[ CAS No. 1005-38-5 ] {[proInfo.proName]}

Name: 1005-38-5|4-Amino-6-chloro-2-(methylthio)pyrimidine|95%
Brand: Ambeed
SKU: A132073
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Quality Control of [ 1005-38-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1005-38-5 ]

SDS Specification

Alternatived Products of [ 1005-38-5 ]

Product Details of [ 1005-38-5 ]

CAS No. :	1005-38-5	MDL No. :	MFCD00006088
Formula :	C₅H₆ClN₃S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ISUXMAHVLFRZQU-UHFFFAOYSA-N
M.W :	175.64	Pubchem ID :	70496
Synonyms :

Calculated chemistry of [ 1005-38-5 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.2
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	43.17
TPSA :	77.1 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.19 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.64
Log Po/w (XLOGP3) :	1.66
Log Po/w (WLOGP) :	1.44
Log Po/w (MLOGP) :	0.19
Log Po/w (SILICOS-IT) :	1.42
Consensus Log Po/w :	1.27

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.35
Solubility :	0.78 mg/ml ; 0.00444 mol/l
Class :	Soluble
Log S (Ali) :	-2.89
Solubility :	0.225 mg/ml ; 0.00128 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.4
Solubility :	0.693 mg/ml ; 0.00394 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.04

Safety of [ 1005-38-5 ]

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:

Application In Synthesis of [ 1005-38-5 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 1005-38-5 ]
Downstream synthetic route of [ 1005-38-5 ]

[ 1005-38-5 ] Synthesis Path-Upstream 1~6

1
[ 6299-25-8 ]
[ 1005-38-5 ]

Yield	Reaction Conditions	Operation in experiment
97.77%	With ammonia In tetrahydrofuran at 50 - 60℃; Autoclave	[00230] Reagents[00231] Experimental procedure:.bul. ; Take ammonia in THF into a 2 L autoclave and add 4, 6-dichloro-2-(Methylthio) pyrimidine slowly..bul. Heat the reaction mixture to 50-60 ° C and maintain the reaction at 50-60 °C for 3-4 hours (Inbuilt pressure 7- 8 Kg/cm )..bul. Check the progress of the reaction by TLC. Upon completion, the reaction was brought to 25-35 ° C..bul. Concentrate the reaction mixture under vacuum..bul. Charge Hexane and stir for 30-45 minutes at 25-35 ° C..bul. Filter the solid and wash the solid with Hexane..bul. Wash the solid with water (2X400 mL)..bul. Dry the solid at 25-35 °C till M.C reaches to less than 2percent.Yield 352.0 gpercent of Yield: 97.77percent.Purity by HPLC: 99.07percent.Other suitable conditions such as ammonia in MeOH or dioxane could be used accordingly when different analogs are used. Example 1- 2. Preparation of 4-Amino-6-chloro-2- meth lthio)pyrimidine, 6.1
66%	With ammonia In water; butan-1-ol at 20 - 80℃; for 0.5 h;	4,6-Dichloro-2-(methylthio)pyrimidine (10 g, 51 mmol) was dissolved in a mixtureButanol/NH₄OH (100 ml/50 ml). It was stirred for V₂ h in a sealed tube (internal pressure 42 PSI) heated to 8O⁰C. After cooling to RT, the organic layer was separated, dried over MgSO₄ and concentrated. 6.0 g (66percent) of the desired intermediate was obtained as a colourless solid; mlz (ES⁺) 175, 177 (MH⁺).

Reference： [1] Patent: WO2011/97594, 2011, A2, . Location in patent: Page/Page column 100-101
[2] Chemistry - A European Journal, 1999, vol. 5, # 12, p. 3450 - 3458
[3] Patent: WO2007/141571, 2007, A2, . Location in patent: Page/Page column 25
[4] American Chemical Journal, 1904, vol. 32, p. 353
[5] Patent: US2005/288502, 2005, A1, . Location in patent: Page/Page column 20
[6] Patent: US4199583, 1980, A,
[7] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 1, p. 42 - 46

2
[ 1074-41-5 ]
[ 1005-38-5 ]

