Name: 89793-11-3|Methyl 2-chloro-6-methylpyrimidine-4-carboxylate|98%
Brand: Ambeed
SKU: A370798
Rating: 91 (32 reviews)

1
[ 51605-97-1 ]
[ 89793-11-3 ]
[ 257615-17-1 ]

Yield	Reaction Conditions	Operation in experiment
53%	In 1,4-dioxane for 24h; Heating;
47%	With sodium hydrogencarbonate In 1,4-dioxane	97 2-(N-(2-bromo-4-(2-propyl)phenyl)amino)-4-carbomethoxy-6-methylpyrimidine EXAMPLE 97 2-(N-(2-bromo-4-(2-propyl)phenyl)amino)-4-carbomethoxy-6-methylpyrimidine A mixture of 2-chloro-4-carbomethoxy-6-methylpyrimidine (47 g, 252 mmol) and 2-bromo-4-(2-propyl)aniline (54.0 g, 252 mmol) in dioxane (400 mL) was stirred at reflux temperature for 20 h under a nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and concentrated on a rotary evaporator. The residue was treated with a saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate and filtered. Solvent was removed in vacuo to provide a red oil. Column chromatography (ethyl acetate:hexanes::1:1) gave the title product as a crude oil. Recrystallization from ether-hexanes, collection by filtration and drying in vacuo afforded the title compound as a solid (42.8 g, 47% yield): mp 75-76° C.; NMR (CDCl3, 300 MHz): 8.4 (d, 1H, J=8); 7.65 (br s, 1H), 7.4 (d, 1H, J=1), 7.3 (s, 1H), 7.2 (dd, 1H, J=8,1), 4.0 (s, 3H), 2.85 (septet, 1H, J=7), 2.5 (br s, 3H), 1.25 (d, 6H, J=7); Anal.(C16 H18 BrN3 O2): C, 52.76, H, 4.98, N, 11.54, Br, 21.94; Found: C, 52.71, H, 4.99, N, 11.38, Br, 21.83.
17%	In 1,4-dioxane for 20h; Heating / reflux;

Reference： [1]Gilligan, Paul J.; He, Liqi; Culp, Steven; Fitzgerald, Lawrence; Tam, S.William; Wong, Y.Nancy [Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 11, p. 2321 - 2328]
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US6107301, 2000, A
[3]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US6342503, 2002, B1 Location in patent: Example 97

2
[ 5720-07-0 ]
[ 89793-11-3 ]
methyl 2-(4-methoxyphenyl)-6-methylpyrimidine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium carbonate In water; toluene for 12h; Heating;
89%	With potassium carbonate In toluene at 100℃;

Reference： [1]Guram, Anil S.; King, Anthony O.; Allen, John G.; Wang, Xianghong; Schenkel, Laurie B.; Chan, Johann; Bunel, Emilio E.; Faul, Margaret M.; Larsen, Robert D.; Martinelli, Michael J.; Reider, Paul J. [Organic Letters, 2006, vol. 8, # 9, p. 1787 - 1789]
[2]Guram, Anil S.; Wang, Xiang; Bunel, Emilio E.; Faul, Margaret M.; Larsen, Robert D.; Martinelli, Michael J. [Journal of Organic Chemistry, 2007, vol. 72, # 14, p. 5104 - 5112]

3
[ 89793-11-3 ]
[ 169883-31-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 53 percent / dioxane / 24 h / Heating 2: 55 percent / NaH / dimethylformamide / 5 h 3: 3.64 g / lithium borohydride / tetrahydrofuran / 19 h / 0 - 20 °C
	Multi-step reaction with 3 steps 1: 1,4-dioxane / 20 h / Heating / reflux 2: sodium hydride / tetrahydrofuran / 24 h / Heating / reflux 3: lithium borohydride / tetrahydrofuran / 15 h

Reference： [1]Gilligan, Paul J.; He, Liqi; Culp, Steven; Fitzgerald, Lawrence; Tam, S.William; Wong, Y.Nancy [Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 11, p. 2321 - 2328]
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US6342503, 2002, B1

4
[ 89793-11-3 ]
[ 169880-48-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 53 percent / dioxane / 24 h / Heating 2: 55 percent / NaH / dimethylformamide / 5 h
	Multi-step reaction with 2 steps 1: 1,4-dioxane / 20 h / Heating / reflux 2: sodium hydride / tetrahydrofuran / 24 h / Heating / reflux

Reference： [1]Gilligan, Paul J.; He, Liqi; Culp, Steven; Fitzgerald, Lawrence; Tam, S.William; Wong, Y.Nancy [Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 11, p. 2321 - 2328]
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US6342503, 2002, B1

5
[ 89793-11-3 ]
[ 169882-77-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 53 percent / dioxane / 24 h / Heating 2: 55 percent / NaH / dimethylformamide / 5 h 3: aq. NaOH / ethanol / 7 h / Heating
	Multi-step reaction with 3 steps 1: 1,4-dioxane / 20 h / Heating / reflux 2: sodium hydride / tetrahydrofuran / 24 h / Heating / reflux 3: sodium hydroxide / ethanol / 18 h / Heating / reflux

Reference： [1]Gilligan, Paul J.; He, Liqi; Culp, Steven; Fitzgerald, Lawrence; Tam, S.William; Wong, Y.Nancy [Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 11, p. 2321 - 2328]
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US6342503, 2002, B1

6
[ 89793-11-3 ]
2-[(2-bromo-4-isopropyl-phenyl)-ethyl-amino]-6-methyl-pyrimidine-4-carboxylic acid methylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 53 percent / dioxane / 24 h / Heating 2: 55 percent / NaH / dimethylformamide / 5 h 3: NaH / tetrahydrofuran / Heating

Reference： [1]Gilligan, Paul J.; He, Liqi; Culp, Steven; Fitzgerald, Lawrence; Tam, S.William; Wong, Y.Nancy [Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 11, p. 2321 - 2328]

7
[ 89793-11-3 ]
2-[(2-bromo-4-isopropyl-phenyl)-ethyl-amino]-6-methyl-pyrimidine-4-carboxylic acid dimethylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 53 percent / dioxane / 24 h / Heating 2: 55 percent / NaH / dimethylformamide / 5 h 3: NaH / tetrahydrofuran

Reference： [1]Gilligan, Paul J.; He, Liqi; Culp, Steven; Fitzgerald, Lawrence; Tam, S.William; Wong, Y.Nancy [Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 11, p. 2321 - 2328]

8
[ 89793-11-3 ]
N-{2-bromo-4-(1-methylethyl)phenyl}-N-ethyl-4-(imidazol-1-yl)methyl-6-methylpyrimidinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: 53 percent / dioxane / 24 h / Heating 2: 55 percent / NaH / dimethylformamide / 5 h 3: 3.64 g / lithium borohydride / tetrahydrofuran / 19 h / 0 - 20 °C 4: 1.6 g / Et₃N / CH₂Cl₂ / 1.5 h / 0 - 5 °C 5: 59 percent / NaH / tetrahydrofuran / 68 h / 20 °C
	Multi-step reaction with 5 steps 1: 1,4-dioxane / 20 h / Heating / reflux 2: sodium hydride / tetrahydrofuran / 24 h / Heating / reflux 3: lithium borohydride / tetrahydrofuran / 15 h 4: triethylamine / dichloromethane / 1.5 h / 0 °C 5: sodium hydride / tetrahydrofuran / 68 h / 20 °C

Reference： [1]Gilligan, Paul J.; He, Liqi; Culp, Steven; Fitzgerald, Lawrence; Tam, S.William; Wong, Y.Nancy [Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 11, p. 2321 - 2328]
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US6342503, 2002, B1

9
[ 89793-11-3 ]
[ 169883-22-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 53 percent / dioxane / 24 h / Heating 2: 55 percent / NaH / dimethylformamide / 5 h 3: 3.64 g / lithium borohydride / tetrahydrofuran / 19 h / 0 - 20 °C 4: 1.6 g / Et₃N / CH₂Cl₂ / 1.5 h / 0 - 5 °C
	Multi-step reaction with 4 steps 1: 1,4-dioxane / 20 h / Heating / reflux 2: sodium hydride / tetrahydrofuran / 24 h / Heating / reflux 3: lithium borohydride / tetrahydrofuran / 15 h 4: triethylamine / dichloromethane / 1.5 h / 0 °C

Reference： [1]Gilligan, Paul J.; He, Liqi; Culp, Steven; Fitzgerald, Lawrence; Tam, S.William; Wong, Y.Nancy [Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 11, p. 2321 - 2328]
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US6342503, 2002, B1

10
[ 89793-11-3 ]
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(2-imidazolyl)carbonyl-6-methylpyrimidinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 53 percent / dioxane / 24 h / Heating 2: 55 percent / NaH / dimethylformamide / 5 h 3: 42 percent / nBuLi / diethyl ether / -78 - 20 °C
	Multi-step reaction with 3 steps 1: 1,4-dioxane / 20 h / Heating / reflux 2: sodium hydride / tetrahydrofuran / 24 h / Heating / reflux 3: n-butyllithium / diethyl ether / 23 h / 20 °C

Reference： [1]Gilligan, Paul J.; He, Liqi; Culp, Steven; Fitzgerald, Lawrence; Tam, S.William; Wong, Y.Nancy [Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 11, p. 2321 - 2328]
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US6342503, 2002, B1

11
[ 89793-11-3 ]
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(4-morpholinylmethyl)-2-pyrimidinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 53 percent / dioxane / 24 h / Heating 2: 55 percent / NaH / dimethylformamide / 5 h 3: 39 percent / NaH / tetrahydrofuran / 17 h / Heating 4: 39 percent / borane / tetrahydrofuran / 19 h / Heating
	Multi-step reaction with 4 steps 1: 1,4-dioxane / 20 h / Heating / reflux 2: sodium hydride / tetrahydrofuran / 24 h / Heating / reflux 3: sodium hydride / tetrahydrofuran / 26 h / 20 °C 4: borane / tetrahydrofuran / 20 h / Heating / reflux

Reference： [1]Gilligan, Paul J.; He, Liqi; Culp, Steven; Fitzgerald, Lawrence; Tam, S.William; Wong, Y.Nancy [Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 11, p. 2321 - 2328]
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US6342503, 2002, B1

12
[ 89793-11-3 ]
[ 169882-87-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 53 percent / dioxane / 24 h / Heating 2: 55 percent / NaH / dimethylformamide / 5 h 3: 39 percent / NaH / tetrahydrofuran / 17 h / Heating
	Multi-step reaction with 3 steps 1: 1,4-dioxane / 20 h / Heating / reflux 2: sodium hydride / tetrahydrofuran / 24 h / Heating / reflux 3: sodium hydride / tetrahydrofuran / 26 h / 20 °C

Reference： [1]Gilligan, Paul J.; He, Liqi; Culp, Steven; Fitzgerald, Lawrence; Tam, S.William; Wong, Y.Nancy [Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 11, p. 2321 - 2328]
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US6342503, 2002, B1

13
[ 89793-11-3 ]
N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-6-methyl-4-(4-methyl-1-piperazinylcarbonyl)-2-pyrimidinamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 53 percent / dioxane / 24 h / Heating 2: 55 percent / NaH / dimethylformamide / 5 h 3: NaH / tetrahydrofuran / Heating
	Multi-step reaction with 3 steps 1: 1,4-dioxane / 20 h / Heating / reflux 2: sodium hydride / tetrahydrofuran / 24 h / Heating / reflux

Reference： [1]Gilligan, Paul J.; He, Liqi; Culp, Steven; Fitzgerald, Lawrence; Tam, S.William; Wong, Y.Nancy [Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 11, p. 2321 - 2328]
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US6342503, 2002, B1

14
[ 5122-94-1 ]
[ 89793-11-3 ]
[ 870266-01-6 ]

