Name: 939986-65-9|6-Chloropyrimidine-4-carbonitrile|98%
Brand: Ambeed
SKU: A337001
Rating: 95 (30 reviews)

1
6-hydroxy-pyrimidine-4-carbaldehyde oxime [ No CAS ]
[ 121-69-7 ]
[ 939986-65-9 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; trichlorophosphate;	6-Hydroxy-pyrimidine-4-carbaldehyde oxime (9.3 g, 67 mmol) was stirred in 37 ml POCl3 under N2 at 40 C. for 30 min, 60 C. for 30 min, and 80 C. for one h. N,N,-Dimethylaniline was added very slowly by syringe, and stirred for one h at 80 C. After cooling to 0 C., the mixture was poured into a separatory funnel containing 300 g of ice. The mixture was carefully swirled, then extracted with 500 ml t-BuOMe. The organic layer was washed with 1 N HCl (4*100 ml), then several times with NaHCO3, then brine. Acidic and basic aqueous layers were separately back-extracted with t-BuOMe, and the organics again washed with 1 N HCl, saturated aqueous NaHCO3, and brine. The combined organic layers were dried with Na2SO4 and concentrated by rotary evaporator. The residue was filtered through a pad of silica gel, applying in CH2Cl2 and eluding with 10:1 hexanes/t-BuOMe. Fractions were carefully concentrated to obtain 6-chloro-pyrimidine-4-carbonitrile as a (volatile) pale yellow, semi-crystalline solid.

Reference： [1]Patent: US6878714,2005,B2

2
[ 939986-65-9 ]
[ 1314964-26-5 ]

Yield	Reaction Conditions	Operation in experiment
	With methylamine; In tetrahydrofuran; dichloromethane;	To <strong>[939986-65-9]6-chloro-pyrimidine-4-carbonitrile</strong> (1.37 g, 9.84 mmol) stirring in 10 ml THF under N2 was added a methylamine solution (2.0 M in THF, Aldrich) in aliquots, causing immediate precipitation. Reaction progress was monitored after addition of 5 ml methylamine solution, then 3 ml, then 2 ml. The mixture was concentrated and filtered through a pad of silica, eluding with 2%->5% MeOH in CH2Cl2 to obtain 6-methylamino-pyrimidine-4-carbonitrile as a pale yellow solid. MS: 135.0 (M+1); Calc'd. for C6H6N4-134.14.

Reference： [1]Patent: US6878714,2005,B2

3
[ 939986-65-9 ]
[ 74-89-5 ]
[ 1314964-26-5 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran;	To <strong>[939986-65-9]6-chloro-pyrimidine-4-carbonitrile</strong> (1.37 g, 9.84 mmol) stirring in 10 ml THF under N2 was added a methylamine solution (2.0 M in THF, Aldrich) in aliquots, causing immediate precipitation. Reaction progress was monitored after addition of 5 ml methylamine solution, then 3 ml, then 2 ml. The mixture was concentrated and filtered through a pad of silica, eluting with 2%->5% MeOH in CH2Cl2 to obtain 6-methylamino-pyrimidine-4-carbonitrile as a pale yellow solid. MS: 135.0 (M+1); Calc'd. for C6H6N4 - 134.14.

Reference： [1]Patent: US2003/225106,2003,A1 .Location in patent: Page 97

4
[ 1370442-07-1 ]
[ 939986-65-9 ]

Yield	Reaction Conditions	Operation in experiment
		6-Hydroxy-pyrimidine-4-carbaldehyde oxime (9.3 g, 67 mmol) was stirred in 37 ml POCl3 under N2 at 40 C. for 30 min, 60 C. for 30 min, and 80 C. for one h. N,N,-Dimethylaniline was added very slowly by syringe, and stirredfor one h at 80 C. After cooling to 0 C., the mixture was poured into a separatory funnel containing 300 g of ice. The mixture was carefully swirled, then extracted with 500 ml t-BuOMe. The organic layer was washed with 1 N HCl (4*100 ml), then several times with NaHCO3, then brine. Acidic and basic aqueous layers were separately back-extracted with t-BuOMe, and the organics again washed with 1 N HCl, saturated aqueous NaHCO3, and brine. The combined organic layers were dried with Na2SO4 and concentrated by rotary evaporator. The residue was filtered through a pad of silica gel, applying in CH2Cl2 and eluting with 10:1 hexanes/t-BuOMe. Fractions were carefully concentrated to obtain 6-chloro-pyrimidine-4-carbonitrile as a (volatile) pale yellow, semi-crystalline solid.

Reference： [1]Patent: US2003/225106,2003,A1 .Location in patent: Page 97

5
[ 939986-65-9 ]
[ 1289106-56-4 ]
[ 1289105-78-7 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 100℃; for 2h;	1-[2-(Trifluoromethyl)-1 H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 100 mg, 0.465 mmol), <strong>[939986-65-9]6-chloro-4-pyrimidinecarbonitrile</strong> (Intermediate 8, 97 mg, 0.697 mmol) and DIPEA (0.162 mL, 0.929 mmol) were added together in N-methyl-2-pyrrolidone (2 mL) and the resulting mixture was heated at 100 C for 2 hours and allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by MDAP. Product containing fractions were combined and evaporated under reduced pressure. The resulting solid was dried under high vacuum at 45 C for 18 hours to give the title compound as an off-white solid (32 mg);m/z (ES+) 319 (M+1 ); 1 H NMR (400 MHz, d6-DMSO): delta 12.90 (1 H, bs), 8.65-8.62 (1 H, m), 8.55 (1 H, bs), 8.45 (1 H, bs), 8.08 (1 H, bs), 7.05 (2H, bs), 4.71-4.69 (2H, d).

Reference： [1]Patent: WO2011/45353,2011,A1 .Location in patent: Page/Page column 62-63

6
ethyl 6-hydroxypyrimidine-4-carboxylate [ No CAS ]
[ 939986-65-9 ]

Reference： [1]Patent: WO2011/45353,2011,A1

7
[ 98024-63-6 ]
[ 939986-65-9 ]

Yield	Reaction Conditions	Operation in experiment
		6-Hydroxy-4-pyrimidinecarboxamide (Intermediate 7, 563 mg, 4.05 mmol) was taken up in phosphorus oxychloride (3.9 ml_, 41.8 mmol) and the resulting mixture was heated under reflux for 18 hours. The reaction mixture was allowed to cool to room temperature and evaporated under reduced pressure. The residue was poured into ice cooled water, neutralised with 0.88 ammonia solution and extracted with ethyl acetate (x 3). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20 % ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil (346 mg);1 H NMR (400 MHz, CDCI3): delta 9.15 (1 H, s), 7.74 (1 H, s).

Reference： [1]Patent: WO2011/45353,2011,A1 .Location in patent: Page/Page column 40

8
[ 939986-65-9 ]
[ 1414782-20-9 ]
[ 1414782-35-6 ]

Yield	Reaction Conditions	Operation in experiment
20%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 110℃; for 18h;Inert atmosphere;	General procedure: To an oven-dried round-bottom flask containing tert-butyl 2-[(R)-5-bromo-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate 3 (1.0 mmol) was added bis(pinacolato)diboron (1.1 mmol), potassium acetate (4.0 mmol) and 10 mL of anhydrous 1,4-dioxane. The resulting mixture was purged with N2 for three times. Pd(dppf)Cl2 (0.05 mmol) was added, the reaction mixture was purged with N2 again three times and heated under N2 at 110 C for 46 h. The course of the reaction was followed by TLC (5% MeOH in CH2Cl2) and LCMS. The reaction mixture was cooled to room temperature, and the aryl halide 5 (1.1 mmol)], Pd(dppf)Cl2 (0.05 mmol) and 3.5 mL of 2M aqueous solution of potassium carbonate (de-oxygenated by bubbling through N2 for 15 minutes before addition) were added. The reaction mixture was purged with N2 three times and then heated under N2 for 618 h at 110 C. The course of the reaction was followed by LCMS. The reaction mixture was cooled to room temperature, and the solvent removed under reduced pressure. The residue was partitioned between EtOAc (100 mL) and 1N NaOH solution (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4 and the solvent was removed under reduced pressure to afford the crude product as a dark brown oil. The crude product was purified by silica gel chromatography, eluting with 010% MeOH in CH2Cl2 to afford the desired product.

