazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: methanol / 42 h / 20 - 80 °C 2: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere 3: triethylamine / dichloromethane / 16 h / 0 - 20 °C 4: hydrazine hydrate / tetrahydrofuran; ethanol / 4 h / 0 - 120 °C / Inert atmosphere 5: trichlorophosphate / 16 h / 70 °C / Inert atmosphere 6: potassium phosphate; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 2-di-tertbutylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl / 1,4-dioxane; toluene / 16.13 h / 120 °C / Inert atmosphere; Sealed tube

Reference： [1]Current Patent Assignee: DENALI THERAPEUTICS INC - WO2016/201168, 2016, A1

28
[ 959958-25-9 ]
3-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methyl-5-(3-(trifluoromethyl)phenyl)-5,6-dihydro-4H-1,2,4-oxadiazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: methanol / 42 h / 20 - 80 °C 2.1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere 3.1: triethylamine / dichloromethane / 1 h / 0 - 20 °C / Inert atmosphere 4.1: hydrazine hydrate / toluene / 3 h / 0 - 20 °C / Inert atmosphere 5.1: trichlorophosphate / 16 h / 70 °C / Inert atmosphere 6.1: potassium phosphate / 1,4-dioxane; toluene / Inert atmosphere 6.2: 16.05 h / 120 °C / Inert atmosphere; Sealed tube

Reference： [1]Current Patent Assignee: DENALI THERAPEUTICS INC - WO2016/201168, 2016, A1

29
[ 959958-25-9 ]
(R)-5-bromo-N-(2-hydroxy-1-(4-methylbenzofuran-2-yl)ethyl)-6-methoxy-N-(4-methoxybenzyl)picolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: methanol / 42 h / 20 - 80 °C 2.1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 1 h / 20 °C 2.2: 0.5 h / 0 - 20 °C
	Multi-step reaction with 2 steps 1.1: methanol / 42 h / 20 - 80 °C 2.1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 1 h / 20 °C 2.2: 17 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: DENALI THERAPEUTICS INC - WO2016/201168, 2016, A1
[2]Current Patent Assignee: DENALI THERAPEUTICS INC - WO2016/201168, 2016, A1

30
[ 959958-25-9 ]
(R)-5-bromo-N-(2-(1,3-dioxoisoindolin-2-yloxy)-1-(4-methylbenzofuran-2-yl)ethyl)-6-methoxy-N-(4-methoxybenzyl)picolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: methanol / 42 h / 20 - 80 °C 2.1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 1 h / 20 °C 2.2: 0.5 h / 0 - 20 °C 3.1: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 17 h / 0 - 20 °C
	Multi-step reaction with 3 steps 1.1: methanol / 42 h / 20 - 80 °C 2.1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 1 h / 20 °C 2.2: 17 h / 0 - 20 °C 3.1: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 17 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: DENALI THERAPEUTICS INC - WO2016/201168, 2016, A1
[2]Current Patent Assignee: DENALI THERAPEUTICS INC - WO2016/201168, 2016, A1

31
[ 959958-25-9 ]
(R)-N-(2-(aminooxy)-1-(4-methylbenzofuran-2-yl)ethyl)-5-bromo-6-methoxy-N-(4-methoxybenzyl)picolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: methanol / 42 h / 20 - 80 °C 2.1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 1 h / 20 °C 2.2: 0.5 h / 0 - 20 °C 3.1: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 17 h / 0 - 20 °C 4.1: hydrazine hydrate / tetrahydrofuran; ethanol / 0.5 h / 20 °C
	Multi-step reaction with 4 steps 1.1: methanol / 42 h / 20 - 80 °C 2.1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 1 h / 20 °C 2.2: 17 h / 0 - 20 °C 3.1: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 17 h / 0 - 20 °C 4.1: hydrazine hydrate / tetrahydrofuran; ethanol / 0.5 h / 20 °C

Reference： [1]Current Patent Assignee: DENALI THERAPEUTICS INC - WO2016/201168, 2016, A1
[2]Current Patent Assignee: DENALI THERAPEUTICS INC - WO2016/201168, 2016, A1

32
[ 959958-25-9 ]
[ 1206775-52-1 ]

Reference： [1]Patent: WO2016/201168,2016,A1

33
[ 959958-25-9 ]
[ 124-41-4 ]
[ 1214334-70-9 ]

Yield	Reaction Conditions	Operation in experiment
94%	In methanol; at 20 - 80℃; for 42h;	5-bromo-6-methoxypicolinic acid: A suspension of 5-bromo-6-chloropicolinic acid (15.0 g, 63.4 mmol, 1.0 equiv.) in MeOH (130 mL) at ambient temperature was treated with a 4.37 M sodium methoxide solution in MeOH (58.0 mL, 253 mmol, 4.0 equiv.). The resultant mixture was heated at 80 C for 18 hours, resulting in a thick mixture. The reaction was diluted with MeOH (100 mL) and stirred at 80 C for 24 hours. The reaction mixture was cooled to ambient temperature, acidified to pH=3 with concentrated aqueous HC1, diluted with water and extracted with EtOAc (three times). The combined organic layers were dried over MgSO4, filtered and concentrated to afford a residue that was co-evaporated with DCM/hexanes (1:1 mixture, 200 mL, three times) to afford 5-bromo-6-methoxypicolinic acid (13.9 g, 94%) as a white solid. ?H NMR (500 MHz, CDC13) 5 10.22 (br s, 1H), 8.06 (d, I = 7.7 Hz, 1H), 7.73 (d, I = 7.7 Hz, 1H), 4.10 (s, 3H). LCMS (ES-) [M-Hj+: 229.9/23 1.9.