Yield	Reaction Conditions	Operation in experiment
41%	With potassium fluoride In tetrahydrofuran at 20℃; for 8h; Heating / reflux;	1.A 2-[(2-Biphenyl-4-yl-6-methyl-pyrimidine-4-carbonyl)amino]-3-(4-chlorophenyl)- ' propionic acid; Step A: 2-Biphenyl-4-yl-6-methyl-pyrimidine-4-carboxylic acid methyl ester ;To a mixture of 2-chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester (560 mg, 3.0 mmol), 4-biphenylboronic acid (653 mg, 3.3 mmol), tris(dibenzylideneacetone)dipalladium(0) (41 mg, 0.045 mmol) and tri-tert- butylphosphine (3 mol%) in THF (15 mL) at 'room temperature was added potassium fluoride (575 mg, 9.9 mmol) and the reaction mixture was heated at reflux temperature for 8 h. After cooling to room temperature, the mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. Purification of the crude product by medium pressure liquid chromatography on silica gel (1: 9 ethyl acetate/hexanes) gave 371 mg (41%) of the title compound.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2005/113514, 2005, A2 Location in patent: Page/Page column 30

15
[ 771-99-3 ]
[ 89793-11-3 ]
[ 870266-04-9 ]

Yield	Reaction Conditions	Operation in experiment
63%	In dichloromethane at 0 - 20℃; for 16.5h;	1.A (R)-3 -B enzylsulfanyl-2- [6-methyl-2-(4-phenylpiperidin-1-yl) pyrimidine-4- carbonyl]amino}propionic acid; Step A: 6-Methyl-2- (4-phenylpiperidin-1-yl)pyrimidine-4-carboxylic acidmethyl ester; To a solution of 2-chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester (186 mg, 1.0 mmol) in dichloromethane (5.0 mL) at 0°C was added 4-phenylpiperidine (161 mg, 1.0 mmol) and the resulting reaction mixture was stirred at 0°C for 30 min. and then at room temperature for 16 h. Saturated sodium bicarbonate (aq. ) was added and the mixture was extracted with dichloromethane. The organic layer was separated, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo. Purification of the crude product by medium pressure liquid chromatography on silica gel (1: 4 ethyl acetate/hexanes) gave 195 mg (63%) of the title compound

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2005/113514, 2005, A2 Location in patent: Page/Page column 31-32

16
[ 89793-11-3 ]
[ 89581-58-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: methyl 2-chloro-6-methylpyrimidine-4-carboxylate With sodium hydroxide In tetrahydrofuran; water monomer for 2h; Stage #2: With hydrogenchloride In tetrahydrofuran; water monomer	1.4 To a solution of NaOH (960 mg, 24 mmol) in water (70 mL) and THF (5 mL) at r.t. was added ester 1e (3.7 g, 20 mmol). The solution was stirred for 2 h and conc. hydrochloride acid (2.5 mL) was added. The solution was then extracted with ethyl acetate (2×150 mL), dried over Na2SO4, filtered and concentrated to give 3.4 g (99%) of 2-chloro-6-methyl-pyrimidine-4-carboxylic acid as a white solid.
89%	With water monomer; lithium hydroxide monohydrate In tetrahydrofuran; methanol at 20℃;	2-chloro-6-methylpyrimidine-4-carboxylic acid (15) To a solution of commercial available methyl 2-chloro-6-methylpyrimidine-4-carboxylate (50 mg, 0.27mmol) in 0.5 m L MeOH, 0.5 mL H2O, and 0.5 mL THF, LiOH (8 mg, 0.3 mmol) was added. The mixture was stirred at RT overnight. Then the mixture was purified by reverse phase column to afford white solid (41 mg, 89%). MS (ESI): m/z 173.0 [M + H]+.
	Stage #1: methyl 2-chloro-6-methylpyrimidine-4-carboxylate With water monomer; sodium hydroxide In acetonitrile at 0℃; for 1h; Stage #2: With hydrogenchloride In water monomer; acetonitrile	a a) To a solution of commercially available methyl-2-chloro-6-methylpyrimidine-4-carboxylate (6.00 g, 32.15 mmol) in acetonitrile (500 mL), 1M aq. solution of NaOH (48.2 mL) is added at 0° C. The mixture is stirred at 0° C. for 1 h then acidified with 25% aq. HCl (7 mL). Volatiles are evaporated and the aq. solution is extracted with ethylacetate, washed with brine, dried over Na2SO4, filtered and concentrated to give 2-chloro-6-methylpyrimidine-4-carboxylic acid (4.22 g) as a yellow crystalline solid; LC-MS: tR=0.42 min, [M+H]+=172.96; 1H NMR (D6-DMSO): δ 2.58 (s, 3H), 7.95 (s, 1H), 14.1 (s br, 1H).

	Stage #1: methyl 2-chloro-6-methylpyrimidine-4-carboxylate With water monomer; sodium hydroxide In acetonitrile at 0℃; for 1h; Stage #2: With hydrogenchloride In water monomer; acetonitrile	a a) To a solution of commercially available methyl-2-chloro-6-methylpyrimidine-4-carboxylate (6.00 g, 32.15 mmol) in acetonitrile (500 mL), 1M aq. solution of NaOH (48.2 mL) is added at 0° C. The mixture is stirred at 0° C. for 1 h then acidified with 25% aq. HCl (7 mL). Volatiles are evaporated and the aq. solution is extracted with ethylacetate, washed with brine, dried over Na2SO4, filtered and concentrated to give 2-chloro-6-methylpyrimidine-4-carboxylic acid (4.22 g) as a yellow crystalline solid; LC-MS: tR=0.42 min, [M+H]+=172.96; 1H NMR (D6-DMSO): δ 2.58 (s, 3H), 7.95 (s, 1H), 14.1 (s br, 1H).
	Stage #1: methyl 2-chloro-6-methylpyrimidine-4-carboxylate With water monomer; sodium hydroxide In acetonitrile at 0℃; for 1h; Stage #2: With hydrogenchloride In water monomer; acetonitrile	a To a solution of commercially available methyl-2-chloro-6-methylpyrimidine-4- carboxylate (6.00 g, 32.15 mmol) in acetonitrile (500 ml_), 1 M aq. solution of NaOH (48.2 ml.) is added at 00C. The mixture is stirred at 00C for 1 h then acidified with 25% aq. HCI (7 ml_). Volatiles are evaporated and the aq. solution is extracted with ethylacetate, washed with brine, dried over Na2SO4, filtered and concentrated to give 2-chloro-6- methylpyrimidine-4-carboxylic acid (4.22 g) as a yellow crystalline solid; LC-MS: tR = 0.42 min, [M+H]+ = 172.96; 1H NMR (D6-DMSO): δ 2.58 (s, 3 H), 7.95 (s, 1 H), 14.1 (s br, 1 H).
	Stage #1: methyl 2-chloro-6-methylpyrimidine-4-carboxylate With water monomer; sodium hydroxide at 20℃; for 3h; Stage #2: With hydrogenchloride In water monomer	X.31 A mixture of 2-chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester (2.Og, 10.7mmol), sodium hydroxide pellets (600mg) and water (60ml) was stirred at room temperature for 3 hours. The reaction was then acidified with 5N hydrochloric acid and left to stand over the weekend. The reaction was cooled on ice and a brown material removed by vacuum filtration. The liquors were extracted with ethyl acetate and the combined organic liquors were concentrated to furnish the acid intermediate as a brown solid (1.59g). 1 H NMR (400 MHz, DMSO-d6): 14.13 (1 H, s), 7.95 (1 H, s), 2.59 (3H, s). The amide was produced according to the method for preparation of 2-chloro-pyrimidine-4-carboxylic acid methylamide. MS: [M+H]+ = 186

Reference： [1]Current Patent Assignee: KALYPSYS, INC. - US2006/116515, 2006, A1 Location in patent: Page/Page column 29
[2]Current Patent Assignee: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI - WO2021/257544, 2021, A1 Location in patent: Page/Page column 155-156
[3]Current Patent Assignee: JOHNSON & JOHNSON INC - US2010/234346, 2010, A1 Location in patent: Page/Page column 12
[4]Current Patent Assignee: JOHNSON & JOHNSON INC - US2011/46170, 2011, A1 Location in patent: Page/Page column 13
[5]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2009/109907, 2009, A1 Location in patent: Page/Page column 33
[6]Current Patent Assignee: OTSUKA HOLDINGS CO LTD - WO2009/150240, 2009, A1 Location in patent: Page/Page column 130-131

17
[ 110-89-4 ]
[ 64-17-5 ]
[ 89793-11-3 ]
[ 873449-93-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine for 20h; Heating / reflux;	1 Method 1; Ethyl 6-methyl-2-piperidin-1 -ylpvrimidine-4-carboxylate; Methyl 2-chloro-6-methylpyrimidine-4-carboxylate (1.45 g, 7.77 mmol), piperidine(0.768 ml, 7.77 mmol) and triethylamine (3.25 ml, 13.32 mmol) were combined in anhydrousethanol (30 ml) and the reaction mixture was allowed to stir at reflux for 20 hours. Thereaction mixture was allowed to cool to 25 °C and concentrated under reduced pressure. Theresidue was then diluted with EtOAc and washed with water and brine. The organic layerswere then dried over Na2SC>4, filtered and concentrated. The product was purified by flashchromatography using EtOAc and hexanes; m/z 250.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2006/3378, 2006, A1 Location in patent: Page/Page column 59

18
[ 89793-11-3 ]
[ 181363-21-3 ]

Yield	Reaction Conditions	Operation in experiment
76%	With methanol; sodium tetrahydroborate; water at 0 - 20℃; for 16h;	X.1 Intermediate X: Preparation of (2-chloro-6-methylpyrirnidin-4-yl)methylmethanesulfonate; Step 1: Preparation of (2-chloro-6-methylpyrimidin-4-yl)methanol; To a 0 °C solution of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (750 mg, 4.02 mmol) in MeOH (4.5 mL)/water (0.4 mL) was added sodium borohydride (190 mg, 5.02 mmol) portionwise. The reaction was allowed to slowly come to room temperature and then stirred an additional 16 h. The resulting solution was concentrated, re-dissolved in EtOAc, transferred into a separatory funnel and extracted with water. The combined organic layers were washed with brine. The organic layer was dried (MgSO4), filtered and concentrated to afford 484 mg of the crude 4-(hydroxymethyl)-2-chloro-6-methylpyrimidine as a brown solid (yield 76%). LCMS: 159 [M+H]+, RT 1.02 min.
1.4 g	With sodium tetrahydroborate In ethanol for 0.75h; Cooling with ice;	A.3 Intermediate 1: (2-Chloro-6-methylpyrimidin-4-yl)methanol Methyl 2-chloro-6-methylpyrimidine-4-carboxylate (4.0 g) was dissolved in ethanol (46 ml) and cooled with ice, and sodium borohydride (8.0 g) was added in portions. After 30 min, the ice bath was removed and the reaction mixture was stirred for a further 15 min. The reaction mixture was admixed with ice and water, concentrated, extracted with EtOAc, dried over MgSO4 and concentrated at 40° C. The crude product was purified by means of HPLC. Yield: 1.4 g of (2-chloro-6-methylpyrimidin-4-yl)methanol.

Reference： [1]Current Patent Assignee: BAYER AG - WO2006/2383, 2006, A2 Location in patent: Page/Page column 60
[2]Current Patent Assignee: BAYER AG - US2015/223461, 2015, A1 Location in patent: Paragraph 0262

19
[ 89793-11-3 ]
[ 136517-99-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium In methanol; dichloromethane; water	4 Methyl 2-methoxy-6-methylpyrimidine-4-carboxylate EXAMPLE 4 Methyl 2-methoxy-6-methylpyrimidine-4-carboxylate 30.0 g of methyl 2-chloro-6-methylpyrimidine-4-carboxylate are added to a solution of 4.2 g of sodium in 100 ml of methanol. The mixture is heated under reflux for 2 h and concentrated under reduced pressure, and the residue is taken upon in dichloromethane/water. The organic phase is separated off and the aqueous solution is extracted a further five times using dichloromethane. The combined organic extracts are dried over sodium sulfate and the solvent is distilled off under reduced pressure. 25.5 g of methyl 2-methoxy-6-methylpyrimidine-4-carboxylate of melting point 101°-103° C. are obtained in this way.