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 6351 - 6354,4

9
[ 939986-65-9 ]
(R)-1-(6-(aminomethyl)pyrimidin-4-yl)-N-phenylpyrrolidine-3-carboxamide hydrochloride [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

10
[ 939986-65-9 ]
1-(6-(aminomethyl)pyrimidin-4-yl)-N-phenylpiperidine-4-carboxamide hydrochloride [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

11
[ 939986-65-9 ]
(4-(6-(aminomethyl)pyrimidin-4-yl)piperazin-1-yl)(phenyl)methanone hydrochloride [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

12
[ 939986-65-9 ]
4-(6-(aminomethyl)pyrimidin-4-yl)-N-phenylpiperazine-1-carboxamide acetate [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

13
[ 939986-65-9 ]
methyl 3-((6-(aminomethyl)pyrimidin-4-yl)oxy)benzoate acetic acid [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

14
[ 939986-65-9 ]
methyl 3-((6-(((tert-butoxycarbonyl)amino)methyl)pyrimidin-4-yl)oxy)benzoate [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

15
[ 939986-65-9 ]
3-((6-(((tert-butoxycarbonyl)amino)methyl)pyrimidin-4-yl)oxy)benzoic acid [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

16
[ 939986-65-9 ]
methyl 3-(((6-(aminomethyl)pyrimidin-4-yl)(methyl)amino)methyl)benzoate [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

17
[ 939986-65-9 ]
tert-butyl ((6-(3-(phenylcarbamoyl)phenoxy)pyrimidin-4-yl)methyl)carbamate [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

18
[ 939986-65-9 ]
ethyl 2-(5-((6-(((tert-butoxycarbonyl)amino)methyl)pyrimidin-4-yl)oxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

19
[ 939986-65-9 ]
2-(5-((6-(((tert-butoxycarbonyl)amino)methyl)pyrimidin-4-yl)oxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

20
[ 939986-65-9 ]
2-(5-((6-(aminomethyl)pyrimidin-4-yl)oxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid hydrochloride [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

21
[ 939986-65-9 ]
ethyl 2-(5-((6-(aminomethyl)pyrimidin-4-yl)oxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

22
[ 939986-65-9 ]
tert-butyl ((6-((1-(2-hydroxyethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)oxy)pyrimidin-4-yl)methyl)carbamate [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

23
[ 939986-65-9 ]
(5-((6-(aminomethyl)pyrimidin-4-yl)oxy)-1-(2-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one) hydrochloride [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

24
[ 939986-65-9 ]
tert-butyl ((6-((1-(2-(methylsulfonyl)ethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)oxy)pyrimidin-4-yl)methyl)carbamate [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

25
[ 939986-65-9 ]
(R)-methyl1-(6-(aminomethyl)pyrimidin-4-yl)pyrrolidine-3-carboxylate [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

26
[ 939986-65-9 ]
(R)-methyl1-(6-(((tert-butoxycarbonyl)amino)methyl)pyrimidin-4-yl)pyrrolidine-3-carboxylate [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

27
[ 939986-65-9 ]
(R)-1-(6-(((tert-butoxycarbonyl)amino)methyl)pyrimidin-4-yl)pyrrolidine-3-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

28
[ 939986-65-9 ]
(R)-tert-butyl((6-(3-(phenylcarbamoyl)pyrrolidin-1-yl)pyrimidin-4-yl)methyl)carbamate [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

29
[ 939986-65-9 ]
1-(6-(aminomethyl)pyrimidin-4-yl)-N-phenylpiperidine-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

30
[ 939986-65-9 ]
tert-butyl ((6-(4-(phenylcarbamoyl)piperidin-1-yl)pyrimidin-4-yl)methyl)carbamate [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

31
[ 939986-65-9 ]
(4-(6-(aminomethyl)pyrimidin-4-yl)piperazin-1-yl)(phenyl)methanone [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

32
[ 939986-65-9 ]
C₂₁H₂₅FN₄O₅ [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

33
[ 939986-65-9 ]
5-((6-(aminomethyl)pyrimidin-4-yl)oxy)-1-(2-(methylsulfonyl)ethyl)-3,4-dihydroquinolin-2(1H)-one hydrochloride [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

34
[ 939986-65-9 ]
3-((6-(aminomethyl)pyrimidin-4-yl)oxy)-N-phenylbenzamide hydrochloride [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

35
[ 939986-65-9 ]
[ 19438-10-9 ]
methyl 3-((6-cyanopyrimidin-4-yl)oxy)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate; In tetrahydrofuran; at 20℃; for 16h;	To a stirred solution of <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> A-i (500 mg, 3.58 mmol) and methyl 3-hydroxybenzoate (550 mg, 3.62 mmol) in THF (12 ml), was added K2C03 (1.49 g, 10.75 mmol). The reaction mixture was stirred at RT for 16h. The mixture was concentrated under reduced pressure and the residue partitioned between water (100 mL) and DCM (50 mL). The organic layer was separated and the aqueous layer was re-extracted with DCM (20 ml). The combined organic layers were dried (MgSO4), filtered, and then concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 0-60% EtOAc in hexanes), to afford compound A-2 as a yellow solid (890 mg, 97%). LCMS Mass: 256.0 (M+1).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00284

36
[ 939986-65-9 ]
[ 67853-03-6 ]
methyl 3-(((6-cyanopyrimidin-4-yl)oxy)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%		To a stirred solution of <strong>[67853-03-6]methyl 3-(hydroxymethyl)benzoate</strong> (1.31 g, 7.88 mmol) in THF (10 mL) at RT, was added Cs2CO3 (3.8 g, 11.7 mmol) and the mixture stirred for 20 mm. To this was added a solution of 6-chloropyrimidine-4-carbonitrile B-i (750 mg, 7.17 mmol) in THF (15 mL) and the mixture stirred at RT for 16 h. The mixture was partitioned between water (100 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer was re-extracted with EtOAc (20 ml). The combined organic layers were dried (MgSO4), filtered, and then concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 0- 60% EtOAc in hexanes), to afford compound B-2 as an off-white solid (1.01 g, 52%). ?H NMR (300 MHz, DMSO-d6): 8.97 (m, 1H), 8.06 (m, 1H), 7.94 (m, 1H), 7.82 (m, 1H), 7.75 (m, 1H), 7.56 (m, 1H), 5.56 (s, 2H), 3.84 (s, 3H); LCMS Mass: 270.0 (M+1).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00288

37
[ 582-33-2 ]
[ 939986-65-9 ]
ethyl 3-((6-cyanopyrimidin-4-yl)amino)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 20 - 40℃; for 64h;	A mixture of <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> C-i (200 mg, 1.43 mmol), ethyl 3- aminobenzoate (247 mg, 1.65 mmol), DIEA (555 mg, 4.30 mmol), THF (2.5 mL), and DMF (2.5 mL), was stirred at RT for 48 h. Additional <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> C-i (133 mg, 0.95 mmol) and DIEA (369 mg, 2.86 mmol) were added and the mixture heated to 40 C for 16 h. The mixture was partitioned between water (100 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer was re-extracted with EtOAc (20 ml). The combined organic layers were dried (MgSO4), filtered, and then concentrated under reduced pressure. The crude residue was purified (via silica gel; eluting with 0-60% EtOAc in hexanes; followed by trituration with Et20) to afford compound C-2 as a light yellow solid (135 mg, 3 5%). LCMS Mass: 269.0 (M+1).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00292

38
[ 939986-65-9 ]
3-aminomethyl-benzoic acid methyl ester hydrochloride [ No CAS ]
methyl 3-(((6-cyanopyrimidin-4-yl)amino)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 20h;	A mixture of <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> D-1 (200 mg, 1.43 mmol), methyl 3- (aminomethyl)benzoate hydrochloride (333 mg, 1.65 mmol), DIEA (738 mg, 5.72 mmol), and THF (6 mL), was stirred at RT for 18 h. Additional <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> C-i (133 mg, 0.95 mmol) and DIEA (369 mg, 2.86 mmol) were added and the mixture stirred at RT for 2 h. The mixture was concentrated under reduced pressure and the residue partitioned between water (100 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer was re-extracted with EtOAc (20 ml). The combined organic layers were dried (MgSO4), filtered, and then concentrated under reduced pressure. The crude residue was purified (via silica gel; eluting with 0-60% EtOAc in hexanes; followed by trituration with a mixture of Et20 and EtOAc) to afford compound D-2 as a light yellow solid (270 mg, 70%). LCMS Mass: 269.0 (M+1).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00296