Reference： [1]Patent: WO2016/201168,2016,A1 .Location in patent: Paragraph 0174

34
[ 959958-25-9 ]
(rac)-trans-[-2-[(benzyloxy)methyl]cyclopropyl]methanol [ No CAS ]
(rac)-trans-6-(-2-benzyloxymethyl-cyclopropylmethoxy)-5-bromopyridine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: (rac)-trans-[-2-[(benzyloxy)methyl]cyclopropyl]methanol With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h; Stage #2: 5-bromo-6-chloropyridine-2-carboxylic acid In N,N-dimethyl-formamide at 80℃; for 3h;
	Stage #1: 5-bromo-6-chloropyridine-2-carboxylic acid With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.333333h; Inert atmosphere; Stage #2: (rac)-trans-[-2-[(benzyloxy)methyl]cyclopropyl]methanol In N,N-dimethyl-formamide; mineral oil at 80℃; for 3h; Inert atmosphere;	22.a a) (Rac)-trans-6-(-2-benzyloxymethyl-cyclopropylmethoxy)-5-bromo-pyridine-2- carboxylic acid A solution of 5-bromo-6-chloro-pyridine-2-carboxylic acid (2.0 g, 8.5 mmol) in DMF (35 mL) was cooled to 0 °C under argon. NaH (60% oil suspension, 1.01 g, 25.4 mmol) was added and the mixture was stirred for 20 minutes at 0 °C. A solution of (rac)-trans-[-2- [(benzyloxy)methyl]cyclopropyl]methanol (2.277 g, 1 1.8 mmol) in DMF (5 L) was slowly added. The mixture was heated to 80 °C for 3 h, cooled to 25 °C and adjusted to pH~2 with 2 N aq. HC1 solution. Water was added (400 mL) and the mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (150 L), dried, filtered and concentrated in vacuo to give crude title compound as light yellow gum which was used in the next step without further purification LCMS: Column Zorbax Ext C 18 (50X4.6 mm), 5 m, (mobile phase: from 90% [ 10 mM NHjOAc in water] and 10% [CH3CN] to 70% [10 mM NH4OAc in water] and 30% [CH3CN] in 1.5 min, further to 10% [10 mM NH4OAc in water] and 90% [CH3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 71.32%, Rt = 2.67 min, MS calculate: 392, MS found: 392.1 [M-H ].

Reference： [1]Haider, Ahmed; Gobbi, Luca; Kretz, Julian; Ullmer, Christoph; Brink, Andreas; Honer, Michael; Woltering, Thomas J.; Muri, Dieter; Iding, Hans; Bürkler, Markus; Binder, Martin; Bartelmus, Christian; Knuesel, Irene; Pacher, Pal; Herde, Adrienne Müller; Spinelli, Francesco; Ahmed, Hazem; Atz, Kenneth; Keller, Claudia; Weber, Markus; Schibli, Roger; Mu, Linjing; Grether, Uwe; Ametamey, Simon M. [Journal of Medicinal Chemistry, 2020, vol. 63, # 18, p. 10287 - 10306]
[2]Current Patent Assignee: ROCHE HOLDING AG; EIDGENÖSSISCHE TECHNISCHE HOCHSCHULE ZÜRICH - WO2020/2270, 2020, A1 Location in patent: Page/Page column 67; 68

35
[ 67-56-1 ]
[ 959958-25-9 ]
[ 142731-84-8 ]
methyl 6-((3-((benzyloxy)methyl)oxetan-3-yl)methoxy)-5-bromopicolinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	Stage #1: 5-bromo-6-chloropyridine-2-carboxylic acid With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.333333h; Stage #2: 2-(benzyloxymethyl)-1,3-epoxy-2-(hydroxymethyl)propane In N,N-dimethyl-formamide at 80℃; for 4h; Stage #3: methanol In N,N-dimethyl-formamide at 20℃; for 18h;	33.a a) Methyl 6-((3-((benzyloxy)methyl)oxetan-3-yl)methoxy)-5-bromopicolinate In a 250 mL three-necked flask, 5-bromo-6-choropicolinic acid (CAN 959958-25-9, 1.8 g, 7.61 mmol, Eq: 1 ) was combined with DMF ( 100 mL) to give a colorless solution. The mixture was cooled to 0 °C and sodium hydride (913 mg, 22.8 mmol, Eq: 3) was added. The reaction mixture was stirred at 0 °C for 20 min. In a 10 mL round-bottomed flask, (3- ((benzyloxy)methyl)oxetan-3-yl)methanol (CAN 142731-84-8, 2.06 g, 9.9 mmol, Eq: 1.3) was combined with DMF ( 10 mL) to give a colorless solution, which was slowly added to the reaction mixture. The reaction mixture was heated to 80 °C for 4 h and cooled to ambient temperature. Methyl iodide (3.24 g, 1.43 mL, 22.8 mmol, Eq: 3) was added and stirring was continued for 18 h. The solvent was removed under reduced pressure. The residue was diluted with EtOAc ( 100 mL) and water ( 100 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine ( 1 x 100 mL), dried over Na2S04, filtered and brought to dryness under reduced pressure. The crude product was purified by columnchromatography (Si02, 50 g, hept. /EtOAc) to give the title compound (2.82 g, 88%) as colorless oil, MS (ISP): 424.121 [MH+].