Reference： [1]Current Patent Assignee: BAYER AG - US5324710, 1994, A

20
[ 89793-11-3 ]
[ 17356-08-0 ]
[ 885685-73-4 ]

Yield	Reaction Conditions	Operation in experiment
38%	In ethanol for 16h; Heating / reflux;	L.1 Step 1. Preparation of2-carbamimidoylsu1fanyl-6-methylpyrimidine-4-carboxyHc acid methyl ester hydrobromide A mixture of 2-chloro-6-methylpyrimidine-4-carboxylic acid methyl ester (0.50 g, 2.7 mmol) and thiourea (0.41 g, 5.4 mmol) in ethanol (8 mL) was heated to reflux for 16 h and then concentrated in vacuo. Attempt to purify the product by recrystalization (methanol/ether) gave 0.229 g (38%) of an oil which was confirmed as the desired product.
38%	In ethanol for 16h; Heating / reflux;	L.1 A mixture of 2-chloro-6-methylpyrimidine-4-carboxylic acid methyl ester (0.50 g, 2.7 mmol) and thiourea (0.41 g, 5.4 mmol) in ethanol (8 ml.) was heated to reflux for 16 h and then concentrated in vacuo. The product was purified by recrystalization (methanol/ether) gave 0.229 g (38%) of an oil which was confirmed as the desired product. LC-MS m/z 226.9 (M+H+); RT 1.07 min.
38%	In ethanol for 16h; Heating / reflux;	1L.1 Step 1. Preparation of2-carbamimidoylsu1fanyl-6-methylpyrimidine-4-carboxyHc acid methyl ester hydrobromide A mixture of 2-chloro-6-methylpyrimidine-4-carboxylic acid methyl ester (0.50 g, 2.7 mmol) and thiourea (0.41 g, 5.4 mmol) in ethanol (8 mL) was heated to reflux for 16 h and then concentrated in vacuo. Attempt to purify the product by recrystalization (methanol/ether) gave 0.229 g (38%) of an oil which was confirmed as the desired product.

Reference： [1]Current Patent Assignee: BAYER AG - WO2006/91506, 2006, A2 Location in patent: Page/Page column 52
[2]Current Patent Assignee: BAYER AG - WO2006/49681, 2006, A2 Location in patent: Page/Page column 50
[3]Current Patent Assignee: BAYER AG - WO2006/121588, 2006, A2 Location in patent: Page/Page column 55 Current Patent Assignee: BAYER AG - WO2006/121860, 2006, A2 Location in patent: Page/Page column 55 Current Patent Assignee: BAYER AG - WO2006/121904, 2006, A1 Location in patent: Page/Page column 55

21
[ 89793-11-3 ]
[ 903558-45-2 ]

Yield	Reaction Conditions	Operation in experiment
74%	With selenium(IV) oxide In 1,4-dioxane at 105℃; for 12h;	295.A Under an argon atmosphere a mixture of commercially available 2-chloro-6-methyl- pyrimidine-4-carboxylic acid methyl ester (9.38 g) and selenium dioxide (8.93 g) in 1,4-dioxane (50 mL) was stirred at 1050C for 12 h. The mixture was filtered twice through celite, the filter cake was rinsed with 1,4-dioxane (2 x 100 mL) and the combined filtrates were concentrated to afford the title compound as viscous orange oil (8.0 g, 74%). [MH]+ = 217.
	With selenium(IV) oxide In 1,4-dioxane at 105℃; for 12h;	24 Intermediate 24: 2-chloro-pyrimidine-4,6-dicarboxylic acid monomethyl ester; To a stirred solution of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (3.73 g, 20 mmol.) in dioxane (20 ml_) is added selenium dioxide (3.55 g, 32 mmol) and the mixture is heated at 10 50C for 12 hours. The suspension is filtered through Celite and washed well with dioxane. The solvent is removed under reduced pressure to give 2-chloro-pyrimidine-4,6- dicarboxylic acid monomethyl ester; HPLC Retention time 0.65 minutes (condition C); MS 217.2 (M+1 ).
	With selenium(IV) oxide In 1,4-dioxane	2-chloro-pyrimidine-4,6-dicarboxylic acid monomethyl ester 2-chloro-pyrimidine-4,6-dicarboxylic acid monomethyl ester To a stirred solution of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (3.73 g, 20 mmol.) in dioxane (20 mL) is added selenium dioxide (3.55 g, 32 mmol) and the mixture is heated at 105° C. for 12 hours. The suspension is filtered through Celite and washed well with dioxane. The solvent is removed under reduced pressure to give 2-chloro-pyrimidine-4,6-dicarboxylic acid monomethyl ester; HPLC Retention time 0.65 minutes (condition A); MS 217.2 (M+1).

With selenium(IV) oxide In 1,4-dioxane at 105℃; for 12h;

2-chloro-pyrimidine-4,6-dicarboxylic acid monomethyl ester To a stirred solution of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (3.73 g, 20 mmol.) in dioxane (20 mL) is added selenium dioxide (3.55 g, 32 mmol) and the mixture is heated at 10 5°C for 12 hours. The suspension is filtered through Celite and washed well with dioxane. The solvent is removed under reduced pressure to give 2-chloro-pyrimidine-4,6-dicarboxylic acid monomethyl ester; HPLC Retention time 0.65 minutes (condition A); MS 217.2 (M+1).

Reference： [1]Current Patent Assignee: AMGEN INC - WO2006/128184, 2006, A2 Location in patent: Page/Page column 364
[2]Current Patent Assignee: SABA & CO INTELLECTUAL PROPERTY; Novartis (w/o Sandoz); NOVARTIS AG - WO2010/136474, 2010, A2 Location in patent: Page/Page column 181-182
[3]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US2012/122844, 2012, A1
[4]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - EP2640375, 2016, B1 Location in patent: Paragraph 0569

22
[ 67-56-1 ]
[ 124-41-4 ]
[ 89793-11-3 ]
[ 136517-99-2 ]

Yield	Reaction Conditions	Operation in experiment
	at 20℃; for 3h;	11.1 A mixture of 1 g of methyl 2-chloro-6-methylpyrimidine-4-carboxylate, 20 mL of methanol and 2 mL of 30% sodium methoxide in methanol was stirred under nitrogen at room temperature for 3 hrs, quenched with 3 mL of acetic acid and concentrated under reduced pressure. The residue was partitioned between 25 mL of saturated sodium bicarbonate and 3 x 20 mL of ethyl acetate and the extracts dried over MgSO4. Concentration under reduced pressure gave a white crystalline solid: MS (m+1) = 183.1; 1H NMR (400 MHz, CDC13) 7.5 (s, IH), 4.1 (s, 3H), 4.0 (s, 3H), 2.58 (s, 3H).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2007/67511, 2007, A2 Location in patent: Page/Page column 34-35

23
[ 89793-11-3 ]
[ 98-80-6 ]
[ 73955-54-1 ]

Yield	Reaction Conditions	Operation in experiment
44%	With potassium fluoride In tetrahydrofuran; hexane for 8h; Heating / reflux;	1 Preparation of methyl 6-methyl-2-phenylpyrimidine-4-carboxylate:; To a mixture of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (1.87 g, 10 mmol), phenylboronic acid (1.34 g, 1 1 mmol), Pd2(dba)3 (0.14 g, 0.15 mmol) and tri-tert-butylphosphine (4 mL, 18 mmol, 10%wt in hexane) in THF (50 mL) at room temperature was added KF (1.9 g, 3.3 mmol) and the reaction mixture was heated at reflux temperature for 8 h. TLC monitored (petroleum etheϖethyl acetate = 5: 1). After cooling to room temperature, the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. Purification of the crude product by medium pressure liquid chromatography on silica gel (with eluent of petroleum etheϖethyl acetate =20: 1 to 10: 1 ) gave methyl 6-methyl-2-phenylpyrimidine-4-carboxylate as a white solid (1.0 g, 44%).
	With potassium phosphate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ In 1,4-dioxane at 100℃;

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/61453, 2009, A1 Location in patent: Page/Page column 109
[2]Caroff, Eva; Meyer, Emmanuel; Treiber, Alexander; Hilpert, Kurt; Riederer, Markus A. [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 17, p. 4323 - 4331]

24
[ 67-56-1 ]
[ 89793-11-3 ]
2-methoxy-6-methyl-pyrimidine-4-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: methanol; methyl 2-chloro-6-methylpyrimidine-4-carboxylate With water; sodium hydroxide at 20℃; for 24h; Stage #2: With hydrogenchloride In water at 0℃;	2-Methoxy-6-methyl-pyrimidine-4-carboxylic acid A suspension of methyl-2-chloro-6-methylpyrimidine-4-carboxylate (5.0 g) in 2N aq. NaOH (67 mL) and methanol (67 mL) is stirred at rt for 24 h. Methanol is evaporated and the aq. phase is acidified with 25% aq. HCl at 0° C. A beige crystalline solid crushes out. It is filtered, rinsed with water and heptane and dried (3.0 g); LC-MS: tR=0.55 min, [M+H]+=169.01; 1H NMR (D6-DMSO): δ 2.50 (s, 3H), 3.94 (s, 3H), 7.52 (s, 1H), 13.7 (s br, 1H).
	Stage #1: methanol; methyl 2-chloro-6-methylpyrimidine-4-carboxylate With water; sodium hydroxide at 20℃; for 24h; Stage #2: With hydrogenchloride In water at 0℃;	2-Methoxy-6-methyl-pyrimidine-4-carboxylic acid A suspension of methyl-2-chloro-6-methylpyrimidine-4-carboxylate (5.0 g) in 2N aq. NaOH (67 mL) and MeOH (67 mL) is stirred at rt for 24 h. MeOH is evaporated and the aq. phase is acidified with 25% aq. HCl at 0° C. A beige crystalline solid crushes out. It is filtered, rinsed with water and heptane and dried to give the title compound (3.0 g); LC-MS: tR=0.55 min, [M+H]+=169.01; 1H NMR (D6-DMSO): δ 2.50 (s, 3H), 3.94 (s, 3H), 7.52 (s, 1H), 13.7 (s br, 1H).
	Stage #1: methanol; methyl 2-chloro-6-methylpyrimidine-4-carboxylate With water; sodium hydroxide at 20℃; for 24h; Stage #2: With hydrogenchloride In water at 0℃;	A suspension of methyl-2-chloro-6-methylpyrimidine-4-carboxylate (5.0 g) in 2N aq. NaOH (67 mL) and MeOH (67 mL) is stirred at rt for 24 h. MeOH is evaporated and the aq. phase is acidified with 25% aq. HCI at 00C. A beige crystalline solid crushes out. It is filtered, rinsed with water and heptane and dried to give the title compound (3.0 g); LC-MS: tR = 0.55 min, [M+H]+ = 169.01 ; 1H NMR (D6-DMSO): δ 2.50 (s, 3 H), 3.94 (s, 3 H), 7.52 (s, 1 H), 13.7 (s br, 1 H).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2010/234346, 2010, A1 Location in patent: Page/Page column 13
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - US2011/46170, 2011, A1 Location in patent: Page/Page column 15
[3]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2009/109907, 2009, A1 Location in patent: Page/Page column 36

25
[ 89793-11-3 ]
[ 16858-56-3 ]

Reference： [1]Patent: US2011/46170,2011,A1
[2]Patent: WO2009/109907,2009,A1

26
[ 1181975-72-3 ]
[ 89793-11-3 ]
[ 1181975-39-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 80℃;

Reference： [1]Location in patent: scheme or table Mittapalli, Gopi Kumar; Jackson, Andrew; Zhao, Fang; Lee, Haekyung; Chow, Stephine; McKelvy, Jeffrey; Wong-Staal, Flossie; MacDonald, James E. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 22, p. 6852 - 6855]

27
[ 827614-67-5 ]
[ 89793-11-3 ]
[ 1460306-51-7 ]

Yield	Reaction Conditions	Operation in experiment
44%	Stage #1: 4-methoxyl-3-nitrophenylboronic acid; methyl 2-chloro-6-methylpyrimidine-4-carboxylate With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In 1,4-dioxane; water for 4h; Reflux; Stage #2: With hydrogenchloride In water	Sat. aq. Na2C03 soln (52.5 mL) was added to a soln of methyl 2-chloro-6- methylpyrimidine-4-carboxylate (107; 5.0 g, 26.8 mmol), 4-methoxy-3- nitrophenylboronic acid (108; 6.86 g, 34.8 mmol) and PdCI2(PPh3)2 (0.94 g, 1 .3 mmol) in dioxane (175 mL). The mixture was heated to reflux for 4 h and partially concentrated, followed by an aqueous workup (EtOAc, 1 M aq. HCI soln; sat. aq. NaCI soln; Na2SC>4). The crude product was suspended in CH2CI2/MeOH 2:1 ; the solid was filtered, washed (MeOH) and dried i.v to afford 109 HCI (3.7 g, 42%). The filtrate was concentrated and purified by FC (CH2CI2/MeOH 100:0 to 70:30) to give 109 HCI (3.87g, 44%).