39
[ 939986-65-9 ]
3-methylaminomethyl benzoic acid methyl ester hydrochloride [ No CAS ]
methyl 3-(((6-cyanopyrimidin-4-yl)(methyl)amino)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 18h;	A mixture of <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> E-1 (100 mg, 0.717 mmol), 3- methylaminomethyl benzoic acid methyl ester hydrochloride (155 mg, 0.7 17 mmol), DIEA (277 mg, 2.15 mmol), and DMF (1 mL), was stirred at RT for 18 h. The mixture was concentrated under reduced pressure and the residue partitioned between water (50 mL) and EtOAc (10 mL). The organic layer was separated and the aqueous layer was re-extracted with EtOAc (2 x 10 ml). The combined organic layers were dried (Na2SO4), filtered, and then concentrated under reduced pressure. The crude residue was purified (via silica gel; eluting with 0-50% EtOAc in hexanes) to afford compound E-2 as a white solid (143 mg, 7 1%). LCMS Mass: 283.0 (M+1).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00300

40
[ 371-41-5 ]
[ 939986-65-9 ]
6-(4-fluorophenoxy)pyrimidine-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In tetrahydrofuran; at 20℃; for 16h;	A mixture of <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> 1 (50 mg, 0.3 58 mmol), 4-fluorophenol (44 mg, 0.394 mmol), K2C03 (140 mg, 1.0 mmol), and THF (2 mL), was stirred atRT for 16 h. The mixture was concentrated under reduced pressure, and the residue partitioned between water (25 mL) and DCM (25 mL). The organic layer was separated, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified (silica gel; eluting with 0-100% EtOAc in hexanes), to afford compound 2 (77 mg, 100%) as a white solid. LCMS Mass:216.0 (M+1).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00305

41
[ 371-41-5 ]
[ 939986-65-9 ]
(6-(4-fluorophenoxy)pyrimidin-4-yl)methanamine trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

42
[ 939986-65-9 ]
[ 713-68-8 ]
(6-(3-phenoxyphenoxy)pyrimidin-4-yl)methanamine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The free base form of the title compound (1-2) was prepared using the procedure for Example 1, using 3-phenoxyphenol and DMF as solvent in Step 1. The free base was converted to the hydrochloride salt, using 2M HC1 in ether. LCMS Mass: 294.0 (M+1).; A mixture of <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> 1 (50 mg, 0.3 58 mmol), 4-fluorophenol (44 mg, 0.394 mmol), K2C03 (140 mg, 1.0 mmol), and THF (2 mL), was stirred atRT for 16 h. The mixture was concentrated under reduced pressure, and the residue partitioned between water (25 mL) and DCM (25 mL). The organic layer was separated, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified (silica gel; eluting with 0-100% EtOAc in hexanes), to afford compound 2 (77 mg, 100%) as a white solid.

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00307

43
[ 939986-65-9 ]
ethyl 2-(5-hydroxy-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate [ No CAS ]
ethyl 2-(5-((6-cyanopyrimidin-4-yl)oxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With 1-methyl-pyrrolidin-2-one; In tetrahydrofuran; at 20℃; for 12h;	To a stirred solution of compound 4 (200 mg, 0.8 mmol) in N-methyl-2-pyrrolidone (5 mL) were added <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> (123 mg, 0.88 mmol) and K2C03 (222 mg, 1.61 mmol). The mixture was stirred at RT for 12 h. The reaction mixture was diluted with water (20 mL) and stirred vigorously for 10 mm. The obtained solid was filtered and dissolved in CH2C12 (40 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified via trituration with n-pentane (2 x 5 mL) to afford compoundS (187 mg, 66%) as an off white solid. ?HNMR (500 IVIFIz, CDC13): 8.82 (s, 1H), 7.35-7.30 (m, 2H), 6.84 (d, J= 8.1 Hz, 1H), 6.76 (d, J= 8.1 Hz, 1H), 4.69 (s, 2H), 4.25 (q, J = 7.0 Hz, 2H), 2.79-2.74 (m, 2H), 2.71-2.66 (m, 2H), 1.30 (t, J= 7.1 Hz, 3H).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00328

44
[ 939986-65-9 ]
5-hydroxy-1-((6-methoxypyridin-3-yl)methyl)-3,4-dihydroquinolin-2(1H)-one [ No CAS ]
6-((1-((6-methoxypyridin-3-yl)methyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)oxy)pyrimidine-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium carbonate; In N,N-dimethyl-formamide; at 55℃; for 2.5h;	To a stirred solution of compound 3 (100 mg, 0.352 mmol) in DMF (2 mL) were added <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> (54 mg, 0.387 mmol) and K2C03 (146 mg, 1.06 mmol). Themixture was heated at 55 C for 2.5 h. The mixture was cooled to RT and concentrated underreduced pressure. The residue was purified (silica gel; eluting 0 to 100% EtOAc in hexanes), to afford compound 4 (135 mg, 99%) as an off white solid. LCMS Mass: 388.0 (M+1).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00336

45
[ 939986-65-9 ]
5-hydroxy-1-((6-methoxypyridin-3-yl)methyl)-3,4-dihydroquinolin-2(1H)-one [ No CAS ]
5-((6-(aminomethyl)pyrimidin-4-yl)oxy)-1-((6-methoxypyridin-3-yl)methyl)-3,4-dihydroquinolin-2(1H)-one acetate [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

46
[ 939986-65-9 ]
[ 627500-98-5 ]
6-((1-ethyl-1H-indol-4-yl)oxy)pyrimidine-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 2h;	To a stirred mixture of compound 3 (58 mg, 0.358 mmol), 6-chloropyrimidine-4- carbonitrile (50 mg, 0.358 mmol), and DMF (2 mL), was added K2C03 (148 mg, 1.07 mmol). The mixture was heated at 50 C for 2 h. The mixture was cooled to RT and then concentrated under reduced pressure. The residue was purified (silica gel; eluting 0 to 100% EtOAc in hexanes), to afford compound 4 (70 mg, 74%) as an amber oil.

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00345

47
[ 939986-65-9 ]
[ 627500-98-5 ]
(6-((1-ethyl-1H-indol-4-yl)oxy)pyrimidin-4-yl)methanamine acetate [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

48
[ 939986-65-9 ]
2-(4-hydroxy-1H-indol-1-yl)-1-(piperidin-1-yl)ethan-1-one [ No CAS ]
6-((1-(2-oxo-2-(piperidin-1-yl)ethyl)-1H-indol-4-yl)oxy)pyrimidine-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With 1-methyl-pyrrolidin-2-one; potassium carbonate; In tetrahydrofuran; at 150℃; for 12h;Microwave irradiation;	To a stirred solution of compound 3 (130 mg, 0.5 mmol) inN-methyl-2-pyrrolidone (5 mL) were added <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> (70 mg, 0.5 mmol) and K2C03 (139 mg, 1.01 mmol). The reaction mixture was heated in a Biotage microwave synthesizer at 150 C for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAC (2 x 25 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified (silica gel; eluting 30% EtOAc in hexanes), to afford compound 4 (60 mg, 33%) as an off-white solid.?HNMR (500 IVIFIz, DMSO-d6): 8.85 (d, J= 0.9 Hz, 1H), 7.99 (d, J 0.9 Hz, 1H), 7.33-7.25 (m, 2H), 7.14 (t, J 8.0 Hz, 1H), 6.88 (d, J= 7.8 Hz, 1H), 6.17 (d, J= 3.2 Hz, 1H),5.18 (s, 2H), 3.53-3.49 (m, 2H), 3.44-3.40 (m, 2H), 1.63-1.54 (m, 4H), 1.47-1.43 (m, 2H); LCMS Mass: 362.0 (M+1).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00351; 00352