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG; EIDGENÖSSISCHE TECHNISCHE HOCHSCHULE ZÜRICH - WO2020/2270, 2020, A1 Location in patent: Page/Page column 85; 86

36
(±)-[(1S,2S)-2-([tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methanol [ No CAS ]
[ 959958-25-9 ]
(rac)-trans-5-bromo-6-((-2-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)picolinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1 g	Stage #1: (±)-[(1S,2S)-2-([tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methanol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 1h; Stage #2: 5-bromo-6-chloropyridine-2-carboxylic acid In N,N-dimethyl-formamide; mineral oil at 20℃; for 20h;	1.a a) (Rac)-trans-5-bromo-6-((-2-(((tert- butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)picolinic acid In a 250 mL round-bottomed flask, sodium hydride in mineral oil (507 mg, 12.7 mmol,Eq: 2) was combined with DMF (50 mL) to give a grey suspension, which was cooled to 0 °C. (Rac)-trans-(-2-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methanol (2.06 g, 9 52 mmol, Eq: 1.5) was dissolved in DMF (100 mL) and added to the reaction mixture, which was stirred at 0 °C for 1 h. 5-Bromo-6-chloropicolinic acid (CAN 959958-25-9,1500 mg, 6.34 mmol, Eq: 1) was dissolved in DMF (20 mL) and added to the reaction mixture. Stirring was continued at RT for 20 h. 250 mg of sodium hydride was added and stirring was continued for 3 h. Another portion of 450 mg NaH and 300 mg of (rac)-trans- (-2-(((tert-butyldimethylsilyl)oxy)methyl)cycIopropyl)methanol were added. After 3 h of stirring at RT the reaction mixture was quenched by the addition of water and concentrated in vacuo. The residue was carefully acidified by the addition of HC1 (1 M). The mixture was diluted with EtOAc and washed with brine (3 x 250 mL). The organic layers were dried over Na2S04 and concentrated in vacuo resulting in a colorless oil. The crude product was purified by column chromatography (SiOj, 50 g, hept./ EtOAc) to give enriched title compound ( 1 g) which was sufficiently pure to be carried on to the next step, MS (ISP): 416.3 [MH+].

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG; EIDGENÖSSISCHE TECHNISCHE HOCHSCHULE ZÜRICH - WO2020/2270, 2020, A1 Location in patent: Page/Page column 33; 34

37
[ 959958-25-9 ]
(+)-trans-ethyl 2-ethyl-2-[6-({-2-[(fluoromethoxy)methyl]cyclopropyl}methoxy)-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 1.2: 3 h / 80 °C 2.1: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / N,N-dimethyl-formamide / 28 h / 20 °C 3.1: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate; palladium diacetate / toluene / 3 h / 110 °C 4.1: palladium on activated charcoal; hydrogen / ethyl acetate; methanol / 48 h / 20 °C 5.1: Resolution of racemate 6.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 6.2: 1.5 h / 20 °C
	Multi-step reaction with 6 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 0 °C 1.2: 20 h / 20 °C 2.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C 3.1: palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / toluene / 4 h / 110 °C / Sealed tube 4.1: acetic acid / tetrahydrofuran; water / 1 h / 20 °C 5.1: ammonium acetate / ethanol; n-heptane / Resolution of racemate 6.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 20 °C 6.2: 1.5 h

Reference： [1]Haider, Ahmed; Gobbi, Luca; Kretz, Julian; Ullmer, Christoph; Brink, Andreas; Honer, Michael; Woltering, Thomas J.; Muri, Dieter; Iding, Hans; Bürkler, Markus; Binder, Martin; Bartelmus, Christian; Knuesel, Irene; Pacher, Pal; Herde, Adrienne Müller; Spinelli, Francesco; Ahmed, Hazem; Atz, Kenneth; Keller, Claudia; Weber, Markus; Schibli, Roger; Mu, Linjing; Grether, Uwe; Ametamey, Simon M. [Journal of Medicinal Chemistry, 2020, vol. 63, # 18, p. 10287 - 10306]
[2]Current Patent Assignee: ROCHE HOLDING AG; EIDGENÖSSISCHE TECHNISCHE HOCHSCHULE ZÜRICH - WO2020/2270, 2020, A1

38
[ 959958-25-9 ]
6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)metboxy)-5-(3-methoxyazetidin-1-yl)picolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 1.2: 3 h / 80 °C 2.1: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / N,N-dimethyl-formamide / 28 h / 20 °C 3.1: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate; palladium diacetate / toluene / 3 h / 110 °C 4.1: palladium on activated charcoal; hydrogen / ethyl acetate; methanol / 48 h / 20 °C 5.1: Resolution of racemate 6.1: potassium hydroxide / tetrahydrofuran; water; methanol / 18 h / 90 °C 7.1: triethylamine; diphenyl phosphoryl azide / toluene / 24 h / 20 °C 7.2: 3 h / 110 °C
	Multi-step reaction with 8 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 0 °C 1.2: 20 h / 20 °C 2.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C 3.1: palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / toluene / 4 h / 110 °C / Sealed tube 4.1: acetic acid / tetrahydrofuran; water / 1 h / 20 °C 5.1: ammonium acetate / ethanol; n-heptane / Resolution of racemate 6.1: water; potassium hydroxide / tetrahydrofuran; methanol / 18 h / 90 °C 7.1: diphenyl phosphoryl azide; triethylamine / toluene / 24 h / 20 °C 8.1: sodium hydroxide / tetrahydrofuran; toluene / 4 h / 90 - 110 °C

Reference： [1]Haider, Ahmed; Gobbi, Luca; Kretz, Julian; Ullmer, Christoph; Brink, Andreas; Honer, Michael; Woltering, Thomas J.; Muri, Dieter; Iding, Hans; Bürkler, Markus; Binder, Martin; Bartelmus, Christian; Knuesel, Irene; Pacher, Pal; Herde, Adrienne Müller; Spinelli, Francesco; Ahmed, Hazem; Atz, Kenneth; Keller, Claudia; Weber, Markus; Schibli, Roger; Mu, Linjing; Grether, Uwe; Ametamey, Simon M. [Journal of Medicinal Chemistry, 2020, vol. 63, # 18, p. 10287 - 10306]
[2]Current Patent Assignee: ROCHE HOLDING AG; EIDGENÖSSISCHE TECHNISCHE HOCHSCHULE ZÜRICH - WO2020/2270, 2020, A1