Reference： [1]Current Patent Assignee: SPEXIS AG - WO2013/139697, 2013, A1 Location in patent: Page/Page column 124

28
(3aR,5r,6aS)-5-(5-fluoro-2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole hydrochloride [ No CAS ]
[ 89793-11-3 ]
methyl 2-((3aR,5r,6aS)-5-(5-fluoro-2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-6-methylpyrimidine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With triethylamine In N,N-dimethyl-formamide at 60℃; for 16h;	57.D Step D: To a solution of (3aR, 5r, 6aS) -5- (5-fluoro-2- ( trifluoromethyl ) henyl) octahydrocyclopenta [c] yrrole hydrochloride (1.0 g, 3.23 mmol) and EtjN (1.43 mL, 10.29 mmolS in DMF (50 mL) was added a methyl 2-chloropyrimidine-4-carboxylate (0.641 g, 3.43 mmol) and the resulting solution was stirred at 60 °C for 16 hours. The reaction was diluted with IfcO (200 mL) and extracted with EtOAc (3 x 100 mL) . The combined organic extracts were washed with 0 (3 χ 100 mL) , brine (100 mL) , dried over Na2S0i , filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0% to 30% EtOAc in hexanes ) to give methyl 2- ( (3aR, 5r, 6aS) - 5- (5-fluoro-2- ( trifluoromethyl )phenyl ) hexahydro-cyclopenta [c] yrrol- 2 ( IH) -yl ) -6~methylpyriinidine-4-carboxylate as an off-white solid (1.14 g, 84%): MS (ESI+) m/z 424 [M + H] *.
	With triethylamine In N,N-dimethyl-formamide at 60℃; for 16h; Inert atmosphere;

Reference： [1]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK - WO2014/152018, 2014, A1 Location in patent: Page/Page column 149
[2]Cioffi, Christopher L.; Racz, Boglarka; Freeman, Emily E.; Conlon, Michael P.; Chen, Ping; Stafford, Douglas G.; Schwarz, Daniel M.C.; Zhu, Lei; Kitchen, Douglas B.; Barnes, Keith D.; Dobri, Nicoleta; Michelotti, Enrique; Cywin, Charles L.; Martin, William H.; Pearson, Paul G.; Johnson, Graham; Petrukhin, Konstantin [Journal of Medicinal Chemistry, 2015, vol. 58, # 15, p. 5863 - 5888]

29
(3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole hydrochloride [ No CAS ]
[ 89793-11-3 ]
methyl 6-methyl-2-((3aR,5R,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)pyrimidine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With triethylamine In N,N-dimethyl-formamide at 60℃; for 16h;	43; 44.A General procedure: General Procedure (GP-K1) for 2-aminopyrimidine formation: A mixture of amine I (1 equiv) , desired methyl 2-chloropyrimidine-4-carboxylate (1 equiv), and triethylamine (EtsN) (3 equiv) in DHF (0.25 M) was stirred at 60 °C until the reaction was complete by TLC or LOMS . The mixture was diluted with H2O and extracted with EtOAc. The combined organic extracts were washed with 0, brine, dried over Na2S0 , filtered, and concentrated under reduced pressure. The resulting residue was purified by either normal phase silica gel column chromatography (typical eluents included either a mixture of or hexanes and EtOAc or a mixture of CH2CI2 and a 90:9:1 mixture of CCl2/CH30H/concentrated NH4OH) or C-18 reversed phase column chromatography (typical eluents included CCN and H20) to afford the desired carboxamide XV. The product structure was verified by NMR and by mass analysis. Example 43 s Mthyl 6-methyl-2- ( (3aR, 5r, 6aS) -5- (2- (trifluoromethyl) phenyl)hexahydroeyelopen a [oJpyrrol-2 (1H) -yl)pyrimidine-4- (58) The above compound was prepared according to General Procedure GP-K1 Step A: To a solution of (3aR, 5J?, 6aS) -5- (2- tri fluoromethyl ) henyl ) octahydrocyclopenta [c] pyrrole hydrochloride (9, 1.0 g, 3.43 rrtmol) and EtiN (1.43 itiL, 10.29 tnmol) in DMF (50 raL) was added a methyl 2-chloro6-methylpyrimidine-4-carboxyla,te (0.641 g, 3.43 mmol) and the resulting solution was stirred at 60 °C for 16 hours . The reaction was diluted with 0 (200 mL) and extracted with EtOAc (3 x 100 mL) . The combined organic extracts were washed with 0 (3 x 100 mL) , brine (100 mL) , dried over Na2S04 , filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel ( 0% to 30% EtOAc in hexanes) to give methyl 6-methyl-2- ( ( 3ai?, SR, 6aS) -5- (2- ( trifluoromethyl ) henyl) hexahydrocyclopenta [c]pyrrol-2 ( IH) -yl ) pyrimidine-4-carboxylate as an off-white solid (1.20 g, 86%): FontWeight="Bold" FontSize="10" H NMR (300 MHz, CDC13) δ 7.61 (m, IH) , 7.58 (m, 2H) , 7.23 (m, IH) , 7.05 (a, IH) , 3.95 (s, 3H) , 3.82 (m, 4H) , 3.59 (m, IH) , 2.92 (m, 2H) , 2.44 (s, 3H) , 2.40 (m, 2H) , 1.69 (m, 2H) ; MS (ESI+) m/z 406 [M + H] '.
	With triethylamine In N,N-dimethyl-formamide at 60℃; for 16h; Inert atmosphere;

Reference： [1]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK - WO2014/152018, 2014, A1 Location in patent: Page/Page column 82; 133-134
[2]Cioffi, Christopher L.; Racz, Boglarka; Freeman, Emily E.; Conlon, Michael P.; Chen, Ping; Stafford, Douglas G.; Schwarz, Daniel M.C.; Zhu, Lei; Kitchen, Douglas B.; Barnes, Keith D.; Dobri, Nicoleta; Michelotti, Enrique; Cywin, Charles L.; Martin, William H.; Pearson, Paul G.; Johnson, Graham; Petrukhin, Konstantin [Journal of Medicinal Chemistry, 2015, vol. 58, # 15, p. 5863 - 5888]

30
(3aR,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole hydrochloride [ No CAS ]
[ 89793-11-3 ]
methyl 6-methyl-2-((3aR,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyrimidine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With triethylamine In N,N-dimethyl-formamide at 60℃; for 16h;	44.A Step A: To a solution of (3ai?, 5R, 6aS) -5- (2- (trifluoromethyl ) henyl ) octahydrocyclopent [c]pyrrole hydrochloride (1, 1.0 g, 3.43 mmol) and EtjN (1.43 mL, 10.29 mmol) in DMF (50 mL) was added a methyl 2-chloropyrirnidine-4~carboxylate (0.641 g, 3.43 mmol) and the resulting solution was stirred at 60 °C for 16 hours . The reaction was diluted with H20 (200 mL) and extracted with EtOAc (3 x 100 mL) . The combined organic extracts were washed with 0 (3 x 100 mL) , brine (100 mL) , dried over Na2SO,i, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0% to 30% EtOAc in hexanes) to give methyl 6-methyl-2- ( (3aB, 5R, 6aS) -5- (2- ( trifluoromethyl) henyl ) hexahydrocyclopenta [c] yrrol-2 (IH) - yl ) yrimidine-4-carboxylate as an off-white solid (1.20 g, 86%): NMR (300 MHz, CDC13) δ 7.61 (m, IH) , 7.58 (m, 2H) , 7.23 (m, IH) , 7.05 (s, IH) , 3.95 (s, 3H) , 3.82 (m, 4H) , 3.59 (m, IH) , 2.92 (m, 2H) , 2.44 (s, 3H) , 2.40 (m, 2H) , 1.69 (m, 2H) ; MS (ESI+) m/z 406 [M + H]•.

Reference： [1]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK - WO2014/151936, 2014, A1 Location in patent: Page/Page column 133

31
(3aR,6aS)-2-(2-(trifluoromethyl)phenyl)octahydropyrrolo[3,4-c]pyrrole hydrochloride [ No CAS ]
[ 89793-11-3 ]
methyl 6-methyl-2-((3aR,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrimidine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With triethylamine In N,N-dimethyl-formamide at 60℃;	55.A General Procedure (GP-A) for 2-amiuopyriznidine formation: General procedure: A mixtureof amine I (1 equiv) desired methyl 2-chloropyrimidine-4-carboxylate (1 eguiv), and triethylamine (EC3N) (3 equiv) in DMF (0.25 M( was stirred at 60° C until the reaction was complete by TLC or LCMS, The mixture was diluted with H2O end extracted with EtOAc. The combined organic extracts were washed with H20, brine,dried over Na2004, filtered, and concentrated under reduced pressure. The resulting residue was purified by either normal phase silica gel column chromatography (typical eluents included either a mixture of or hexanes and EtOAc or a mixture of CH2C12 and a 90:9:1 mixture of CH2C12/CH3OH/concentrated NH4OH) or Cl8 reversed phase columnchromatography (typical eluents included CH3CN and H20) to afford the desired ester II. The product structure was verified by 1H NNR and by mass analysis.
28%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60℃; for 16h; Inert atmosphere;

Reference： [1]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK - WO2014/151936, 2014, A1 Location in patent: Page/Page column 139; 140; 141
[2]Cioffi, Christopher L.; Racz, Boglarka; Freeman, Emily E.; Conlon, Michael P.; Chen, Ping; Stafford, Douglas G.; Schwarz, Daniel M.C.; Zhu, Lei; Kitchen, Douglas B.; Barnes, Keith D.; Dobri, Nicoleta; Michelotti, Enrique; Cywin, Charles L.; Martin, William H.; Pearson, Paul G.; Johnson, Graham; Petrukhin, Konstantin [Journal of Medicinal Chemistry, 2015, vol. 58, # 15, p. 5863 - 5888]

32
[ 827614-67-5 ]
[ 89793-11-3 ]
C₁₄H₁₃N₃O₅*ClH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	Stage #1: 4-methoxyl-3-nitrophenylboronic acid; methyl 2-chloro-6-methylpyrimidine-4-carboxylate With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate In 1,4-dioxane; water for 4h; Reflux; Stage #2: With hydrogenchloride In water; ethyl acetate	Sat. aq. Na2CO3 soln (52.5 mE) was added to a soln of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (107; 5.0 g, 26.8 mmol), 4-methoxy-3-nitrophenylboronic acid (108; 6.86 g, 34.8 mmol) and PdC12(PPh3)2 (0.94 g, 1.3 mmol) in dioxane (175 mE). The mixture was heated to reflux for 4 h and partially concentrated, followed by an aqueous workup (EtOAc, 1 M aq. HC1 soln; sat. aq. NaC1 soln; Na2504). The crude product was suspended in CH2C12/ MeOH 2:1; the solid was filtered, washed (MeOH) and dried i.v to afford 109.HC1 (3.7 g, 42%). The filtrate was concentrated and purified by FC(CH2C12/MeOH 100:0 to 70:30) to give 109.HC1 (3.87 g, 44%).