49
[ 939986-65-9 ]
2-(4-hydroxy-1H-indol-1-yl)-N-methyl-N-phenylacetamide [ No CAS ]
2-(4-((6-cyanopyrimidin-4-yl)oxy)-1H-indol-1-yl)-N-methyl-N-phenylacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With 1-methyl-pyrrolidin-2-one; potassium carbonate; at 20℃; for 12h;	j00356j To a stirred solution of compound 3 (1 g, 3.57 mmol) in N-methyl-2-pyrrolidone (2 mL) at RT, were added <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> (55 mg, 3.93 mmol) and K2C03 (986 mg, 7.14 mmol). The mixture was stirred at RT for 12 h. The reaction mixture was diluted with water (40 mL) and extracted with Et20 (2 x 50 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2504, filtered and concentrated under reduced pressure. The residue was purified (silica gel; eluting with 20% EtOAc in Hexanes), to afford compound 4 (1 g, 76%) as pale brown solid. ?H NIVIR (500 MHz, DMSO-d6): 8.84 (s, 1H), 7.98 (s, 1H), 7.61-7.41 (m, 5H), 7.24-7.11 (m, 3H), 6.88 (d, J= 7.5 Hz, 1H), 6.16-6.14 (m, 1H), 4.77 (br s, 2H), 3.19 (br s, 3H); LCMS Mass: 384.0 (M+1).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00356

50
[ 939986-65-9 ]
1-(2-(methylsulfonyl)ethyl)-1H-indol-4-ol [ No CAS ]
6-((1-(2-(methylsulfonyl)ethyl)-1H-indol-4-yl)oxy)pyrimidine-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 12h;	To a stirred solution of compound 4 (260 mg, 1.08 mmol) in DMF (5 mL) at 0 C, were added <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> (303 mg, 2.17 mmol) and Cs2CO3 (706 mg, 2.l7mmol). The reaction mixture was gradually warmed to RT and stirred for an additional 12 h. The reaction mixture was quenched with ice water (25 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified (silica gel; eluting with 45% EtOAc in Hexanes), to afford compound 5 (350 mg, 94%) as pale yellow sticky solid. ?H NIVIR (500 MHz, DMSO-d6): 8.84 (s, 1H), 7.99 (s, 1H), 7.52 (d, J= 8.7 Hz, 1H), 7.43 (d, J 2.9 Hz, 1H), 7.23 (t, J= 8.1 Hz, 1H), 6.94 (d, J= 8.1 Hz, 1H), 6.23 (d, J 3.5 Hz, 1H), 4.64 (t, J 7.0 Hz, 2H), 3.70 (t, J= 7.2 Hz, 2H), 2.93 (s, 3H); LCMS Mass: 342.9 (M+1).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00360

51
[ 939986-65-9 ]
1-((6-methoxypyridin-3-yl)methyl)-1H-indol-5-ol [ No CAS ]
6-((1-((6-methoxypyridin-3-yl)methyl)-1H-indol-5-yl)oxy)pyrimidine-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In N,N-dimethyl-formamide; at 55℃; for 2.5h;	A stirred mixture of compound 4 (100 mg, 0.3 90 mmol), <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> (54 mg, 0.387 mmol), K2C03 (146 mg, 1.05 mmol) and DMF (2 mL), was heated at 55 C for 2.5 h. j00368j The reaction mixture was concentrated under reduced pressure and the residue purified (silica gel; eluting with 0-100% EtOAc in hexanes), to afford compound 5 (140 mg, 100%) as an amber oil. LCMS Mass: 358.0 (M+1).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00367; 00368

52
[ 939986-65-9 ]
1-((6-methoxypyridin-3-yl)methyl)-1H-indol-5-ol [ No CAS ]
(6-((1-((6-methoxypyridin-3-yl)methyl)-1H-indol-5-yl)oxy)pyrimidin-4-yl)methanamine acetate [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

53
[ 939986-65-9 ]
1-((6-methoxypyridin-3-yl)methyl)-2-methyl-1H-indol-4-ol [ No CAS ]
6-((1-((6-methoxypyridin-3-yl)methyl)-2-methyl-1H-indol-4-yl)oxy)pyrimidine-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 7.5h;	A mixture of compound 4 (50 mg, 0.186 mmol), <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> (34 mg, 0.242 mmol), K2C03 (52 mg, 0.373 mmol) and DMF (1 mL), was stirred at RT for 5 h. Additional K2C03 (26 mg, 0.188 mmol) was added and the mixture stirred for a further 2.5 h. The reaction mixture was partitioned between water (10 mL), brine (5 mL), aq 2M HC1 (5 mL), and EtOAc (10 mL). The organic layer was separated, dried over MgSO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified (silica gel; eluting with 0-35% EtOAc in hexanes), to afford compound 5 (69 mg, 100%) as a white solid. ?H NIVIR (300 MHz, DMSO-d6): 8.84 (m, 1H), 7.95 - 7.99 (m, 2H), 7.37 - 7.46 (m, 2H), 7.09 (m, 1H), 6.86 (m, 1H), 6.75 (m, 1H), 6.02 (m, 1H), 5.37 (s, 2H), 3.78 (s, 3H), 2.35 (s, 3H); LCMS Mass: 372.0 (M+1).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00373; 00374

54
[ 939986-65-9 ]
1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-4-ol [ No CAS ]
6-((1-(1-methyl-1H-pyrazol-4-yl)-1H-indol-4-yl)oxy)pyrimidine-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h;	To a stirred solution of compound 3 (55 mg, 0.26 mmol) in DMF (1.5 mL) at RT, were added <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> (36 mg, 0.26 mmol) and K2C03 (71 mg, 0.52 mmol). The mixture was stirred at RT for 16 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2504 and concentrated under reduced pressure. The residue was purified via preparative HPLC (X-Select C-18 5 jiM 19 x 250mm column; eluting with 5-90% ACN/H20 containing 0.05% TFA, over 35 mm), to afford compound 4 (24 mg, 30%) as brown sticky solid. ?HNIVIR (500 IVIHz, DMSO-d6): 8.86 (s, 1H), 8.25 (s, 1H), 8.04 (s, 1H), 7.84 (s, 1H), 7.51 (d, J = 3.2 Hz, 1H), 7.45 (d, J 8.4 Hz, 1H), 7.25 (t, J 8.0 Hz, 1H), 6.99 (d, J= 7.5 Hz, 1H), 6.40 (d, J 3.2 Hz, 1H), 3.92 (s, 3H).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00379

55
[ 939986-65-9 ]
5-hydroxy-1-(2-(methylsulfonyl)ethyl)-3,4-dihydroquinolin-2(1H)-one [ No CAS ]
6-((1-(2-(methylsulfonyl)ethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)oxy)pyrimidine-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With 1-methyl-pyrrolidin-2-one; potassium carbonate; at 20℃; for 12h;	To a stirred solution of compound 3 (80 mg, 0.3 mmol) in N-methyl-2-pyrrolidone (10 mL) at RT, were added K2C03 (82 mg, 0.6 mmol) and <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> (62 mg, 0.45 mmol). The reaction mixture was stirred at RT for 12 h. The mixture was diluted with water (15 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified via trituration with n-pentane (2 x 2 mL) to afford compound 4 (80 mg, 73%) as pale brown solid. ?H NIVIR (500MHz, DMSO-d6): 8.89 (d, J= 0.9 Hz, 1H), 8.00 (d, J= 0.9 Hz, 1H), 7.38 (t, J= 8.1 Hz, 1H), 7.15 (d, J 8.1 Hz, 1H), 6.97 (d, J 8.1 Hz, 1H), 4.32 (t, J 7.2 Hz, 2H), 3.43 (brt, J 7.4 Hz, 2H), 3.09 (s, 3H), 2.66-2.60 (m, 2H), 2.5 1-2.49 (m, 2H); LCMS Mass: 372.9 (M+1).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00399

56
[ 939986-65-9 ]
1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indol-4-ol [ No CAS ]
6-((1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indol-4-yl)oxy)pyrimidine-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With caesium carbonate; In N,N-dimethyl-formamide; at 0℃; for 12h;	To a stirred solution of compound 4 (550 mg, 1.89 mmol) in DMF (15 mL) at 0 C, were added <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> (529 mg, 3.78 mmol) and Cs2CO3 (1.23 g, 3.78 mmol). The reaction mixture was stirred at 0 C for 12 h. The mixture was quenched with ice cold water (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2 SO4, filtered, and concentrated under reduced pressure. The residue was purified (silica gel; eluting with 3-5% EtOAc in hexanes), to afford compound 5 (600 mg, 80%) as pale yellow oil. ?H NIVIR (500MHz, DMSO-d6): 8.86 (d, J= 0.9 Hz, 1H), 7.83 (d, J= 1.2 Hz, 1H), 7.47 (d, J 8.4 Hz, 1H), 7.33 (d, J 3.2 Hz, 1H), 7.17 (t, J 8.0 Hz, 1H), 6.89 (d, J= 7.5 Hz, 1H), 6.17 (d, J 2.9 Hz, 1H), 4.30 (t, J 5.2 Hz, 2H), 3.89 (t, J = 5.2 Hz, 2H), 0.73 (s, 9H), 0.21 (s, 6H); LCMS Mass: 395.1 (M+1).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00406