Yield	Reaction Conditions	Operation in experiment
83%	for 1 h; Reflux	General procedure: 2-Alkylthio-4-amino-6-hydroxylpyrimidine (2a,b) (27 mmol), POCl₃ (15 mL, 162 mmol), and PhNMe₂ (6.8 mL, 54 m mol) were refluxed together for 1 h. The excess POCl₃ was removed in vacuo, and then the residue was poured into 60 mL (1:1, v/v) of cooled concentrated ammonium hydroxide and chloroform. The solution was kept stirring at room temperature. After POCl₃ was dissolved completely, the aqueous phase was extracted with CHCl₃ (3.x.20 mL), the combined organic phases were dried with MgSO₄, concentrated, and purified by flash column chromatography (Et₃N-neutralized silica gel, gradient elution separation with EtOAc/P.E., 1:50-1:2, v/v) and then by recrystallization from cyclohexane to afford the product as colorless crystals.

Reference： [1] Tetrahedron, 2011, vol. 67, # 29, p. 5156 - 5161
[2] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 19, p. 6336 - 6352
[3] Phosphorus, Sulfur and Silicon and the Related Elements, 2012, vol. 187, # 5, p. 650 - 659

3
[ 1074-41-5 ]
[ 1005-38-5 ]

Reference： [1] Journal of the Chemical Society, 1944, p. 678
[2] Journal of Organic Chemistry, 1954, vol. 19, p. 631,635

4
[ 6299-25-8 ]
[ 7664-41-7 ]
[ 1005-38-5 ]

Reference： [1] American Chemical Journal, 1904, vol. 32, p. 353

5
[ 7664-41-7 ]
[ 1005-38-5 ]
[ 1004-38-2 ]

Reference： [1] American Chemical Journal, 1904, vol. 32, p. 353

6
[ 1005-38-5 ]
[ 1431-40-9 ]

Reference： [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 23, p. 10080 - 10100

[ 1005-38-5 ] Synthesis Path-Downstream 1~88

1
[ 6299-25-8 ]
[ 1005-38-5 ]

Yield	Reaction Conditions	Operation in experiment
97.77%	With ammonia; In tetrahydrofuran; at 50 - 60℃; under 5149.01 - 5884.58 Torr;Autoclave;	[00230] Reagents[00231] Experimental procedure:.bul. ; Take ammonia in THF into a 2 L autoclave and add 4, 6-dichloro-2-(Methylthio) pyrimidine slowly..bul. Heat the reaction mixture to 50-60 ° C and maintain the reaction at 50-60 °C for 3-4 hours (Inbuilt pressure 7- 8 Kg/cm )..bul. Check the progress of the reaction by TLC. Upon completion, the reaction was brought to 25-35 ° C..bul. Concentrate the reaction mixture under vacuum..bul. Charge Hexane and stir for 30-45 minutes at 25-35 ° C..bul. Filter the solid and wash the solid with Hexane..bul. Wash the solid with water (2X400 mL)..bul. Dry the solid at 25-35 °C till M.C reaches to less than 2percent.Yield 352.0 gpercent of Yield: 97.77percent.Purity by HPLC: 99.07percent.Other suitable conditions such as ammonia in MeOH or dioxane could be used accordingly when different analogs are used. Example 1- 2. Preparation of 4-Amino-6-chloro-2- meth lthio)pyrimidine, 6.1
66%	With ammonia; In water; butan-1-ol; at 20 - 80℃; under 2172.08 Torr; for 0.5h;	4,6-Dichloro-2-(methylthio)pyrimidine (10 g, 51 mmol) was dissolved in a mixtureButanol/NH4OH (100 ml/50 ml). It was stirred for V2 h in a sealed tube (internal pressure 42 PSI) heated to 8O0C. After cooling to RT, the organic layer was separated, dried over MgSO4 and concentrated. 6.0 g (66percent) of the desired intermediate was obtained as a colourless solid; mlz (ES+) 175, 177 (MH+).
	With ammonia; In water; isopropyl alcohol; at 100℃; for 15h;	Ammonium hydroxide (50 mL) was added to a solution of 4,6-dicloro-2-methylsulfanyl-pyrimidine (1.9 g, 9.7 mmol) in isopropanol (20 mL) in a sealed tube and the resulting mixture was heated to 100° C. for 15 h. The mixture was brought to RT, poured into water and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried and concentrated under vacuum to provide a white solid. MS m/z 176 (MH)+.