Reference： [1]Current Patent Assignee: SPEXIS AG - US2015/51183, 2015, A1 Location in patent: Paragraph 0411

33
[ 255051-14-0 ]
[ 89793-11-3 ]
methyl 6-methyl-2-(4-(2-(trifluoromethyl)phenyl)piperidin-1-yl)pyrimidine-4-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 5863 - 5888

34
[ 40160-26-7 ]
[ 89793-11-3 ]
6-methyl-2-(4-(2-(trifluoromethyl)phenyl)piperazin-1-yl)pyrimidine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60℃; for 16h; Inert atmosphere;

Reference： [1]Cioffi, Christopher L.; Racz, Boglarka; Freeman, Emily E.; Conlon, Michael P.; Chen, Ping; Stafford, Douglas G.; Schwarz, Daniel M.C.; Zhu, Lei; Kitchen, Douglas B.; Barnes, Keith D.; Dobri, Nicoleta; Michelotti, Enrique; Cywin, Charles L.; Martin, William H.; Pearson, Paul G.; Johnson, Graham; Petrukhin, Konstantin [Journal of Medicinal Chemistry, 2015, vol. 58, # 15, p. 5863 - 5888]

35
(3aR,5S,6aS)-5-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrole [ No CAS ]
[ 89793-11-3 ]
6-methyl-2-((3aR,5s,6aS)-5-(2-(trifluoromethyl)phenyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyrimidine-4-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With triethylamine In N,N-dimethyl-formamide at 60℃; for 16h; Inert atmosphere;

Reference： [1]Cioffi, Christopher L.; Racz, Boglarka; Freeman, Emily E.; Conlon, Michael P.; Chen, Ping; Stafford, Douglas G.; Schwarz, Daniel M.C.; Zhu, Lei; Kitchen, Douglas B.; Barnes, Keith D.; Dobri, Nicoleta; Michelotti, Enrique; Cywin, Charles L.; Martin, William H.; Pearson, Paul G.; Johnson, Graham; Petrukhin, Konstantin [Journal of Medicinal Chemistry, 2015, vol. 58, # 15, p. 5863 - 5888]

36
[ 89793-11-3 ]
C₇H₆BrClN₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 80℃; for 48h; Inert atmosphere;	2 EXAMPLE 2 Synthesis of (S)-2-chloro-6-(((2-oxopyrrolidin-3-yl)amino)methyl)pyrimidine-4-carboxamide (Compound 12) A mixture of Compound 8 (1.536 g, 8.23 mmol) (Sigma- Aldrich), NBS (1.757 g, 9.87 mmol) and benzoyl peroxide (199 mg, 0.823 mmol) in CC14 (43 mL) was purged with argon for 2 min. The mixture was heated at 80 °C under argon for 24 h. Additional NBS (1.757 g, 9.87 mmol) and benzoyl peroxide (199 mg, 0.823 mmol) were added and the mixture heated at 80 °C for an additional 24 h. After cooling to RT, the mixture was filtered and the filtrate concentrated. The residue was adsorbed onto S1O2 and purified by flash chromatography (Si02, 0-40% EtOAc/hexanes) to give 0.44 g (20%) of Compound 9 as a brown liquid. LC/MS: m/z= 266 [M+H]+ (Calc: 265).
20%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 80℃; for 48h; Inert atmosphere;	2 EXAMPLE 2Synthesis of (S)-2-chloro-6-(((2-oxopyrrolidin-3-yl)amino)methyl)pyrimidine-4-carboxamide (Compound 12)A mixture of Compound 8 (1.536 g, 8.23 mmol) (Sigma-Aldrich), NBS (1.757 g, 9.87 mmol) and benzoyl peroxide (199 mg, 0.823 mmol) in CCl4 (43 mL) was purged with argon for 2 min. The mixture was heated at 80 °C under argon for 24 h. Additional NBS (1.757 g, 9.87 mmol) and benzoyl peroxide (199 mg, 0.823 mmol) were added and the mixture heated at 80 °C for an additional 24 h. After cooling toRT, the mixture was filtered and the filtrate concentrated. The residue was adsorbed onto Si02 and purified by flash chromatography (Si02, 0-40% EtOAc/hexanes) to give Compound 9 as a brown liquid (440 mg). Yield 20%. LC/MS: mlz= 266 [M+H]+ (Calc: 265).
20%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 80℃; for 24h; Inert atmosphere;	2 A mixture of Compound 8 (1.536 g, 8.23 mmol) (Sigma-Aldrich), N135 (1.757 g, 9.87 mmol) and benzoyl peroxide (199mg, 0.823 mmol) in CC14 (43 mE) was purged with argon for 2 mm. The mixture was heated at 80° C. under argon for 24 h. Additional N135 (1.757 g, 9.87 mmol) and benzoyl peroxide (199 mg, 0.823 mmol) were added and the mixture heated at 80° C. for an additional 24 h. After cooling to RT, the mixture was filtered and the filtrate concentrated. The residue was adsorbed onto 5i02 and purified by flash chromatography (5i02, 0-40% EtOAc/ hexanes) to give 0.44 g (20%) of Compound 9 as a brown liquid. EC/MS: mlz=266 [M+H] (Calc: 265).

Reference： [1]Current Patent Assignee: PURDUE PHARMA L.P. - WO2015/112801, 2015, A1 Location in patent: Page/Page column 68
[2]Current Patent Assignee: PURDUE PHARMA L.P. - WO2015/94443, 2015, A1 Location in patent: Page/Page column 62; 63
[3]Current Patent Assignee: PURDUE PHARMA L.P. - US2017/8882, 2017, A1 Location in patent: Paragraph 0267; 0268

37
[ 89793-11-3 ]
(S)-2-chloro-6-(((2-oxopyrrolidin-3-yl)amino)methyl)pyrimidine-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / 48 h / 80 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / acetonitrile / 2 h / 20 °C 3: ammonia / methanol / 1 h / 20 °C
	Multi-step reaction with 3 steps 1: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / 48 h / 80 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / acetonitrile / 2 h / 20 °C 3: ammonia / methanol / 1 h / 20 °C
	Multi-step reaction with 3 steps 1: N-Bromosuccinimide; dibenzoyl peroxide / tetrachloromethane / 24 h / 80 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / acetonitrile / 2 h / 20 °C 3: ammonia / methanol / 1 h / 20 °C

Reference： [1]Current Patent Assignee: PURDUE PHARMA L.P. - WO2015/112801, 2015, A1
[2]Current Patent Assignee: PURDUE PHARMA L.P. - WO2015/94443, 2015, A1
[3]Current Patent Assignee: PURDUE PHARMA L.P. - US2017/8882, 2017, A1

38
[ 1367127-40-9 ]
[ 89793-11-3 ]
C₂₀H₁₅F₃N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,2-dimethoxyethane; ethanol; water at 85℃; for 3h; Inert atmosphere;	4 EXAMPLE 4Synthesis of (S)-6-(((2-oxopyrrolidin-3-y1)amino)methy1)-2-(4-(4- (trifluoromethy1)phenoxy)pheny1)pyrimidine-4-carboxamide (Compound 20)A mixture of Compound 7 (9.76 g, 26.8 mmol), Compound 8 (5 g, 26.8 mmol), Cs2C03 (17.46 g, 53.6 mmol), Pd(PPh3hCh (1.5 g, 2.14 mmol) in DME (50 mL), H20 (50 mL) and EtOH (25 mL) was purged with argo and heated at 85 oc for 3h. After cooling to RT the mixture was diluted with EtOAc (200 mL) and brine (100 mL). 1M aq. HCl (20 mL) was used to adjust the pH to 6. The aq. layer was extracted with additional EtOAc (100 mL) and the combined EtOAc portions were dried over Na2S04, filtered and concentrated. The crude material was dissolved in MeOH, 4N HCl in dioxane (10 mL) was added and the mixture stirred at RT overnight. The mixture was concentrated, adsorbed onto Si02 and purified by flash chromatography (Si02, 0-15% EtOAc/hexanes) to give Compound 17 as a white solid (3.2 g, yield 30%): LC/MS: mlz= 389 [M+Ht (Calc: 388).

Reference： [1]Current Patent Assignee: PURDUE PHARMA L.P. - WO2015/94443, 2015, A1 Location in patent: Page/Page column 65; 66

39
[ 89793-11-3 ]
[ 126689-00-7 ]
C₁₀H₁₂N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 2h;Microwave irradiation;	1-128: A degassed soln of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (500 mg, 2.68 mmol), 2-methyl-l-propenylboronic acid pinacol ester (687 mu, 3.35 mmol), Pd(Ph3)4 (310 mg, 0.268 mmol), sodium carbonate (2 aq soln, 2.68 mL, 5.40 mmol) in DME (10 mL) was heated to 120C under microwave radiation for 2 h. The rxn mixture was then cooled to RT and acidified with concentrated aq HCl to a final pH of 2. Minimal water was added (5 mL) and the mixture was extracted with EtOAc (3x25 mL). The combined organics were dried (Na2S04), decanted and concentrated. The resulting crude residue was purified via flash chromatography (Si02; 10-40% 5: 1 : 10 MeOH: AcOH: EtOAc in heptane) to afford compound 1-128.

Reference： [1]Patent: WO2017/4609,2017,A1 .Location in patent: Paragraph 0189

40
3-[4-(4-chlorophenyl)piperazine-1-carbonyl]-1H-indole [ No CAS ]
[ 89793-11-3 ]
methyl 2-{3-[4-(4-chlorophenyl)piperazine-1-carbonyl]-1H-indol-1-yl}-6-methylpyrimidine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	With sodium hydride In N,N-dimethyl-formamide at 0 - 100℃; for 18.03h;	193 (193) Synthesis of 2- {3- [4- (4-chlorophenyl) piperazine-1 -carbonyl] -lH-indol-1 -yl} -6-methylpyrimidine-4-carboxylic acid hydrochloride (Compound 193) 3- [4-(4-chlorophenyl) piperazine-1-carbonyl] -1H-indole (340 mg)Of DMF (2 mL)60% sodium hydride (44 mg) was slowly added to the solution,After stirring at 0 ° C. for 20 minutes,Methyl 2-chloro-6-methylpyrimidine-4-carboxylate (177 mg) was added and the mixture was stirred at 100 ° C. for 18 hours.After cooling the reaction solution to room temperature,Saturated sodium hydrogencarbonate rice plant solution was added and extracted with ethyl acetate,And washed with saturated brine.The organic layer was dried over sodium sulfate,The solvent was evaporated under reduced pressure to obtain a residue,Purification by silica gel column chromatography (hexane-ethyl acetate)Methyl 2- {3- [4- (4-chlorophenyl) piperazine-1 -carbonyl] -1 H-indol-1-yl}-6-methylpyrimidine-4-carboxylate138 mg (yield 28%) was obtained.

Reference： [1]Current Patent Assignee: NATIONAL CENTER FOR GERIATRICS AND GERONTOLOGY - JP2017/171619, 2017, A Location in patent: Paragraph 0271; 0273

41
[ 89793-11-3 ]
2-[(2-biphenyl-4-yl-6-methyl-pyrimidine-4-carbonyl)amino]-3-(4-chlorophenyl)-propionic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: potassium fluoride / tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; tri-tert-butyl phosphine / tetrahydrofuran / 8 h / 20 °C / Heating / reflux 2.1: lithium hydroxide; water / tetrahydrofuran / 3 h / 20 °C 2.2: pH ~ 5 3.1: dmap; triethylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate / dichloromethane / 15 h / 20 °C 4.1: lithium hydroxide; water / tetrahydrofuran / 3 h / 20 °C 4.2: pH ~ 5

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2005/113514, 2005, A2

42
[ 89793-11-3 ]
[ 870266-02-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: potassium fluoride / tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; tri-tert-butyl phosphine / tetrahydrofuran / 8 h / 20 °C / Heating / reflux 2.1: lithium hydroxide; water / tetrahydrofuran / 3 h / 20 °C 2.2: pH ~ 5

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2005/113514, 2005, A2

43
[ 89793-11-3 ]
[ 870266-03-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium fluoride / tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; tri-tert-butyl phosphine / tetrahydrofuran / 8 h / 20 °C / Heating / reflux 2.1: lithium hydroxide; water / tetrahydrofuran / 3 h / 20 °C 2.2: pH ~ 5 3.1: dmap; triethylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate / dichloromethane / 15 h / 20 °C

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2005/113514, 2005, A2

44
bromo(cyclopropyl)zinc [ No CAS ]
[ 89793-11-3 ]
methyl 2-cyclopropyl-6-methylpyrimidine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
510 mg	With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In tetrahydrofuran for 24h; Reflux;	339.1 Step 1. Synthesis of methyl 4-cyclopropyl-lH-benzo[d]imidazole-2-carboxylate. Cyclopropyl zinc bromide (16.2 mL of 0.5M solution in THF, 8.1 mmol, 1.5 eq) was added to a solution of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (1.0 g, 5.4 mmol, 1 eq), tetrakistriphenylphosphinepalladium(O) (500 mg, 0.43 mmol, 0.08 eq) and THF (30 mL). The resulting black solution was heated at reflux for 24 h. The reaction was allowed to cool to rt, then poured into sat NH4C1 (75 mL) and EtOAc (50 mL). The phases were separated and the aq extracted with EtOAc (2xl0mL). The combined organic phases were dried (sodium sulfate) filtered, and concentrated onto Celite. The residue was purified by chromatography over Si02 with EtO Ac/hexanes to afford 510 mg of the title compound as a colorless solid.