57
[ 939986-65-9 ]
1-(oxetan-3-yl)-1H-indol-4-ol [ No CAS ]
6-((1-(oxetan-3-yl)-1H-indol-4-yl)oxy)pyrimidine-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With 1-methyl-pyrrolidin-2-one; caesium carbonate; at 20℃; for 12h;Microwave irradiation;	To a stirred solution of compound 3 (55 mg, 0.29 mmol) inN-methyl-2-pyrrolidone (5 mL) at RT, were added <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> (60 mg, 0.43 mmol) and Cs2CO3 (189 mg, 0.58 mmol), and the mixture was stirred for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 15 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified via trituration with n-pentane (2 x 2 mL) to afford compound 4 (55 mg, 65%) as pale brown solid. ?HNMR (500MHz, DMSO-d6): 8.85 (d, J 0.9 Hz, 1H), 8.00 (d, J= 0.9 Hz, 1H), 7.77 (d, J= 3.2 Hz, 1H), 7.56 (d, J 8.4 Hz, 1H), 7.23 (t, J 8.0 Hz, 1H), 6.95 (d, J= 7.5 Hz, 1H), 6.32 (d, J= 3.2 Hz, 1H), 5.86-5.78 (m, 1H), 5.05 (t, J 7.4 Hz, 2H), 4.95 (t, J= 6.7 Hz, 2H); LCMS Mass: 293.0 (M+1).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00411

58
[ 939986-65-9 ]
4-(((tert-butyldimethylsilyl)oxy)methyl)-1H-indole [ No CAS ]
6-(4-(((tert-butyldimethylsilyl)oxy)methyl)-1H-indol-1-yl)pyrimidine-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 72h;	A mixture of indole 2 (300 mg, 1.15 mmol), <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> (180 mg, 1.29 mmol), K2C03 (220 mg, 1.59 mmol), THF (1.5 mL), and DMF (2.5 mL), was stirred atRT for 36 h then heated at 50 C for 36 h. The mixture was partitioned between brine and EtOAc. The organic layer was separated and the aq. further extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified (silica gel; eluting with 0 - 40% EtOAc in Hexanes), to afford compound 3 (88 mg, 21%) as a solid. LCMS Mass: 365.0 (M+1).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00466

59
[ 2380-86-1 ]
[ 939986-65-9 ]
6-((1H-indol-6-yl)oxy)pyrimidine-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With potassium carbonate; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 36h;	A mixture of <strong>[2380-86-1]6-hydroxyindole</strong> 1 (157 mg, 1.18 mmol), 6-chloropyrimidine-4-carbonitrile (150 mg, 1.07 mmol), K2C03 (444 mg, 3.21 mmol), DMF (2 mL), and THF (4 mL), was stirred at RT for 20 h. Additional 6-chloropyrimidine-4-carbonitrile (30 mg, 0.2 15 mmol) was added and the mixture stirred at RT for a further 16 h. The mixture was concentrated under reduced pressure. The residue was purified (silica gel; eluting 0 to 100% EtOAc in hexanes), to afford compound 2 (190 mg, 56%) as a yellow solid. LCMS Mass: 237.0 (M+1).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00338

60
[ 2380-86-1 ]
[ 939986-65-9 ]
(6-((1H-Indol-6-yl)oxy)pyrimidin-4-yl)methanamine [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

61
[ 1953-54-4 ]
[ 939986-65-9 ]
6-((1H-indol-5-yl)oxy)pyrimidine-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With dmap; caesium carbonate; at 50℃; for 16h;	A stirred mixture of 5-hydroxyindole 1 (95 mg, 0.7 17 mmol), 6-chloropyrimidine-4- carbonitrile (100 mg, 0.717 mmol), Cs2CO3 (466 mg, 1.43 mmol), and DMA (3 mL), was heated at 50 C for 16 h. The mixture was cooled to RT, then partitioned between water (30 mL) and EtOAc (15 ml). The organic layer was separated, and the aq. layer re-extracted with additional EtOAc (15 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified (via trituration with 20% MeOH in DCM), to afford compound 2 (95 mg, 56%) as a tan solid. LCMS Mass: 237.0 (M+1).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00340

62
[ 1953-54-4 ]
[ 939986-65-9 ]
(6-((1H-Indol-5-yl)oxy)pyrimidin-4-yl)methanamine [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

63
[ 2380-94-1 ]
[ 939986-65-9 ]
(6-((1H-Indol-4-yl)oxy)pyrimidin-4-yl)methanamine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The title compound (1-19) was prepared using the procedure for Example 17, using 4- hydroxyindole in Step 1. The free base form of the title compound was purified via silica gel (eluting with 1-20% MeOH in DCM) and then converted to the hydrochloride salt, using 2 M HC1 in ether. ?HNIVIR (300 IVIHz, DMSO-d6): 11.35 (s, 1H), 8.57 (s, 1H), 7.30-7.34 (m, 2H), 7.08 - 7.14 (m, 2H), 6.79 (m, 1H), 6.05 (m, 1H), 3.73 (s, 2H); LCMS Mass: 241.0 (M+1).; A mixture of 6-hydroxyindole 1 (157 mg, 1.18 mmol), <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> (150 mg, 1.07 mmol), K2C03 (444 mg, 3.21 mmol), DMF (2 mL), and THF (4 mL), was stirred at RT for 20 h. Additional <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> (30 mg, 0.2 15 mmol) was added and the mixture stirred at RT for a further 16 h. The mixture was concentrated under reduced pressure. The residue was purified (silica gel; eluting 0 to 100% EtOAc in hexanes), to afford compound 2 (190 mg, 56%) as a yellow solid. To a stirred solution of compound 2 (40 mg, 0.169 mmol) in EtOAc (3 mL) and HOAc (0.3 mL) at RT, was added 10% Pd/C (10 mol%). The reaction mixture was stirred at RT under hydrogen (1 atmosphere pressure) for 1 h. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The residue was purified via preparative HPLC (Waters XTerra Prep MS C-18 OBD 5 jiM 50 x 100mm column; eluting with 10-90% ACN/H20 containing 0.1% TFA, over 20 mm), followed by silica gel (eluting 0 to 100% EtOAc in hexanes), to afford compound 1-17 (3 mg, 7%) as a solid.

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00338; 00339; 00342

64
[ 939986-65-9 ]
[ 81382-45-8 ]
(6-((1H-indazol-4-yl)oxy)pyrimidin-4-yl)methanamine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The title compound (1-60) was prepared using the procedure for Example 17, using 4- hydroxy- 1H-indazole in Step 1. The free base form of the title compound was purified via silica gel (eluting with 1-20% MeOH in DCM) and then converted to the hydrochloride salt, using 2 M HC1 in ether. ?H NIVIR (300 IVIHz, DMSO-d6): 8.78 (s, 1H), 8.60 (br s, 3H), 7.77 (s, 1H), 7.48 (m, 1H), 7.35-7.45 (m, 2H), 6.94(m, 1H), 4.10-4.20(m, 2H).; A mixture of 6-hydroxyindole 1 (157 mg, 1.18 mmol), 6-chloropyrimidine-4-carbonitrile (150 mg, 1.07 mmol), K2C03 (444 mg, 3.21 mmol), DMF (2 mL), and THF (4 mL), was stirred at RT for 20 h. Additional 6-chloropyrimidine-4-carbonitrile (30 mg, 0.2 15 mmol) was added and the mixture stirred at RT for a further 16 h. The mixture was concentrated under reduced pressure. The residue was purified (silica gel; eluting 0 to 100% EtOAc in hexanes), to afford compound 2 (190 mg, 56%) as a yellow solid. LCMS Mass: 237.0 (M+1).To a stirred solution of compound 2 (40 mg, 0.169 mmol) in EtOAc (3 mL) and HOAc (0.3 mL) at RT, was added 10% Pd/C (10 mol%). The reaction mixture was stirred at RT under hydrogen (1 atmosphere pressure) for 1 h. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The residue was purified via preparative HPLC (Waters XTerra Prep MS C-18 OBD 5 jiM 50 x 100mm column; eluting with 10-90% ACN/H20 containing 0.1% TFA, over 20 mm), followed by silica gel (eluting 0 to 100% EtOAc in hexanes), to afford compound 1-17 (3 mg, 7%) as a solid. ?H NIVIR (300 IVIFIz, MeOH-d4): 8.76 (m, 1H), 7.61 (m, 1H), 7.29 (m, 1H), 7.18 (m, 1H), 6.94 (m, 1H), 6.80 (m, 1H), 6.49 (m, 1H), 4.22 (s, 2H); LCMS Mass: 241.0 (M+1).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00338; 00339; 00423