39
[ 959958-25-9 ]
6-(((1S,2S)-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 1.2: 3 h / 80 °C 2.1: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / N,N-dimethyl-formamide / 28 h / 20 °C 3.1: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate; palladium diacetate / toluene / 3 h / 110 °C 4.1: palladium on activated charcoal; hydrogen / ethyl acetate; methanol / 48 h / 20 °C 5.1: Resolution of racemate 6.1: potassium hydroxide / tetrahydrofuran; water; methanol / 18 h / 90 °C 7.1: triethylamine; diphenyl phosphoryl azide / toluene / 24 h / 20 °C 7.2: 3 h / 110 °C 8.1: sodium hydroxide / water; methanol / Heating
	Multi-step reaction with 9 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 0 °C 1.2: 20 h / 20 °C 2.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C 3.1: palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / toluene / 4 h / 110 °C / Sealed tube 4.1: acetic acid / tetrahydrofuran; water / 1 h / 20 °C 5.1: ammonium acetate / ethanol; n-heptane / Resolution of racemate 6.1: water; potassium hydroxide / tetrahydrofuran; methanol / 18 h / 90 °C 7.1: diphenyl phosphoryl azide; triethylamine / toluene / 24 h / 20 °C 8.1: sodium hydroxide / tetrahydrofuran; toluene / 4 h / 90 - 110 °C 9.1: water; sodium hydroxide / methanol / 12 h / 85 °C

Reference： [1]Haider, Ahmed; Gobbi, Luca; Kretz, Julian; Ullmer, Christoph; Brink, Andreas; Honer, Michael; Woltering, Thomas J.; Muri, Dieter; Iding, Hans; Bürkler, Markus; Binder, Martin; Bartelmus, Christian; Knuesel, Irene; Pacher, Pal; Herde, Adrienne Müller; Spinelli, Francesco; Ahmed, Hazem; Atz, Kenneth; Keller, Claudia; Weber, Markus; Schibli, Roger; Mu, Linjing; Grether, Uwe; Ametamey, Simon M. [Journal of Medicinal Chemistry, 2020, vol. 63, # 18, p. 10287 - 10306]
[2]Current Patent Assignee: ROCHE HOLDING AG; EIDGENÖSSISCHE TECHNISCHE HOCHSCHULE ZÜRICH - WO2020/2270, 2020, A1

40
[ 959958-25-9 ]
(rac)-trans-ethyl 2-[[6-[[-2-(benzyloxymethyl)cyclopropyl]methoxy]-5-bromopyridine-2-carbonyl]amino]-2-ethylbutanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 1.2: 3 h / 80 °C 2.1: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / N,N-dimethyl-formamide / 28 h / 20 °C
	Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.33 h / 0 °C / Inert atmosphere 1.2: 3 h / 80 °C / Inert atmosphere 2.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / N,N-dimethyl-formamide / 16 h / 25 °C

Reference： [1]Haider, Ahmed; Gobbi, Luca; Kretz, Julian; Ullmer, Christoph; Brink, Andreas; Honer, Michael; Woltering, Thomas J.; Muri, Dieter; Iding, Hans; Bürkler, Markus; Binder, Martin; Bartelmus, Christian; Knuesel, Irene; Pacher, Pal; Herde, Adrienne Müller; Spinelli, Francesco; Ahmed, Hazem; Atz, Kenneth; Keller, Claudia; Weber, Markus; Schibli, Roger; Mu, Linjing; Grether, Uwe; Ametamey, Simon M. [Journal of Medicinal Chemistry, 2020, vol. 63, # 18, p. 10287 - 10306]
[2]Current Patent Assignee: ROCHE HOLDING AG; EIDGENÖSSISCHE TECHNISCHE HOCHSCHULE ZÜRICH - WO2020/2270, 2020, A1

41
[ 959958-25-9 ]
3-fluoropropyl 2-[[6-[[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]-2-vinyl-but-3-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 1.2: 3 h / 80 °C 2.1: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / N,N-dimethyl-formamide / 28 h / 20 °C 3.1: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate; palladium diacetate / toluene / 3 h / 110 °C 4.1: palladium on activated charcoal; hydrogen / ethyl acetate; methanol / 48 h / 20 °C 5.1: Resolution of racemate 6.1: potassium hydroxide / tetrahydrofuran; water; methanol / 18 h / 90 °C 7.1: triethylamine; diphenyl phosphoryl azide / toluene / 24 h / 20 °C 7.2: 3 h / 110 °C 8.1: sodium hydroxide / water; methanol / Heating 9.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / dichloromethane / 20 °C
	Multi-step reaction with 10 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 0 °C 1.2: 20 h / 20 °C 2.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C 3.1: palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / toluene / 4 h / 110 °C / Sealed tube 4.1: acetic acid / tetrahydrofuran; water / 1 h / 20 °C 5.1: ammonium acetate / ethanol; n-heptane / Resolution of racemate 6.1: water; potassium hydroxide / tetrahydrofuran; methanol / 18 h / 90 °C 7.1: diphenyl phosphoryl azide; triethylamine / toluene / 24 h / 20 °C 8.1: sodium hydroxide / tetrahydrofuran; toluene / 4 h / 90 - 110 °C 9.1: water; sodium hydroxide / methanol / 12 h / 85 °C 10.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 1 h / 20 °C