Reference： [1]Current Patent Assignee: NURIX THERAPEUTICS INC - WO2019/148005, 2019, A1 Location in patent: Paragraph 2118

45
[ 824390-04-7 ]
[ 89793-11-3 ]
methyl 6-methyl-2-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)pyrimidine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 16h; Inert atmosphere; Reflux;
87%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 16h; Reflux; Inert atmosphere;	1.E Step E: A mixture of 4-(2-(trifluoromethyl)phenoxy)piperidine 19 (0.100 g, 0.408 mmol), methyl 2-chloro-6-methylpyrimidine-4- carboxylate (76.1 mg, 0.408 mmol), and i-Pr2NEt (0.21 mL, 1.22 mmol) in THE (10 mL) was heated at reflux for 16 h under an atmosphere of N2. The reaction was concentrated under reduced pressure and the resulting residue was chromatographed over silica gel (0% to 100% EtOAc in hexanes) to give methyl 6-methyl-2-(4-(2- (0204) (trifluoromethyl)phenoxy)piperidin-l-yl)pyrimidine-4-carboxylate 20 as an off-white solid (0.140 g, 87%): MS (ESI+) m/z 396 [M + H]+.
87%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 16h; Reflux; Inert atmosphere;	1.E Step E: A mixture of 4-(2-(trifluoromethyl)phenoxy)piperidine 19 (0.100 g, 0.408 mmol), methyl 2-chloro-6-methylpyrimidine-4- carboxylate (76.1 mg, 0.408 mmol), and i-Pr2NEt (0.21 mL, 1.22 mmol) in THE (10 mL) was heated at reflux for 16 h under an atmosphere of N2. The reaction was concentrated under reduced pressure and the resulting residue was chromatographed over silica gel (0% to 100% EtOAc in hexanes) to give methyl 6-methyl-2-(4-(2- (0204) (trifluoromethyl)phenoxy)piperidin-l-yl)pyrimidine-4-carboxylate 20 as an off-white solid (0.140 g, 87%): MS (ESI+) m/z 396 [M + H]+.

Reference： [1]Cioffi, Christopher L.; Muthuraman, Parthasarathy; Raja, Arun; Varadi, Andras; Racz, Boglarka; Petrukhin, Konstantin [Journal of Medicinal Chemistry, 2020, vol. 63, # 19, p. 11054 - 11084]
[2]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK; ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES IN THE CITY OF ALBANY - WO2022/20305, 2022, A2 Location in patent: Page/Page column 46; 48
[3]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK; ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES IN THE CITY OF ALBANY - WO2022/20305, 2022, A2 Location in patent: Page/Page column 46; 48

46
[ 946760-13-0 ]
[ 89793-11-3 ]
(±)-methyl 6-methyl-2-(3-(2-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)pyrimidine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 16h; Inert atmosphere; Reflux;
88%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 16h; Reflux; Inert atmosphere;	2.D Step D: A mixture of (±)-3-(2-(trifluoromethyl)phenoxy)pyrrolidine (±)-25 (0.100 g, 0.432 mmol), methyl 2-chloro-6-methylpyrimidine-4- carboxylate (80.6 mg, 0.432 mmol), and i-Pr2NEt (0.23 mL, 1.29 mmol) in THE (10 mL) was heated at reflux for 16 h under an atmosphere of N2. The reaction was allowed to cool to rt and then concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0% to 100% EtOAc in hexanes) to give (±)-methyl 6- methyl-2-(3-(2-(trifluoromethyl)phenoxy)pyrrolidin-l-yl)pyrimidine- 4-carboxylate (±)-26 as an off-white solid (0.145 g, 88%): 1H NMR (400 MHz, CDCI3) δ 7.52 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 7.6 Hz, (0219) 1H), 7.00 (s, 1H), 6.98-6.95 (m, 2H), 5.10 (s, 1H), 4.00-3.86 (m, 3H), 3.89 (s, 3Η), 3.76-3.74 (m, 2Η), 2.38 (s, 3Η), 2.22-2.19 (m, 1Η); ESI MS m/z 382 [M + H]+.
88%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 16h; Reflux; Inert atmosphere;	2.D Step D: A mixture of (±)-3-(2-(trifluoromethyl)phenoxy)pyrrolidine (±)-25 (0.100 g, 0.432 mmol), methyl 2-chloro-6-methylpyrimidine-4- carboxylate (80.6 mg, 0.432 mmol), and i-Pr2NEt (0.23 mL, 1.29 mmol) in THE (10 mL) was heated at reflux for 16 h under an atmosphere of N2. The reaction was allowed to cool to rt and then concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0% to 100% EtOAc in hexanes) to give (±)-methyl 6- methyl-2-(3-(2-(trifluoromethyl)phenoxy)pyrrolidin-l-yl)pyrimidine- 4-carboxylate (±)-26 as an off-white solid (0.145 g, 88%): 1H NMR (400 MHz, CDCI3) δ 7.52 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 7.6 Hz, (0219) 1H), 7.00 (s, 1H), 6.98-6.95 (m, 2H), 5.10 (s, 1H), 4.00-3.86 (m, 3H), 3.89 (s, 3Η), 3.76-3.74 (m, 2Η), 2.38 (s, 3Η), 2.22-2.19 (m, 1Η); ESI MS m/z 382 [M + H]+.

Reference： [1]Cioffi, Christopher L.; Muthuraman, Parthasarathy; Raja, Arun; Varadi, Andras; Racz, Boglarka; Petrukhin, Konstantin [Journal of Medicinal Chemistry, 2020, vol. 63, # 19, p. 11054 - 11084]
[2]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK; ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES IN THE CITY OF ALBANY - WO2022/20305, 2022, A2 Location in patent: Page/Page column 49-51
[3]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK; ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES IN THE CITY OF ALBANY - WO2022/20305, 2022, A2 Location in patent: Page/Page column 49-51

47
3-[2-(trifluoromethyl)phenoxy]azetidine [ No CAS ]
[ 89793-11-3 ]
methyl 6-methyl-2-(3-(2-(trifluoromethyl)phenoxy)azetidin-1-yl)pyrimidine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 16h; Inert atmosphere; Reflux;
90%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 16h; Reflux; Inert atmosphere;	3.C Step C: A mixture of 3-(2-(trifluoromethyl)phenoxy)azetidine 30 (0228) (0.100 g, 0.460 mmol), methyl 2-chloro-6-methylpyrimidine-4- carboxylate (85.9 mg, 0.460 mmol), and i-Pr2NEt (0.24 mL, 1.38 mmol) in THE (10 mL) was heated at reflux for 16 h under an atmosphere of N2. The reaction was concentrated under reduced pressure and the resulting residue was chromatographed over silica gel (0% to 100% (0229) EtOAc in hexanes) to give methyl 6-methyl-2-(3-(2- (trifluoromethyl)phenoxy)azetidin-l-yl)pyrimidine-4-carboxylate 31 as an off-white solid (0.152 g, 90%): MS (ESI+) m/z [M + H]+.
90%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 16h; Reflux; Inert atmosphere;	3.C Step C: A mixture of 3-(2-(trifluoromethyl)phenoxy)azetidine 30 (0228) (0.100 g, 0.460 mmol), methyl 2-chloro-6-methylpyrimidine-4- carboxylate (85.9 mg, 0.460 mmol), and i-Pr2NEt (0.24 mL, 1.38 mmol) in THE (10 mL) was heated at reflux for 16 h under an atmosphere of N2. The reaction was concentrated under reduced pressure and the resulting residue was chromatographed over silica gel (0% to 100% (0229) EtOAc in hexanes) to give methyl 6-methyl-2-(3-(2- (trifluoromethyl)phenoxy)azetidin-l-yl)pyrimidine-4-carboxylate 31 as an off-white solid (0.152 g, 90%): MS (ESI+) m/z [M + H]+.

Reference： [1]Cioffi, Christopher L.; Muthuraman, Parthasarathy; Raja, Arun; Varadi, Andras; Racz, Boglarka; Petrukhin, Konstantin [Journal of Medicinal Chemistry, 2020, vol. 63, # 19, p. 11054 - 11084]
[2]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK; ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES IN THE CITY OF ALBANY - WO2022/20305, 2022, A2 Location in patent: Page/Page column 51-52
[3]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK; ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES IN THE CITY OF ALBANY - WO2022/20305, 2022, A2 Location in patent: Page/Page column 51-52

48
3-((2-(trifluoromethyl)phenoxy)methyl)azetidine [ No CAS ]
[ 89793-11-3 ]
methyl 6-methyl-2-(3-((2-(trifluoromethyl)phenoxy)methyl)azetidin-1-yl)pyrimidine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.64 g	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 16h; Inert atmosphere; Reflux;
1.64 g	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 16h; Reflux; Inert atmosphere;	4.D Step D: A mixture of 3-((2-(trifluoromethyl)phenoxy)methyl)azetidine 36 (1.0 g, 4.32 mmol), methyl 2-chloro-6-methylpyrimidine-4- carboxylate (0.807 g, 4.32 mmol), and i-Pr2NEt (2.25 mL, 12.9 mmol) in THE (20 mL) was heated at reflux for 16 h under an atmosphere of N2. The reaction was concentrated under reduced pressure and the resulting residue was chromatographed over silica gel (0% to 100% EtOAc in hexanes) to give methyl 6-methyl-2-(3-((2- (trifluoromethyl)phenoxy)methyl)azetidin-l-yl)pyrimidine-4- carboxylate 37 as an off-white solid (1.64 g, 86%): 1H NMR (400 MHz, CDCI3) δ 7.52 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.05 (s, 1H), 7.00-6.95 (m, 2H), 4.33 (t, J = 8.8 Hz, 2H), 4.22-4.21 (m, 2H), 4.08-4.04 (m, 2Η), 3.91 (s, 3Η), 3.18-3.16 (m, 1Η), 2.40 (s, (0243) 3H); ESI MS m/z 382 [M + H]+.
1.64 g	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 16h; Reflux; Inert atmosphere;	4.D Step D: A mixture of 3-((2-(trifluoromethyl)phenoxy)methyl)azetidine 36 (1.0 g, 4.32 mmol), methyl 2-chloro-6-methylpyrimidine-4- carboxylate (0.807 g, 4.32 mmol), and i-Pr2NEt (2.25 mL, 12.9 mmol) in THE (20 mL) was heated at reflux for 16 h under an atmosphere of N2. The reaction was concentrated under reduced pressure and the resulting residue was chromatographed over silica gel (0% to 100% EtOAc in hexanes) to give methyl 6-methyl-2-(3-((2- (trifluoromethyl)phenoxy)methyl)azetidin-l-yl)pyrimidine-4- carboxylate 37 as an off-white solid (1.64 g, 86%): 1H NMR (400 MHz, CDCI3) δ 7.52 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.05 (s, 1H), 7.00-6.95 (m, 2H), 4.33 (t, J = 8.8 Hz, 2H), 4.22-4.21 (m, 2H), 4.08-4.04 (m, 2Η), 3.91 (s, 3Η), 3.18-3.16 (m, 1Η), 2.40 (s, (0243) 3H); ESI MS m/z 382 [M + H]+.