65
[ 939986-65-9 ]
[ 709608-85-5 ]
6-(4-(hydroxymethyl)-1H-indazol-1-yl)pyrimidine-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 0.416667h;	A solution of <strong>[709608-85-5]4-(hydroxymethyl)-1H-indazole</strong> 1 (233 mg, 1.57 mmol), 6-chloropyrimidine-4-carbonitrile (200 mg, 1.43 mmol), and DMF (4 mL) was added dropwise at RT to NaH (57 mg of a 60% dispersion in mineral oil, 1.43 mmol). The mixture was stirred at RT for 25 mm. The mixture was partitioned between aq HC1, brine, and EtOAc. The organic layer was separated, dried (Na2504), filtered, and concentrated under reduced pressure. The residue was purified (silica gel; eluting 0 to 100% EtOAc in hexanes), to afford compound 2 (162 mg, 45%) as a yellow solid. LCMS Mass: 252.0 (M+1).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00424

66
[ 939986-65-9 ]
[ 709608-85-5 ]
(1-(6-(aminomethyl)pyrimidin-4-yl)-1H-indazol-4-yl)methanol hydrochloride [ No CAS ]

Reference： [1]Patent: WO2017/3862,2017,A1

67
[ 939986-65-9 ]
[ 75-75-2 ]
[ 61468-43-7 ]
5-((6-(aminomethyl)pyrimidin-4-yl)oxy)-3,4-dihydroquinolin-2(1H)-one methanesulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The title compound (1-101) was prepared using the procedure for Example 17, using 5- hydroxy-3,4-dihydro-2-(1H)-quinoline in Step 1. The free base form of the title compound was purified via silica gel (eluting with 0-20% MeOH in DCM) and then converted to the methanesulfonate salt, using methanesulfonic acid in DCM. LCMS Mass: 271.0 (M+1).; A mixture of 6-hydroxyindole 1 (157 mg, 1.18 mmol), <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> (150 mg, 1.07 mmol), K2C03 (444 mg, 3.21 mmol), DMF (2 mL), and THF (4 mL), was stirred at RT for 20 h. Additional <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> (30 mg, 0.2 15 mmol) was added and the mixture stirred at RT for a further 16 h. The mixture was concentrated under reduced pressure. The residue was purified (silica gel; eluting 0 to 100% EtOAc in hexanes), to afford compound 2 (190 mg, 56%) as a yellow solid. To a stirred solution of compound 2 (40 mg, 0.169 mmol) in EtOAc (3 mL) and HOAc (0.3 mL) at RT, was added 10% Pd/C (10 mol%). The reaction mixture was stirred at RT under hydrogen (1 atmosphere pressure) for 1 h. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The residue was purified via preparative HPLC (Waters XTerra Prep MS C-18 OBD 5 jiM 50 x 100mm column; eluting with 10-90% ACN/H20 containing 0.1% TFA, over 20 mm), followed by silica gel (eluting 0 to 100% EtOAc in hexanes), to afford compound 1-17 (3 mg, 7%) as a solid.

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00338; 00339; 00472

68
[ 939986-65-9 ]
[ 874964-22-4 ]
(R)-methyl1-(6-cyanopyrimidin-4-yl)pyrrolidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 1.5h;	A mixture of 6-chloropyrimidine-4-carbonitrile (250 mg, 1.79 mmol), methyl (3R)- pyrrolidine-3-carboxylate hydrochloride 1 (356 mg, 2.15 mmol), K2C03 (495 mg, 3.58 mmol), DCM (6 mL), and DMF (4 mL) was stirred at RT for 1.5 h. The mixture was concentrated under reduced pressure. The residue was partitioned between water, brine, and EtOAc. The organic layer was separated and the aqueous layer re-extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure to afford compound 2 (402 mg, 97%) as a white solid. ?H NIVIR (300 IVIHz, DMSO-d6):8.54 (s, 1H), 7.24 (m, 1H), 3.35 - 3.80 (m, 8H), 2.05 - 2.35 (m, 2H); LCMS Mass: 233.0 (M+1).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00473

69
[ 939986-65-9 ]
[ 73415-54-0 ]
1-(6-cyanopyrimidin-4-yl)-N-phenylpiperidine-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium carbonate; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 16h;	A mixture of <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> (153 mg, 1.10 mmol), Nphenylpiperidine-4-carboxamide hydrochloride 1 (221 mg, 0.914 mmol), K2C03 (253 mg, 1.83 mmol), THF (5 mL), and DMF (4 mL) was stirred at RT for 16 h. The mixture was concentrated under reduced pressure. The residue was partitioned between water, brine, and EtOAc. The organic layer was separated and the aqueous layer re-extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure to afford compound 2 (274 mg, 81%) as a white solid. LCMS Mass:308.0 (M+1).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00479

70
[ 939986-65-9 ]
[ 56227-55-5 ]
6-(4-benzoylpiperazin-1-yl)pyrimidine-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 16h;	A mixture of <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> (120 mg, 0.859 mmol), 1- benzoylpiperazine hydrochloride 1 (221 mg, 0.919 mmol), K2C03 (237 mg, 1.78 mmol), DIEA (221 mg, 1.78 mmol) THF (3 mL), and DMF (3 mL) was stirred at RT for 16 h. The mixture was concentrated under reduced pressure. The residue was partitioned between water, brine, and EtOAc. The organic layer was separated and the aqueous layer re-extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure to afford compound 2 (243 mg, 97%) as a light yellow solid. ?HNMR (300 MFIz, DMSO-d6): 8.58 (m, 1H), 7.57 (m, 1H), 7.40-7.50 (m, 5H), 3.60- 3.90 (br m, 6H), 3.30 - 3.50 (br m, 2H); LCMS Mass: 294.0 (M+1).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00483

71
[ 939986-65-9 ]
[ 474711-91-6 ]
4-(6-cyanopyrimidin-4-yl)-N-phenylpiperazine-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With potassium carbonate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 16h;	A mixture of <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> (120 mg, 0.859 mmol), Nphenylpiperazine-1-carboxamide hydrochloride 1 (228 mg, 0.944 mmol), K2C03 (237 mg, 1.78mmol), DIEA (221 mg, 1.78 mmol) THF (3 mL), and DMF (3 mL) was stirred at RT for 16 h.The mixture was concentrated under reduced pressure. The residue was partitioned between water, brine, and EtOAc. The organic layer was separated and the aqueous layer re-extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure to afford compound 2 (253 mg, 96%) as a light yellow solid. ?HNMR (300 MFIz, DMSO-d6): 8.62 (m, 1H), 8.58 (m, 1H), 7.62 (m, 1H), 7.41 - 7.48 (m, 2H), 7.20- 7.26 (m, 2H), 6.93 (m, 1H), 3.65 -3.80 (br m, 4H), 3.50 -3.60 (m, 4H); LCMS Mass: 309.0 (M+1).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00486