Reference： [1]Haider, Ahmed; Gobbi, Luca; Kretz, Julian; Ullmer, Christoph; Brink, Andreas; Honer, Michael; Woltering, Thomas J.; Muri, Dieter; Iding, Hans; Bürkler, Markus; Binder, Martin; Bartelmus, Christian; Knuesel, Irene; Pacher, Pal; Herde, Adrienne Müller; Spinelli, Francesco; Ahmed, Hazem; Atz, Kenneth; Keller, Claudia; Weber, Markus; Schibli, Roger; Mu, Linjing; Grether, Uwe; Ametamey, Simon M. [Journal of Medicinal Chemistry, 2020, vol. 63, # 18, p. 10287 - 10306]
[2]Current Patent Assignee: ROCHE HOLDING AG; EIDGENÖSSISCHE TECHNISCHE HOCHSCHULE ZÜRICH - WO2020/2270, 2020, A1

42
[ 959958-25-9 ]
3-[(4-methylbenzene)sulfonyl]oxy}propyl 2-ethyl-2-[(6-[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridin-2-yl)formamido]butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 1.2: 3 h / 80 °C 2.1: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / N,N-dimethyl-formamide / 28 h / 20 °C 3.1: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate; palladium diacetate / toluene / 3 h / 110 °C 4.1: palladium on activated charcoal; hydrogen / ethyl acetate; methanol / 48 h / 20 °C 5.1: Resolution of racemate 6.1: potassium hydroxide / tetrahydrofuran; water; methanol / 18 h / 90 °C 7.1: potassium carbonate / N,N-dimethyl-formamide / 16 h / 20 °C
	Multi-step reaction with 7 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 0 °C 1.2: 20 h / 20 °C 2.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C 3.1: palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / toluene / 4 h / 110 °C / Sealed tube 4.1: acetic acid / tetrahydrofuran; water / 1 h / 20 °C 5.1: ammonium acetate / ethanol; n-heptane / Resolution of racemate 6.1: water; potassium hydroxide / tetrahydrofuran; methanol / 18 h / 90 °C 7.1: potassium carbonate / N,N-dimethyl-formamide / 16 h / 25 °C

Reference： [1]Haider, Ahmed; Gobbi, Luca; Kretz, Julian; Ullmer, Christoph; Brink, Andreas; Honer, Michael; Woltering, Thomas J.; Muri, Dieter; Iding, Hans; Bürkler, Markus; Binder, Martin; Bartelmus, Christian; Knuesel, Irene; Pacher, Pal; Herde, Adrienne Müller; Spinelli, Francesco; Ahmed, Hazem; Atz, Kenneth; Keller, Claudia; Weber, Markus; Schibli, Roger; Mu, Linjing; Grether, Uwe; Ametamey, Simon M. [Journal of Medicinal Chemistry, 2020, vol. 63, # 18, p. 10287 - 10306]
[2]Current Patent Assignee: ROCHE HOLDING AG; EIDGENÖSSISCHE TECHNISCHE HOCHSCHULE ZÜRICH - WO2020/2270, 2020, A1

43
[ 959958-25-9 ]
[1,1,2,2,3,3-hexadeuterio-3-(p-tolylsulfonyIoxy)propyl] 2-ethyl-2-[[6-[[(1S,2S)-2- (hydroxymethyl)cyclopropyl]methoxy]-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino]butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 1.2: 3 h / 80 °C 2.1: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / N,N-dimethyl-formamide / 28 h / 20 °C 3.1: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate; palladium diacetate / toluene / 3 h / 110 °C 4.1: palladium on activated charcoal; hydrogen / ethyl acetate; methanol / 48 h / 20 °C 5.1: Resolution of racemate 6.1: potassium hydroxide / tetrahydrofuran; water; methanol / 18 h / 90 °C 7.1: potassium carbonate / N,N-dimethyl-formamide / 16 h / 20 °C
	Multi-step reaction with 7 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 0 °C 1.2: 20 h / 20 °C 2.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C 3.1: palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / toluene / 4 h / 110 °C / Sealed tube 4.1: acetic acid / tetrahydrofuran; water / 1 h / 20 °C 5.1: ammonium acetate / ethanol; n-heptane / Resolution of racemate 6.1: water; potassium hydroxide / tetrahydrofuran; methanol / 18 h / 90 °C 7.1: potassium carbonate / N,N-dimethyl-formamide / 17 h / 25 °C

Reference： [1]Haider, Ahmed; Gobbi, Luca; Kretz, Julian; Ullmer, Christoph; Brink, Andreas; Honer, Michael; Woltering, Thomas J.; Muri, Dieter; Iding, Hans; Bürkler, Markus; Binder, Martin; Bartelmus, Christian; Knuesel, Irene; Pacher, Pal; Herde, Adrienne Müller; Spinelli, Francesco; Ahmed, Hazem; Atz, Kenneth; Keller, Claudia; Weber, Markus; Schibli, Roger; Mu, Linjing; Grether, Uwe; Ametamey, Simon M. [Journal of Medicinal Chemistry, 2020, vol. 63, # 18, p. 10287 - 10306]
[2]Current Patent Assignee: ROCHE HOLDING AG; EIDGENÖSSISCHE TECHNISCHE HOCHSCHULE ZÜRICH - WO2020/2270, 2020, A1

44
[ 959958-25-9 ]
ethyl 2-ethyl-2-[6-[(1S,2S)-2-(fluoromethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridine-2-carbonyl]amino}butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 1.2: 3 h / 80 °C 2.1: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / N,N-dimethyl-formamide / 28 h / 20 °C 3.1: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate; palladium diacetate / toluene / 3 h / 110 °C 4.1: palladium on activated charcoal; hydrogen / ethyl acetate; methanol / 48 h / 20 °C 5.1: triethylamine / dichloromethane / 2 h / 0 - 20 °C 6.1: tetrabutyl ammonium fluoride / acetonitrile; tetrahydrofuran / 16 h / 80 °C / Inert atmosphere
	Multi-step reaction with 6 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 0 °C 1.2: 20 h / 20 °C 2.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C 3.1: palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / toluene / 4 h / 110 °C / Sealed tube 4.1: acetic acid / tetrahydrofuran; water / 1 h / 20 °C 5.1: triethylamine / dichloromethane / 2.5 h / 0 - 20 °C 6.1: tetrabutyl ammonium fluoride / tetrahydrofuran; acetonitrile / 1 h / 80 °C / Sealed tube; Inert atmosphere