Reference： [1]Cioffi, Christopher L.; Muthuraman, Parthasarathy; Raja, Arun; Varadi, Andras; Racz, Boglarka; Petrukhin, Konstantin [Journal of Medicinal Chemistry, 2020, vol. 63, # 19, p. 11054 - 11084]
[2]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK; ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES IN THE CITY OF ALBANY - WO2022/20305, 2022, A2 Location in patent: Page/Page column 53-55
[3]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK; ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES IN THE CITY OF ALBANY - WO2022/20305, 2022, A2 Location in patent: Page/Page column 53-55

49
(±)-3-((2-(trifluoromethyl)phenoxy)methyl)pyrrolidine [ No CAS ]
[ 89793-11-3 ]
(±)-methyl 6-methyl-2-(3-((2-(trifluoromethyl)phenoxy)methyl)pyrrolidin-1-yl)pyrimidine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 16h; Inert atmosphere; Reflux;
85%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 16h; Reflux; Inert atmosphere;	5.D Step D: To a solution of (±)-tert-butyl 3-((2- (0266) (trifluoromethyl)phenoxy)methyl)pyrrolidine-l-carboxylate (±) -42 (0.265 g 1.08 mmol) in THE (5 mL) were added i-Pr2NEt (0.6 mL, 3.24 mmol) and methyl 2-chloro-6-methylpyrimidine-4-carboxylate (0.242 g, (0267) 1.29 mmol) and the resulting mixture stirred at reflux for 16 h. The mixture was allowed to cool to rt and then concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0% to 50% EtOAc in hexanes) to give (±)-methyl 6-methyl- 2-(3-((2-(trifluoromethyl)phenoxy)methyl)pyrrolidin-l-yl)pyrimidine- (0268) 4-carboxylate (±) -43 as a white solid (0.362 g, 85%): 1H NMR (400 MHz, CDCI3) δ 7.54 (d, J = 7.6 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 6.99 (s, 1H), 6.97-6.92 (m, 2H), 4.10-4.06 (m, 1H), 4.00-3.96 (m, (0269) 1H), 3.91 (s, 3H), 3.89-3.86 (m, 1H), 3.79-3.76 (m, 1H), 3.66-3.61 (m, 1H), 3.51-3.47 (m, 1H), 2.86-2.82 (m, 1H), 2.39 (s, 3H), 2.24- (0270) 2.20 (m, 1H), 1.99-1.94 (m, 1H); ESI MS m/z 396 [M + H]+.
85%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 16h; Reflux; Inert atmosphere;	5.D Step D: To a solution of (±)-tert-butyl 3-((2- (0266) (trifluoromethyl)phenoxy)methyl)pyrrolidine-l-carboxylate (±) -42 (0.265 g 1.08 mmol) in THE (5 mL) were added i-Pr2NEt (0.6 mL, 3.24 mmol) and methyl 2-chloro-6-methylpyrimidine-4-carboxylate (0.242 g, (0267) 1.29 mmol) and the resulting mixture stirred at reflux for 16 h. The mixture was allowed to cool to rt and then concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0% to 50% EtOAc in hexanes) to give (±)-methyl 6-methyl- 2-(3-((2-(trifluoromethyl)phenoxy)methyl)pyrrolidin-l-yl)pyrimidine- (0268) 4-carboxylate (±) -43 as a white solid (0.362 g, 85%): 1H NMR (400 MHz, CDCI3) δ 7.54 (d, J = 7.6 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 6.99 (s, 1H), 6.97-6.92 (m, 2H), 4.10-4.06 (m, 1H), 4.00-3.96 (m, (0269) 1H), 3.91 (s, 3H), 3.89-3.86 (m, 1H), 3.79-3.76 (m, 1H), 3.66-3.61 (m, 1H), 3.51-3.47 (m, 1H), 2.86-2.82 (m, 1H), 2.39 (s, 3H), 2.24- (0270) 2.20 (m, 1H), 1.99-1.94 (m, 1H); ESI MS m/z 396 [M + H]+.

Reference： [1]Cioffi, Christopher L.; Muthuraman, Parthasarathy; Raja, Arun; Varadi, Andras; Racz, Boglarka; Petrukhin, Konstantin [Journal of Medicinal Chemistry, 2020, vol. 63, # 19, p. 11054 - 11084]
[2]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK; ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES IN THE CITY OF ALBANY - WO2022/20305, 2022, A2 Location in patent: Page/Page column 45; 55; 57
[3]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK; ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES IN THE CITY OF ALBANY - WO2022/20305, 2022, A2 Location in patent: Page/Page column 45; 55; 57

50
(±)-3-((2-(trifluoromethyl)phenoxy)methyl)piperidine [ No CAS ]
[ 89793-11-3 ]
(±)-methyl 6-methyl-2-(3-((2-(trifluoromethyl)phenoxy)methyl)piperidin-1-yl)pyrimidine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 16h; Inert atmosphere; Reflux;
87%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 16h; Reflux; Inert atmosphere;	8.D Step D: To a solution of (±)-3-((2- (trifluoromethyl)phenoxy)methyl)piperidine (±) -60 (0.100 g, 0.385 mmol) in THF (5 mL) were added i-PrzNEt (0.20 mL, 1.16 mmol) and methyl 2-chloro-6-methylpyrimidine-4-carboxylate (71.8 mg, 0.385 mmol) and the resulting mixture stirred at reflux for 16 h under an atmosphere of N2. The mixture was allowed to cool to rt and then concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0% to 50% EtOAc in hexanes) to give (±)-methyl 6-methyl-2-(3-((2- (trifluoromethyl)phenoxy)methyl)piperidin-l-yl)pyrimidine-4- carboxylate (±) -61 as a white solid (0.137 g, 87%): 1H NMR (400 MHz, DMSO-de) δ 7.59-7.55 (m, 2H), 7.22 (d, J= 8.4 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.94 (s, 1H), 4.79 (d, J = 12.8 Hz, 1H), 4.55 (d, J = 12.8 Hz, 1H), 4.04-3.96 (m, 2H), 3.80 (s, 3H), 2.93-2.83 (m, 3H), 2.29 (s, 3H), 1.85-1.71 (m, 4H); ESI MS m/z 410 [M + H]+.
87%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 16h; Reflux; Inert atmosphere;	8.D Step D: To a solution of (±)-3-((2- (trifluoromethyl)phenoxy)methyl)piperidine (±) -60 (0.100 g, 0.385 mmol) in THF (5 mL) were added i-PrzNEt (0.20 mL, 1.16 mmol) and methyl 2-chloro-6-methylpyrimidine-4-carboxylate (71.8 mg, 0.385 mmol) and the resulting mixture stirred at reflux for 16 h under an atmosphere of N2. The mixture was allowed to cool to rt and then concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0% to 50% EtOAc in hexanes) to give (±)-methyl 6-methyl-2-(3-((2- (trifluoromethyl)phenoxy)methyl)piperidin-l-yl)pyrimidine-4- carboxylate (±) -61 as a white solid (0.137 g, 87%): 1H NMR (400 MHz, DMSO-de) δ 7.59-7.55 (m, 2H), 7.22 (d, J= 8.4 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 6.94 (s, 1H), 4.79 (d, J = 12.8 Hz, 1H), 4.55 (d, J = 12.8 Hz, 1H), 4.04-3.96 (m, 2H), 3.80 (s, 3H), 2.93-2.83 (m, 3H), 2.29 (s, 3H), 1.85-1.71 (m, 4H); ESI MS m/z 410 [M + H]+.

Reference： [1]Cioffi, Christopher L.; Muthuraman, Parthasarathy; Raja, Arun; Varadi, Andras; Racz, Boglarka; Petrukhin, Konstantin [Journal of Medicinal Chemistry, 2020, vol. 63, # 19, p. 11054 - 11084]
[2]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK; ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES IN THE CITY OF ALBANY - WO2022/20305, 2022, A2 Location in patent: Page/Page column 59; 61
[3]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK; ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES IN THE CITY OF ALBANY - WO2022/20305, 2022, A2 Location in patent: Page/Page column 59; 61

51
(±)-2-(2-(trifluoromethyl)phenyl)-2,7-diazaspiro[4.4]nonane [ No CAS ]
[ 89793-11-3 ]
(±)-methyl 6-methyl-2-(7-(2-(trifluoromethyl)phenyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 16h; Inert atmosphere; Reflux;
88%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 16h; Reflux; Inert atmosphere;	9.C Step C: To a solution of (±)-2-(2-(trifluoromethyl)phenyl)-2,7- diazaspiro[4.4]nonane (±)-65 (0.150 g, 0.554 mmol) in THF (5 mL) were added i-Pr2NEt (0.29 mL, 1.66 mmol) and methyl 2-chloro-6- methylpyrimidine-4-carboxylate (0.103 g, 0.554 mmol) and the resulting mixture stirred at reflux for 16 h under an atmosphere of N2. The mixture was allowed to cool to rt and then concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0% to 50% EtOAc in hexanes) to give (±)-methyl 6- methyl-2-(7-(2-(trifluoromethyl)phenyl)-2,7-diazaspiro[4.4]nonan-2- yl)pyrimidine-4-carboxylate (±)-66 as a white solid (0.205 g, 88%): ΧΗ NMR (400 MHz, CDC13) δ 7.55 (d, J = 6.4 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.00 (s, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.87 (t, J = 7.6 Hz, 1H), 3.91 (s, 3H), 3.74-3.61 (m, 4H), 3.47-3.44 (m, 2H), 3.30 (0308) (s, 2H), 2.39 (s, 3H), 2.08-1.93 (m, 4H); ESI MS m/z 421 [M + H]+.
88%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 16h; Reflux; Inert atmosphere;	9.C Step C: To a solution of (±)-2-(2-(trifluoromethyl)phenyl)-2,7- diazaspiro[4.4]nonane (±)-65 (0.150 g, 0.554 mmol) in THF (5 mL) were added i-Pr2NEt (0.29 mL, 1.66 mmol) and methyl 2-chloro-6- methylpyrimidine-4-carboxylate (0.103 g, 0.554 mmol) and the resulting mixture stirred at reflux for 16 h under an atmosphere of N2. The mixture was allowed to cool to rt and then concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0% to 50% EtOAc in hexanes) to give (±)-methyl 6- methyl-2-(7-(2-(trifluoromethyl)phenyl)-2,7-diazaspiro[4.4]nonan-2- yl)pyrimidine-4-carboxylate (±)-66 as a white solid (0.205 g, 88%): ΧΗ NMR (400 MHz, CDC13) δ 7.55 (d, J = 6.4 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.00 (s, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.87 (t, J = 7.6 Hz, 1H), 3.91 (s, 3H), 3.74-3.61 (m, 4H), 3.47-3.44 (m, 2H), 3.30 (0308) (s, 2H), 2.39 (s, 3H), 2.08-1.93 (m, 4H); ESI MS m/z 421 [M + H]+.

Reference： [1]Cioffi, Christopher L.; Muthuraman, Parthasarathy; Raja, Arun; Varadi, Andras; Racz, Boglarka; Petrukhin, Konstantin [Journal of Medicinal Chemistry, 2020, vol. 63, # 19, p. 11054 - 11084]
[2]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK; ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES IN THE CITY OF ALBANY - WO2022/20305, 2022, A2 Location in patent: Page/Page column 62-63
[3]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK; ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES IN THE CITY OF ALBANY - WO2022/20305, 2022, A2 Location in patent: Page/Page column 62-63

52
(±)-N-(pyrrolidin-3-ylmethyl)-2-(trifluoromethyl)aniline [ No CAS ]
[ 89793-11-3 ]
(±)-methyl 6-methyl-2-(3-(((2-(trifluoromethyl)phenyl)amino)methyl)pyrrolidin-1-yl)pyrimidine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 16h; Inert atmosphere; Reflux;
63%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 16h; Reflux; Inert atmosphere;	11.C Step C: To a solution of ((±)--N-(pyrrolidin-3-ylmethyl)-2- (0324) (trifluoromethyl)aniline (±)-74 (0.360 g, 1.16 mmol) in THF (5 mL) were added i-PrzNEt (0.61 mL, 3.48 mmol) and methyl 2-chloro-6- methylpyrimidine-4-carboxylate (0.216 g, 1.16 mmol) and the resulting mixture stirred at reflux for 16 h under an atmosphere of N2. The mixture was allowed to cool to rt and then concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0% to 50% EtOAc in hexanes) to give (±)-methyl 6- methyl-2-(3-(((2-(trifluoromethyl)phenyl)amino)methyl)pyrrolidin-1- yl)pyrimidine-4-carboxylate (±)-75 as a white solid (0.290 g, 63%): 1Η NMR (400 MHz, CDC13) δ 7.43-7.40 (m, 1H), 7.35-7.31 (m, 1H), 7.00 (s, 1H), 6.71-6.68 (m, 2H), 4.40 (brs, 1H), 3.91 (s, 3H), 3.90-3.86 (m, 1H), 3.79-3.58 (m, 1H), 3.41-3.19 (m, 4H), 2.68-2.62 (m, 1H), 2.40 (s, 3H), 2.22-2.16 (m, 1H), 1.82-1.77 (m, 1H) ; ESI MS m/z 395 [M + H]+.
63%	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 16h; Reflux; Inert atmosphere;	11.C Step C: To a solution of ((±)--N-(pyrrolidin-3-ylmethyl)-2- (0324) (trifluoromethyl)aniline (±)-74 (0.360 g, 1.16 mmol) in THF (5 mL) were added i-PrzNEt (0.61 mL, 3.48 mmol) and methyl 2-chloro-6- methylpyrimidine-4-carboxylate (0.216 g, 1.16 mmol) and the resulting mixture stirred at reflux for 16 h under an atmosphere of N2. The mixture was allowed to cool to rt and then concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0% to 50% EtOAc in hexanes) to give (±)-methyl 6- methyl-2-(3-(((2-(trifluoromethyl)phenyl)amino)methyl)pyrrolidin-1- yl)pyrimidine-4-carboxylate (±)-75 as a white solid (0.290 g, 63%): 1Η NMR (400 MHz, CDC13) δ 7.43-7.40 (m, 1H), 7.35-7.31 (m, 1H), 7.00 (s, 1H), 6.71-6.68 (m, 2H), 4.40 (brs, 1H), 3.91 (s, 3H), 3.90-3.86 (m, 1H), 3.79-3.58 (m, 1H), 3.41-3.19 (m, 4H), 2.68-2.62 (m, 1H), 2.40 (s, 3H), 2.22-2.16 (m, 1H), 1.82-1.77 (m, 1H) ; ESI MS m/z 395 [M + H]+.