72
[ 939986-65-9 ]
(S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperidin-4-yl)methanone 1R-(-)-camphor-10-sulphonic acid salt [ No CAS ]
(S)-6-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperidin-1-yl)pyrimindine-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 2h;Sealed tube;	To a suspension of (S)-(5 -(3,5 -difluorophenyl)-4,5-dihydro- 1H-pyrazol- 1 -yl)(piperidin-4- yl)methanone, 1R-(-)-camphor-10-sulphonic acid salt (300 mg, 0.57 mmol) in MeCN (30mL) was added <strong>[939986-65-9]6-chloropyrimindine-4-carbonitrile</strong> (80 mg, 0.57 mmol) and DIPEA (0.25 mL,1.43 mmol) The vessel was sealed and heated at 80C for 2 h. The reaction minxture was evaporated in vacuo. This residue was purified by normal phase column chromatography [CyHI(EtOAc/EtOH 3:1) 100/0 to 70/301. A trituration into iPr2O afforded, after filtration, (S)-6-(4-(5 -(3 ,5-difluorophenyl)-4,5 -dihydro- 1H-pyrazole- 1 -carbonyl)piperidin- 1-yl)pyrimindine-4-carbonitrile (130 mg, 0.33 mmol, purity: 100 %, recovery: 58 %) as a light yellow powder. LCMS (m/z) 397 (M+H), retention time: 2.48 min LC/MS Method 1. ?H NMR (400 min-Tz, DMSO-d6) delta ppm 8.54 (s, 1H), 7.57 (s, 1H), 7.26 (s, 1H), 7.12 (tt, J9.4, 2.1 Hz, 1H), 6.84 (d, J=6.5 Hz, 2H), 5.34 (dd, J=12.0, 4.9 Hz, 1H), 4.47 (br.s, 2H), 3.49 (ddd, J=19.0, 12.0, 1.0 Hz, 1H), 3.43 (tt, J=11.4, 3.7 Hz, 1H), 3.13 (brs, 2H), 2.75 (ddd, J19.2,4.9, 1.5 Hz, 1H), 1.95 (d, J=12.7 Hz, 1H), 1.81 (d, J=12.7 Hz, 1H), 1.48 (m, 2H).

Reference： [1]Patent: WO2018/92089,2018,A1 .Location in patent: Page/Page column 136

73
[ 939986-65-9 ]
(S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperidin-4-yl)methanone,((1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate salt [ No CAS ]
(S)-6-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperidin-1-yl)pyrimindine-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
130 mg	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 2h;Sealed tube;	To a suspension of (S)-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazol-l-yl)(piperidin-4- yl)methanone, lR-(-)-camphor-10-sulphonic acid salt (300 mg, 0.57 mmol) in MeCN (30 mL) was added <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> (80 mg, 0.57 mmol) and DIPEA (0.25 mL, 1.43 mmol) The vessel was sealed and heated at 80C for 2 h. The reaction mixture was evaporated in vacuo. This residue was purified by normal phase column chromatography [CyH/(EtOAc/EtOH 3: 1) 100/0 to 70/30]. A trituration into PnO afforded, after filtration (S)-6-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l- carbonyl)piperidin-l-yl)pyrimidine-4-carbonitrile (130 mg, 0.33 mmol, purity: 100 %, recovery: 58 %) as a light yellow powder. LCMS (m/z) 397 (M+H)+, retention time: 2.48 min, LC/MS Method 1. NMR (400 MHz, DMSO- 6) delta ppm 8.54 (s, IH), 7.57 (s, IH), 7.26 (s, IH), 7.12 (tt, J=9.4, 2.1Hz, IH), 6.84 (d, J=6.5 Hz, 2H), 5.34 (dd, J=12.0, 4.9 Hz, IH), 4.47 (br.s, 2H), 3.49 (ddd, J=19.0, 12.0, 1.0 Hz, IH), 3.43 (tt, J=11.4, 3.7 Hz, IH), 3.13 (br s, 2H), 2.75 (ddd, J=19.2, 4.9, 1.5 Hz, 1H), 1.95 (d, J=12.7 Hz, 1H), 1.81 (d, J=12.7 Hz, 1H), 1.48 (m, 2H).

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 5096 - 5110
[2]Patent: WO2018/154520,2018,A1 .Location in patent: Page/Page column 120; 121

74
[ 939986-65-9 ]
1-Phenyl-pentylideneamine; hydrochloride [ No CAS ]
C₁₅H₁₈ClN₃ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2020,vol. 142,p. 468 - 478

75
[ 939986-65-9 ]
(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-trans-(3-methylpiperidin-4-yl)methanone [ No CAS ]
6-(trans-4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-methylpiperidin-1-yl)pyrimidine-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	A mixture of give (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-trans-(3- methylpiperidin-4-yl)methanone (1.4 g, 4.6 mmol), <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> (1.0 g, 7.3 mmol) and K2CO3 (1.3 g, 9.1 mmol) in DMF (20 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was diluted with DCM (150 mL) and filtered. The filtrate was concentrated and the resulting residue was purified by silica gel column chromatography (2.5-10% MeOH in DCM) to give the 6-(trans-4-(5-(3,5- difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3-methylpiperidin-1-yl)pyrimidine-4- carbonitrile (1.34 g, 72% yield) as a yellow gel. MS (m/z) 411 (M+H)+. The racemate was separated via chiral HPLC separation using IC-H Column to provide 6- ((3R,4S)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- methylpiperidin-1-yl)pyrimidine-4-carbonitril and 6-((3R,4S)-4-((S)-5-(3,5-difluorophenyl)- 4,5-dihydro-1H-pyrazole-1-carbonyl)-3-methylpiperidin-1-yl)pyrimidine-4-carbonitrile and 6-((3S,4R)-4-((R)-5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)-3- methylpiperidin-1-yl)pyrimidine-4-carbonitrile and 6-((3S,4R)-4-((S)-5-(3,5-difluorophenyl)- 4,5-dihydro-1H-pyrazole-1-carbonyl)-3-methylpiperidin-1-yl)pyrimidine-4-carbonitrile. The first isomer was afforded as a solid (270 mg, 20% yield). Chiral HPLC Anal. Method 22, retention time: 9.536 min, % ee = 100%. The second isomer was afforded as a solid (240 mg, 18% yield). Chiral HPLC Anal. Method 22, retention time: 11.061 min, % ee = 99.7%. The third isomer was afforded as a solid (260 mg, 19% yield). Chiral HPLC Anal. Method 22, retention time: 14.190 min, % ee = 99.7%. The fourth isomer was afforded as a solid (230 mg, 17% yield). Chiral HPLC Anal. Method 22, retention time: 17.474 min, % ee = 98.9%.

Reference： [1]Patent: WO2019/224773,2019,A1 .Location in patent: Page/Page column 187-190

76
[ 939986-65-9 ]
(4-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl)methanamine [ No CAS ]
6-((4-(5-ethyl-1,2,4-oxadiazol-3-yl)benzyl)amino)pyrimidine-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 160℃; for 1.5h;Microwave irradiation; Sealed tube;	[0202] To a mixture of (4-(5-Ethyl-l,2,4-oxadiazol-3-yl)phenyl)methanamine (50 mg, 0.25 mmol, 1.0 equiv) and IPA (3 mL) in a microwave vial were added 6-chloropyrimidine- 4-carbonitrile (41 mg, 0.30 mmol, 1.2 equiv) and DIPEA (103 uL, 0.59 mmol, 2.4 equiv). The vial was sealed and heated at 160 C in a microwave reactor for 90 min. The mixture was concentrated and purified by RP-HPLC (Phenomenex, gemini 5u C18 150 x 21.2 mm, 10-100% ACN/water both with 0.1% formic acid gradient over 40 min) to provide 23 mg (31%) of 6-((4-(5-ethyl-l,2,4-oxadiazol-3-yl)benzyl)amino)pyrimidine-4-carbonitrile as a white solid. LRMS (ES) m/z 307.2 (M+H). 1 H-NMR (Methanol-^, 400 MHz, ppm) d 8.49 (s, 1H), 8.02 (d, J = 7.9 Hz, 2H), 7.49 (d, J = 7.8 Hz, 2H), 6.96 (s, 1H), 4.72 (s, 2H), 3.10- 2.88 (m, 2H), 1.43 (t, 7 = 7.6 Hz, 2H).