Reference： [1]Haider, Ahmed; Gobbi, Luca; Kretz, Julian; Ullmer, Christoph; Brink, Andreas; Honer, Michael; Woltering, Thomas J.; Muri, Dieter; Iding, Hans; Bürkler, Markus; Binder, Martin; Bartelmus, Christian; Knuesel, Irene; Pacher, Pal; Herde, Adrienne Müller; Spinelli, Francesco; Ahmed, Hazem; Atz, Kenneth; Keller, Claudia; Weber, Markus; Schibli, Roger; Mu, Linjing; Grether, Uwe; Ametamey, Simon M. [Journal of Medicinal Chemistry, 2020, vol. 63, # 18, p. 10287 - 10306]
[2]Current Patent Assignee: ROCHE HOLDING AG; EIDGENÖSSISCHE TECHNISCHE HOCHSCHULE ZÜRICH - WO2020/2270, 2020, A1

45
[ 959958-25-9 ]
(rac)-trans-ethyl 2-ethyl-2-(6-((-2-(hydroxymethyl)cyclopropyl)methoxy)-5-(3-methoxyazetidin-1-yl)picolinamido)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 1.2: 3 h / 80 °C 2.1: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / N,N-dimethyl-formamide / 28 h / 20 °C 3.1: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate; palladium diacetate / toluene / 3 h / 110 °C 4.1: palladium on activated charcoal; hydrogen / ethyl acetate; methanol / 48 h / 20 °C
	Multi-step reaction with 4 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 0 °C 1.2: 20 h / 20 °C 2.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C 3.1: palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / toluene / 4 h / 110 °C / Sealed tube 4.1: acetic acid / tetrahydrofuran; water / 1 h / 20 °C

Reference： [1]Haider, Ahmed; Gobbi, Luca; Kretz, Julian; Ullmer, Christoph; Brink, Andreas; Honer, Michael; Woltering, Thomas J.; Muri, Dieter; Iding, Hans; Bürkler, Markus; Binder, Martin; Bartelmus, Christian; Knuesel, Irene; Pacher, Pal; Herde, Adrienne Müller; Spinelli, Francesco; Ahmed, Hazem; Atz, Kenneth; Keller, Claudia; Weber, Markus; Schibli, Roger; Mu, Linjing; Grether, Uwe; Ametamey, Simon M. [Journal of Medicinal Chemistry, 2020, vol. 63, # 18, p. 10287 - 10306]
[2]Current Patent Assignee: ROCHE HOLDING AG; EIDGENÖSSISCHE TECHNISCHE HOCHSCHULE ZÜRICH - WO2020/2270, 2020, A1

46
[ 959958-25-9 ]
(rac)-trans-ethyl 2-ethyl-2-(5-(3-methoxyazetidin-1-yl)-6-((-2-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)picolinamido)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 1.2: 3 h / 80 °C 2.1: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / N,N-dimethyl-formamide / 28 h / 20 °C 3.1: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate; palladium diacetate / toluene / 3 h / 110 °C 4.1: palladium on activated charcoal; hydrogen / ethyl acetate; methanol / 48 h / 20 °C 5.1: triethylamine / dichloromethane / 2 h / 0 - 20 °C
	Multi-step reaction with 5 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 0 °C 1.2: 20 h / 20 °C 2.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C 3.1: palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / toluene / 4 h / 110 °C / Sealed tube 4.1: acetic acid / tetrahydrofuran; water / 1 h / 20 °C 5.1: triethylamine / dichloromethane / 2.5 h / 0 - 20 °C

Reference： [1]Haider, Ahmed; Gobbi, Luca; Kretz, Julian; Ullmer, Christoph; Brink, Andreas; Honer, Michael; Woltering, Thomas J.; Muri, Dieter; Iding, Hans; Bürkler, Markus; Binder, Martin; Bartelmus, Christian; Knuesel, Irene; Pacher, Pal; Herde, Adrienne Müller; Spinelli, Francesco; Ahmed, Hazem; Atz, Kenneth; Keller, Claudia; Weber, Markus; Schibli, Roger; Mu, Linjing; Grether, Uwe; Ametamey, Simon M. [Journal of Medicinal Chemistry, 2020, vol. 63, # 18, p. 10287 - 10306]
[2]Current Patent Assignee: ROCHE HOLDING AG; EIDGENÖSSISCHE TECHNISCHE HOCHSCHULE ZÜRICH - WO2020/2270, 2020, A1

47
[ 959958-25-9 ]
ethyl 2-ethyl-2-[(6-[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridin-2-yl)formamido]butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 1.2: 3 h / 80 °C 2.1: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / N,N-dimethyl-formamide / 28 h / 20 °C 3.1: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate; palladium diacetate / toluene / 3 h / 110 °C 4.1: palladium on activated charcoal; hydrogen / ethyl acetate; methanol / 48 h / 20 °C 5.1: Resolution of racemate
	Multi-step reaction with 5 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 0 °C 1.2: 20 h / 20 °C 2.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C 3.1: palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / toluene / 4 h / 110 °C / Sealed tube 4.1: acetic acid / tetrahydrofuran; water / 1 h / 20 °C 5.1: ammonium acetate / ethanol; n-heptane / Resolution of racemate