Reference： [1]Cioffi, Christopher L.; Muthuraman, Parthasarathy; Raja, Arun; Varadi, Andras; Racz, Boglarka; Petrukhin, Konstantin [Journal of Medicinal Chemistry, 2020, vol. 63, # 19, p. 11054 - 11084]
[2]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK; ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES IN THE CITY OF ALBANY - WO2022/20305, 2022, A2 Location in patent: Page/Page column 65-66
[3]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK; ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES IN THE CITY OF ALBANY - WO2022/20305, 2022, A2 Location in patent: Page/Page column 65-66

53
(±)-3-((2-(trifluoromethyl)benzyl)oxy)pyrrolidine [ No CAS ]
[ 89793-11-3 ]
(±)-methyl 6-methyl-2-(3-((2-(trifluoromethyl)benzyl)oxy)pyrrolidin-1-yl)pyrimidine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.11 g	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran for 16h; Inert atmosphere; Reflux;
0.11 g	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 80℃; for 16h; Inert atmosphere;	12.C Step C: To a solution of (±) -3- ( (2- (0336) (trifluoromethyl)benzyl)oxy)pyrrolidine (±)-78 (0.100 g, 0.407 mmol) in THF (5 mL) were added i-Pr2NEt (0.25 mL, 1.23 mmol) and methyl 2- chloro-6-methylpyrimidine-4-carboxylate (76.2 mg, 0.408 mmol) and the resulting solution was stirred at 80 °C for 16 h under an atmosphere of N2. The mixture was allowed to cool to rt and then concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0% to 50% EtOAc in hexanes) to give (±)-methyl 6-methyl-2-(3-((2-(trifluoromethyl)benzyl)oxy)pyrrolidin- 1-yl)pyrimidine-4-carboxylate (±)-79 as a white solid (0.110 g, (0337) 68%): 1H NMR (400 MHz, acetone-d6) δ 7.75-7.68 (m, 2H), 7.62 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 6.97 (s, 1H), 4.78-4.76 (m, 2H), 4.41-4.39 (m, 1H), 3.85 (s, 3H), 3.74-3.66 (m, 4H), 2.36 (s, (0338) 3H), 2.31-2.04 (m, 2H); ESI MS m/z 396 [M + H]+.
0.11 g	With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 80℃; for 16h; Inert atmosphere;	12.C Step C: To a solution of (±) -3- ( (2- (0336) (trifluoromethyl)benzyl)oxy)pyrrolidine (±)-78 (0.100 g, 0.407 mmol) in THF (5 mL) were added i-Pr2NEt (0.25 mL, 1.23 mmol) and methyl 2- chloro-6-methylpyrimidine-4-carboxylate (76.2 mg, 0.408 mmol) and the resulting solution was stirred at 80 °C for 16 h under an atmosphere of N2. The mixture was allowed to cool to rt and then concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0% to 50% EtOAc in hexanes) to give (±)-methyl 6-methyl-2-(3-((2-(trifluoromethyl)benzyl)oxy)pyrrolidin- 1-yl)pyrimidine-4-carboxylate (±)-79 as a white solid (0.110 g, (0337) 68%): 1H NMR (400 MHz, acetone-d6) δ 7.75-7.68 (m, 2H), 7.62 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 6.97 (s, 1H), 4.78-4.76 (m, 2H), 4.41-4.39 (m, 1H), 3.85 (s, 3H), 3.74-3.66 (m, 4H), 2.36 (s, (0338) 3H), 2.31-2.04 (m, 2H); ESI MS m/z 396 [M + H]+.

Reference： [1]Cioffi, Christopher L.; Muthuraman, Parthasarathy; Raja, Arun; Varadi, Andras; Racz, Boglarka; Petrukhin, Konstantin [Journal of Medicinal Chemistry, 2020, vol. 63, # 19, p. 11054 - 11084]
[2]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK; ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES IN THE CITY OF ALBANY - WO2022/20305, 2022, A2 Location in patent: Page/Page column 67-68
[3]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK; ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES IN THE CITY OF ALBANY - WO2022/20305, 2022, A2 Location in patent: Page/Page column 67-68

54
[ 124-41-4 ]
[ 89793-11-3 ]
2-methoxy-6-methylpyrimidine-4-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3 g	Stage #1: sodium methylate; methyl 2-chloro-6-methylpyrimidine-4-carboxylate In methanol at 20℃; for 1h; Stage #2: With hydrogenchloride at 0℃;	F5.K5.1 F5.K5.1 2-Methoxy-b-methyl-pyrimidine-4-carboxyHc acid Methyl 2-chloro-methylpyrimidine-4-carboxylate (5.0g) was suspended in MeOH (67mL) and NaOH 1N (67mL) was added. The mixture was stirred for 1h at RT, then MeOH was evaporated off. At 0°C the mixture was acidified to pH=2 with HCI (25%). The crystals were filtrated, washed with water and heptane and dried at HV at 35°C overnight to give 3.0g beige crystals 1H NMR (400 MHz, DMSO) d: 13.67-13.76 (m, 1 H), 7.52 (s, 1 H), 3.94 (s, 3 H), 2.50 (s, 3 H)

Reference： [1]Current Patent Assignee: IDORSIA PHARMACEUTICALS LTD - WO2021/219849, 2021, A1 Location in patent: Page/Page column 196

55
[ 57260-73-8 ]
[ 89793-11-3 ]
methyl 2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-6-methylpyrimidine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃;	Intermediate Z9 methyl 2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-6-methylpyrimidine-4-carboxylate. To a solution of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (200 mg, 1.08 mmol) and DIPEA (0.56 mL, 3.23 mmol) in CH3CN (5 mL) was added tert-butyl (2-aminoethyl)carbamate (259 mg, 1.62 mmol). The reaction mixture was heated to 80 °C overnight. The reaction was monitored by UPLC. Upon completion, the reaction mixture was purified by reverse column to give Z9 (248 mg, 0.8 mmol, 74% yield) as white solid.

Reference： [1]Current Patent Assignee: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI - WO2021/257544, 2021, A1 Location in patent: Page/Page column 117

56
[ 195314-59-1 ]
[ 89793-11-3 ]
C₁₈H₂₈N₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 10h;	165 A mixture of tert-butyl (4-aminocyclohexyl)carbamate (0.2 mmol), methyl 2-chloro-6-methylpyrimidine-4-carboxylate (0.2 mmol) and DIPEA (0.4 mmol) in MeCN was stirred at 80 oC for 10 h. The reaction was monitored by LC-MS and upon completion; the solvent was evaporated under reduced pressure to obtain methyl 2-chloro-6-methylpyrimidine-4-carboxylate. This intermediate was used for the next step without further purification.

Reference： [1]Current Patent Assignee: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI - WO2021/257544, 2021, A1 Location in patent: Page/Page column 136

57
[ 1001-53-2 ]
[ 89793-11-3 ]
methyl 2-((2-acetamidoethyl)amino)-6-methylpyrimidine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In acetonitrile at 80℃; for 10h;	166 A mixture of N-(2-aminoethyl)acetamide (0.2 mmol), methyl 2-chloro-6-methylpyrimidine-4-carboxylate (0.2 mmol) and DIPEA (0.4 mmol) in MeCN was stirred at 80 oC for 10 h. The reaction was monitored by LC-MS and upon completion; the solvent was evaporated under reduced pressure to obtain methyl 2-((2-acetamidoethyl)amino)-6-methylpyrimidine-4-carboxylate. This intermediate was used for the next step without further purification.

Reference： [1]Current Patent Assignee: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI - WO2021/257544, 2021, A1 Location in patent: Page/Page column 136

58
[ 462-08-8 ]
[ 89793-11-3 ]
2-chloro-6-methyl-N-(pyridin-3-yl)pyrimidine-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With tris(methyl)aluminum In toluene at 100℃; for 1h; Microwave irradiation;	6.1 2-chl oro-6-methyl -A'-fpyri din-3 -yl)pyrimidine-4-carboxamide To a solution of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (250 mg, 1.34 mmol) in toluene was added pyri din-3 -amine (126 mg, 1,34 mmol) and 2M trimethylaluminum solution in toluene (1.34 mL, 2.68 mmol). The reaction mixture was stirred in a CEM microwave at 100 °C for 1 hr. The reaction mixture was cooled to RT, quenched with water then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure to obtain crude material which was purified by Combiflash column chromatography using ethyl acetate- hexane gradient. The target compound eluted at about 50% ethyl acetate-hexane. The pure fractions were collected and evaporated to afford 2-chloro-6- methyl-A-(pyridin-3-yl)pyrimidine-4-carboxamide (0.20 g, 60% yield) as a pale yellow solid. ]H NMR (400 MHz, DMSO-de) 5 10.90 (s, 1H), 9.0 (s, 1H), 8.36 - 8.35 (m, 1H), 8.25 - 8.23 (m, 1H), 8.04 (s, 1H), 7.43 - 7.36 (m, 1 H), 2.61 (s, 31 1 ) LCMS(ES) m/z - 249.0 [M+Hf.

Reference： [1]Current Patent Assignee: BUCK INSTITUTE FOR RESEARCH ON AGING; NAPA THERAPEUTICS - WO2022/77034, 2022, A1 Location in patent: Paragraph 0348

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

CAS No. :	89793-11-3	MDL No. :	MFCD00117906
Formula :	C₇H₇ClN₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZNPORLVPCMFKOR-UHFFFAOYSA-N
M.W :	186.60 g/mol	Pubchem ID :	2736835
Synonyms :

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	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. 89793-11-3 ]

Quality Control of [ 89793-11-3 ]

Related Doc. of [ 89793-11-3 ]

Product Details of [ 89793-11-3 ]

Safety of [ 89793-11-3 ]

Application In Synthesis of [ 89793-11-3 ]

[ 89793-11-3 ] Synthesis Path-Upstream 1~1

[ 89793-11-3 ] Synthesis Path-Downstream 1~58

Related Functional Groups of
[ 89793-11-3 ]

Chlorides

Esters

Related Parent Nucleus of
[ 89793-11-3 ]

Pyrimidines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

[ CAS No. 89793-11-3 ]

Quality Control of [ 89793-11-3 ]

Related Doc. of [ 89793-11-3 ]

Product Details of [ 89793-11-3 ]

Safety of [ 89793-11-3 ]

Application In Synthesis of [ 89793-11-3 ]

[ 89793-11-3 ] Synthesis Path-Upstream 1~1

[ 89793-11-3 ] Synthesis Path-Downstream 1~58

Related Functional Groups of [ 89793-11-3 ]

Chlorides

Esters

Related Parent Nucleus of [ 89793-11-3 ]

Pyrimidines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 89793-11-3 ]

Related Parent Nucleus of
[ 89793-11-3 ]