Reference： [1]Patent: WO2020/5888,2020,A1 .Location in patent: Paragraph 0202

77
[ 939986-65-9 ]
(5-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-2-yl)methanamine [ No CAS ]
6-(((5-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-2-yl)methyl)amino)pyrimidine-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 160℃; for 0.5h;Microwave irradiation; Sealed tube;	[0206] To a mixture of (5-(5-Methyl-l,2,4-oxadiazol-3-yl)pyridin-2-yl)methanamine (50 mg, 0.26 mmol, 1.0 equiv) and IPA (3 mL) in a microwave vial were added 6-chloro-4- cyanopyrimidine (44 mg, 0.32 mmol, 1.2 equiv) and DIPEA (110 uL, 0.63 mmol, 2.4 equiv). The vial was sealed and heated at 160 C in a microwave reactor for 30 min. The mixture was concentrated and purified by reverse phase HPLC (Phenomenex, gemini 5u C18 150 x 21.2 mm, 10-100% ACN in water both with 0.1% formic acid gradient over 40 min) to provide 8.5 mg (11%) of 6-(((5-(5-methyl-l,2,4-oxadiazol-3-yl)pyridin-2- yl)methyl)amino)pyrimidine-4-carbonitrile as a white solid. LRMS (ES) m/z 294.2 (M+H). 1H-NMR (Methanol-

Reference： [1]Patent: WO2020/5888,2020,A1 .Location in patent: Paragraph 0206

78
[ 939986-65-9 ]
C₁₅H₂₀N₂O₂ [ No CAS ]
C₂₀H₂₁N₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 80 - 100℃; for 18h;	Compound 8 (800 mg, crude) was added to a DMF (8 ml) solution, then DBU (912 mg, 6 mmol) was added, and compound 9 (<strong>[939986-65-9]6-chloro-4-pyrimidinecarbonitrile</strong>) (552 mg, 4 mmol) was added. The reaction was performed at 80 C. After 6 hours, TLC showed that a large amount of the starting compound 8 remained, and then compound 9 (<strong>[939986-65-9]6-chloro-4-pyrimidinecarbonitrile</strong>) (276 mg, 2 mmol) was added. The reaction temperature was raised to 100 C for 12 hours, and the reaction solution was poured into Water was extracted with dichloromethane. The organic phases were combined, washed with water, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The residue was spin-dried and passed through a silica gel column (mobile phase: PE: EA = 3: 1) to obtain a crude product. Further, the compound I (also referred to as "compound NHWD-1062") is prepared through a high-performance liquid phase.MS (ESI) m / z: 364.4 (M + H +). 1HNMR (400MHz, CDCl3) 8.6 (s, 1H), 7.2-7.4 (m, 5H), 6.8 (s, 1H), 5.4 (m, 1H) , 4.3 (m, 2H), 3.9 (m, 1H), 3.1-3.2 (m, 3H), 2.8 (m, 1H), 2.4 (m, 1H), 2.1 (m, 1H), 1.7-1.9 (m , 3H), 1.3 (m, 1H).

Reference： [1]Patent: CN110872285,2020,A .Location in patent: Paragraph 0123; 0140-0143

79
[ 939986-65-9 ]
(S)-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(piperidin-4-yl)methanone 1R-(-)-camphor-10-sulphonic acid salt [ No CAS ]
(S)-6-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carbonyl)piperidin-1-yl)pyrimindine-4-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 2h;Sealed tube;	To a suspension of (S)-(5-(3, 5-difluorophenyl)-4, 5-dihydro- lH-pyrazol-l-yl)(piperidin-4- yl)methanone, lR-(-)-camphor-lO-sulphonic acid salt (300 mg, 0.57 mmol) in MeCN (30 mL) was added <strong>[939986-65-9]6-chloropyrimidine-4-carbonitrile</strong> (80 mg, 0.57 mmol) and DIPEA (0.25 mL, 1.43 mmol) The vessel was sealed and heated at 80C for 2 h. The reaction mixture was evaporated in vacuo. This residue was purified by normal phase column chromatography [CyH/(EtOAc/EtOH 3: 1) 100/0 to 70/30] A trituration into /PnO afforded, after filtration, (S)-6-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l- carbonyl)piperidin-l-yl)pyrimidine-4-carbonitrile (130 mg, 0.33 mmol, purity: 100 %, recovery: 58 %) as a light yellow powder. LCMS (m/z) 397 (M+H)+, retention time: 2.48 min, LC/MS Method 1. 'HNMR (400 MHz, DMSO- 6) d ppm 8.54 (s, 1H), 7.57 (s, 1H), 7.26 (s, 1H), 7.12 (tt, J=9.4, 2.1 Hz, 1H), 6.84 (d, J=6.5 Hz, 2H), 5.34 (dd, J=l2.0, 4.9 Hz, 1H), 4.47 (br.s, 2H), 3.49 (ddd, J=l9.0, 12.0, 1.0 Hz, 1H), 3.43 (tt, J=l 1.4, 3.7 Hz, 1H), 3.13 (br s, 2H), 2.75 (ddd, J=l9.2, 4.9, 1.5 Hz, 1H), 1.95 (d, J=l2.7 Hz, 1H), 1.81 (d, J= 12.7 Hz, 1H), 1.48 (m, 2H).

Reference： [1]Patent: WO2020/44206,2020,A1 .Location in patent: Page/Page column 114; 116; 117

80
[ 939986-65-9 ]
[ 892493-65-1 ]
tert-butyl 1-(6-cyanopyrimidin-4-yl)piperidine-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In acetonitrile at 120℃; for 2.5h; Inert atmosphere;	I-39a: Tert-butyl 1-(6-cyanopyrimidin-4-yl)piperidine-4-carboxylate Tert-butyl piperidine-4-carboxylate hydrochloride (1.000 g) was dissolved in dry ACN (10 ml). At RT DIPEA (3.7 ml) and 6-chloropyrimidine-4-carbonitrile (629.4 mg) were added and the mixture was heated at 120°C for 2.5 hunder argon. After cooling the solvent was removed in vacuo. The residue thus obtained was dissolved in a mixture of water and DCM, the phases were separated and the aqueous phase was extracted with DCM (3x). The combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (25 g; 0 % to 80 % EA in heptane in 9 min). The compound containing fractions were combined and the solvent was removed in vacuo to yield 906 mg of the title compound. LC/MS: m/z = 289.2 [M+H]+; tR: 1.46 min (LC/MS-method D)
	With N-ethyl-N,N-diisopropylamine In acetonitrile at 120℃; for 2.5h; Inert atmosphere;	I-39a: Tert-butyl 1-(6-cyanopyrimidin-4-yl)piperidine-4-carboxylate Tert-butyl piperidine-4-carboxylate hydrochloride (1.000 g) was dissolved in dry ACN (10 ml). At RT DIPEA (3.7 ml) and 6-chloropyrimidine-4-carbonitrile (629.4 mg) were added and the mixture was heated at 120°C for 2.5 hunder argon. After cooling the solvent was removed in vacuo. The residue thus obtained was dissolved in a mixture of water and DCM, the phases were separated and the aqueous phase was extracted with DCM (3x). The combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (25 g; 0 % to 80 % EA in heptane in 9 min). The compound containing fractions were combined and the solvent was removed in vacuo to yield 906 mg of the title compound. LC/MS: m/z = 289.2 [M+H]+; tR: 1.46 min (LC/MS-method D)

Reference： [1]Current Patent Assignee: SANOFI - WO2021/245070, 2021, A1 Location in patent: Page/Page column 177-178
[2]Current Patent Assignee: SANOFI - WO2021/245070, 2021, A1 Location in patent: Page/Page column 177-178

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CAS No. :	939986-65-9	MDL No. :	MFCD09607731
Formula :	C₅H₂ClN₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	AJRPBTWNTZPVSO-UHFFFAOYSA-N
M.W :	139.54	Pubchem ID :	22498881
Synonyms :

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Precautionary Statements-General
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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. 939986-65-9 ] {[proInfo.proName]}

Quality Control of [ 939986-65-9 ]

Related Doc. of [ 939986-65-9 ]

Product Details of [ 939986-65-9 ]

Safety of [ 939986-65-9 ]

Application In Synthesis of [ 939986-65-9 ]

[ 939986-65-9 ] Synthesis Path-Upstream 1~3

[ 939986-65-9 ] Synthesis Path-Downstream 1~80

Related Functional Groups of
[ 939986-65-9 ]

Chlorides

Nitriles

Related Parent Nucleus of
[ 939986-65-9 ]

Pyrimidines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

[ CAS No. 939986-65-9 ] {[proInfo.proName]}

Quality Control of [ 939986-65-9 ]

Related Doc. of [ 939986-65-9 ]

Product Details of [ 939986-65-9 ]

Safety of [ 939986-65-9 ]

Application In Synthesis of [ 939986-65-9 ]

[ 939986-65-9 ] Synthesis Path-Upstream 1~3

[ 939986-65-9 ] Synthesis Path-Downstream 1~80

Related Functional Groups of [ 939986-65-9 ]

Chlorides

Nitriles

Related Parent Nucleus of [ 939986-65-9 ]

Pyrimidines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 939986-65-9 ]

Related Parent Nucleus of
[ 939986-65-9 ]