Reference： [1]Haider, Ahmed; Gobbi, Luca; Kretz, Julian; Ullmer, Christoph; Brink, Andreas; Honer, Michael; Woltering, Thomas J.; Muri, Dieter; Iding, Hans; Bürkler, Markus; Binder, Martin; Bartelmus, Christian; Knuesel, Irene; Pacher, Pal; Herde, Adrienne Müller; Spinelli, Francesco; Ahmed, Hazem; Atz, Kenneth; Keller, Claudia; Weber, Markus; Schibli, Roger; Mu, Linjing; Grether, Uwe; Ametamey, Simon M. [Journal of Medicinal Chemistry, 2020, vol. 63, # 18, p. 10287 - 10306]
[2]Current Patent Assignee: ROCHE HOLDING AG; EIDGENÖSSISCHE TECHNISCHE HOCHSCHULE ZÜRICH - WO2020/2270, 2020, A1

48
[ 959958-25-9 ]
2-ethyl-2-[(6-[(1S,2S)-2-(hydroxymethyl)cyclopropyl]methoxy}-5-(3-methoxyazetidin-1-yl)pyridin-2-yl)formamido]butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 - 20 °C 1.2: 3 h / 80 °C 2.1: N-ethyl-N,N-diisopropylamine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate / N,N-dimethyl-formamide / 28 h / 20 °C 3.1: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate; palladium diacetate / toluene / 3 h / 110 °C 4.1: palladium on activated charcoal; hydrogen / ethyl acetate; methanol / 48 h / 20 °C 5.1: Resolution of racemate 6.1: potassium hydroxide / tetrahydrofuran; water; methanol / 18 h / 90 °C
	Multi-step reaction with 6 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 1 h / 0 °C 1.2: 20 h / 20 °C 2.1: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C 3.1: palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl / toluene / 4 h / 110 °C / Sealed tube 4.1: acetic acid / tetrahydrofuran; water / 1 h / 20 °C 5.1: ammonium acetate / ethanol; n-heptane / Resolution of racemate 6.1: water; potassium hydroxide / tetrahydrofuran; methanol / 18 h / 90 °C

Reference： [1]Haider, Ahmed; Gobbi, Luca; Kretz, Julian; Ullmer, Christoph; Brink, Andreas; Honer, Michael; Woltering, Thomas J.; Muri, Dieter; Iding, Hans; Bürkler, Markus; Binder, Martin; Bartelmus, Christian; Knuesel, Irene; Pacher, Pal; Herde, Adrienne Müller; Spinelli, Francesco; Ahmed, Hazem; Atz, Kenneth; Keller, Claudia; Weber, Markus; Schibli, Roger; Mu, Linjing; Grether, Uwe; Ametamey, Simon M. [Journal of Medicinal Chemistry, 2020, vol. 63, # 18, p. 10287 - 10306]
[2]Current Patent Assignee: ROCHE HOLDING AG; EIDGENÖSSISCHE TECHNISCHE HOCHSCHULE ZÜRICH - WO2020/2270, 2020, A1

49
[ 959958-25-9 ]
((1S,2S)-2-((benzyloxy)methyl)cyclopropyl) methanol [ No CAS ]
6-[(1S,2S)-2-[(benzyloxy)methyl]cyclopropyl]methoxy}-5-bromopyridine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: ((1S,2S)-2-((benzyloxy)methyl)cyclopropyl) methanol With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.333333h; Stage #2: 5-bromo-6-chloropyridine-2-carboxylic acid In N,N-dimethyl-formamide at 80℃; for 3h;
	Stage #1: 5-bromo-6-chloropyridine-2-carboxylic acid With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.333333h; Stage #2: ((1S,2S)-2-((benzyloxy)methyl)cyclopropyl) methanol In N,N-dimethyl-formamide at 0 - 80℃; for 3.25h;	1.g g) 6-[(l5',25)-2-[(Benzyloxy)methyl]cyclopropyl]methoxy}-5-bromopyridine-2- carboxylic acid To a solution of 5-bromo-6-chloropyridine-2-carboxylic acid (CAN 959958-25-9, 4 g, 19.80 mmol) in DMF (45 mL) was added NaH (2.77 g, 69.31 mmol) portion wise at 0 °C and stirred for 20 min at 0 °C. [( l S,2A)-2-[(bcnzyloxy)mcthyl]cyclopropyl]mcthanol (4.18 g, 21.78 mmol) in DMF (15 mL) was added drop wise at 0 °C. The mixture was stirred for 15 min at 25 °C, heated to 80 °C for 3 h, cooled to 25 °C and quenched with 2 N aq. HC1 to pH ~2. Water (100 mL) was added and the mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with water (4 x 50 mL) and brine (50 mL), dried over Na2S04 and concentrated under reduced pressure to get 6- j [( 1 S,2S)-2- [(benzyloxy)methyl]cyclopropyl]methoxy}-5-bromopyridine-2-carboxylic acid (7.7 g, 99%) as off white sticky liquid. LCMS: Column Zorbax Ext C 18 (50X4.6 mm), 5 m, (mobile phase: from 90% [10 mM NH4OAC in water] and 10% [CH3CN] to 70% [10 mM NH4OAc in water] and 30% [CH3CN] in 1.5 min, further to 10% [10 mM NH4OAc in water] and 90% [CH3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 76.8%, Rt = 2.60 min, MS calculate: 391, MS found: 391.8 ([M+H]+).
	Stage #1: 5-bromo-6-chloropyridine-2-carboxylic acid With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.333333h; Stage #2: ((1S,2S)-2-((benzyloxy)methyl)cyclopropyl) methanol In N,N-dimethyl-formamide at 0 - 80℃; for 3.25h;	15.g g) 6-{ [( lS,2S)-2-[(Benzyloxy)methyl]cyclopropyl]methoxy}-5-bromopyridine-2- carboxylic acid To a solution of 5-bromo-6-chloropyridine-2-carboxylic acid (CAN 959958-25-9, 4 g, 19.80 mmol) in DMF (45 mL) was added NaH (2.77 g, 69.31 mmol) portion wise at 0 °C and stirred for 20 min at 0 °C. [( lS,2S)-2-[(Benzyloxy)methyl]cyclopropyl]methanol (4.18 g, 21.78 mmol) in DMF ( 15 mL) was added drop wise at 0 °C. The mixture was stirred for 15 min at 25 °C, heated to 80 °C for 3 h, cooled to 25 °C and quenched with 2 N aq. HC1 to pH -2. Waster ( 100 mL) was added and the mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with water (4 x 50 mL) and brine (50 mL), dried over Na2SC)4 and concentrated under reduced pressure to get 6-{ [( lS,2S)-2- [(benzyloxy)methyl]cyclopropyl]methoxy}-5-bromopyridine-2-carboxylic acid (7.7 g, 99%) as off white sticky liquid. LCMS: Column Zorbax Ext C 18 (50X4.6 m), 5 m, (mobile phase: from 90% [ 10 mM NH4OAC in water] and 10% [CH3CN] to 70% [10 mM NH4OAc in water] and 30% [CH3CN] in 1.5 min, further to 10% [10 mM NEUOAc in water] and 90% [CH3CN] in 3.0 min, held this mobile phase composition to 4 min and finally back to initial condition in 5 min). Purity is 76.78%, Rt = 2.60 min, MS calculate: 391, MS found: 391.8[M+H].

Reference： [1]Haider, Ahmed; Gobbi, Luca; Kretz, Julian; Ullmer, Christoph; Brink, Andreas; Honer, Michael; Woltering, Thomas J.; Muri, Dieter; Iding, Hans; Bürkler, Markus; Binder, Martin; Bartelmus, Christian; Knuesel, Irene; Pacher, Pal; Herde, Adrienne Müller; Spinelli, Francesco; Ahmed, Hazem; Atz, Kenneth; Keller, Claudia; Weber, Markus; Schibli, Roger; Mu, Linjing; Grether, Uwe; Ametamey, Simon M. [Journal of Medicinal Chemistry, 2020, vol. 63, # 18, p. 10287 - 10306]
[2]Current Patent Assignee: EIDGENÖSSISCHE TECHNISCHE HOCHSCHULE ZÜRICH; ROCHE HOLDING AG - WO2020/2314, 2020, A1 Location in patent: Page/Page column 15; 19-20
[3]Current Patent Assignee: ROCHE HOLDING AG; EIDGENÖSSISCHE TECHNISCHE HOCHSCHULE ZÜRICH - WO2020/2270, 2020, A1 Location in patent: Page/Page column 49; 53; 54

50
[ 959958-25-9 ]
[ 124200-37-9 ]
(rac)-cis-5-bromo-6-((-2-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)picolinic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3%	Stage #1: (±)-[(1R,2S)-2-([tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methanol With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h; Stage #2: 5-bromo-6-chloropyridine-2-carboxylic acid In N,N-dimethyl-formamide at 20℃; for 16h;

Reference： [1]Haider, Ahmed; Gobbi, Luca; Kretz, Julian; Ullmer, Christoph; Brink, Andreas; Honer, Michael; Woltering, Thomas J.; Muri, Dieter; Iding, Hans; Bürkler, Markus; Binder, Martin; Bartelmus, Christian; Knuesel, Irene; Pacher, Pal; Herde, Adrienne Müller; Spinelli, Francesco; Ahmed, Hazem; Atz, Kenneth; Keller, Claudia; Weber, Markus; Schibli, Roger; Mu, Linjing; Grether, Uwe; Ametamey, Simon M. [Journal of Medicinal Chemistry, 2020, vol. 63, # 18, p. 10287 - 10306]

51
[ 66582-32-9 ]
[ 959958-25-9 ]
6-(3-(benzyloxy)-2,2-dimethylpropoxy)-5-bromopicolinic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2020,vol. 63,p. 10287 - 10306

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CAS No. :	959958-25-9	MDL No. :	MFCD09910220
Formula :	C₆H₃BrClNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SEBJRHGSFJEWFZ-UHFFFAOYSA-N
M.W :	236.45	Pubchem ID :	44607714
Synonyms :

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

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 959958-25-9 ] {[proInfo.proName]}

Quality Control of [ 959958-25-9 ]

Related Doc. of [ 959958-25-9 ]

Product Details of [ 959958-25-9 ]

Safety of [ 959958-25-9 ]

Application In Synthesis of [ 959958-25-9 ]

[ 959958-25-9 ] Synthesis Path-Upstream 1~1

[ 959958-25-9 ] Synthesis Path-Downstream 1~51

Related Functional Groups of
[ 959958-25-9 ]

Bromides

Chlorides

Carboxylic Acids

Related Parent Nucleus of
[ 959958-25-9 ]

Pyridines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

[ CAS No. 959958-25-9 ] {[proInfo.proName]}

Quality Control of [ 959958-25-9 ]

Related Doc. of [ 959958-25-9 ]

Product Details of [ 959958-25-9 ]

Safety of [ 959958-25-9 ]

Application In Synthesis of [ 959958-25-9 ]

[ 959958-25-9 ] Synthesis Path-Upstream 1~1

[ 959958-25-9 ] Synthesis Path-Downstream 1~51

Related Functional Groups of [ 959958-25-9 ]

Bromides

Chlorides

Carboxylic Acids

Related Parent Nucleus of [ 959958-25-9 ]

Pyridines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 959958-25-9 ]

Related Parent Nucleus of
[ 959958-25-9 ]