With ammonium hydroxide; In ethanol; water; Petroleum ether;

Part C--4-Amino- 6-chloro-2-(methylthio)pyrimidine A reaction mixture consisting of 124.7 g. (0.64 mole) 4,6-dichloro-2-(methylthio)pyrimidine (prepared as in Part B, above), 500 ml. ethanol, and 250 ml. of substantially saturated aqueous ammonia was heated, with stirring, at 100° C. in an autoclave for 6 hrs. After cooling the reaction mixture, water was added, and a precipitate formed. The precipitate was collected on a filter, and recrystallized from a mixture of ether and petroleum ether to give 40 g. of the desired 4-amino-6-chloro-2-(methylthio)pyrimidine having a melting point at 130° to 131° C.

Reference： [1]Patent: WO2011/97594,2011,A2 .Location in patent: Page/Page column 100-101
[2]Chemistry - A European Journal,1999,vol. 5,p. 3450 - 3458
[3]Patent: WO2007/141571,2007,A2 .Location in patent: Page/Page column 25
[4]American Chemical Journal,1904,vol. 32,p. 353
[5]Patent: US2005/288502,2005,A1 .Location in patent: Page/Page column 20
[6]Patent: US4199583,1980,A
[7]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 42 - 46

2
[ 110-89-4 ]
[ 1005-38-5 ]
[ 96225-84-2 ]

Reference： [1]Journal of Organic Chemistry,1954,vol. 19,p. 1793,1798

3
[ 1005-38-5 ]
[ 124-40-3 ]
[ 52222-40-9 ]

Yield	Reaction Conditions	Operation in experiment
73%	In methanol; at 80℃; for 18h;	6-chloro-2-(methylthio)pyrimidin-4-amine (3.98g, 22.7mmol) is added to a solution of dimethylamine (2.0M in methanol, 2OmL). The mixture is heated to 8O0C for 18h. The reaction is allowed to cool, the precipitate is collected, washed with ethanol, (3.1g, 73percent)

Reference： [1]Patent: WO2009/22185,2009,A2 .Location in patent: Page/Page column 32
[2]Journal of Organic Chemistry,1954,vol. 19,p. 631,635

4
[ 1005-38-5 ]
[ 109-89-7 ]
[ 99182-45-3 ]

Reference： [1]Heterocycles,1985,vol. 23,p. 611 - 616
[2]Journal of Organic Chemistry,1954,vol. 19,p. 1793,1798

5
[ 1005-38-5 ]
[ 62-53-3 ]
2-methylsulfanyl-N⁴-phenyl-pyrimidine-4,6-diyldiamine [ No CAS ]

Reference： [1]American Chemical Journal,1905,vol. 34,p. 190

6
[ 1005-38-5 ]
[ 62-53-3 ]
N²,N⁴-diphenyl-pyrimidine-2,4,6-triyltriamine [ No CAS ]

Reference： [1]American Chemical Journal,1905,vol. 34,p. 190
[2]American Chemical Journal,1905,vol. 34,p. 190

7
[ 1005-38-5 ]
[ 74-89-5 ]
[ 96225-63-7 ]

Reference： [1]Journal of Organic Chemistry,2016,vol. 81,p. 3780 - 3789
[2]Journal of the Chemical Society,1943,p. 383,384
Journal of the Chemical Society,1944,p. 318,321

8
[ 1005-38-5 ]
[ 100-61-8 ]
[ 108481-08-9 ]

Reference： [1]Journal of Organic Chemistry,1954,vol. 19,p. 1793,1798

9
[ 108-24-7 ]
[ 1005-38-5 ]
[ 38897-12-0 ]

Yield	Reaction Conditions	Operation in experiment
	at 135℃; for 5h;Heating / reflux;	Acetic anhydride (10.4 MI, 0. 11 MOL) was added to 6-chloro-2- (methylthio) pyrimidin-4-amine (2.5 g, 0.01 mol) and the reaction mixture was refluxed at 135 °C for 5 hr. The reaction mixture was cooled to room temperature and basified to pH 7 with saturated sodium bicarbonate solution (20 ML). The mixture was partitioned between EtOAc and water, the organic layer was washed with water and brine, dried over MgS04 and concentrated to give the title compound (2.62 g). MS (ES . : 218 (MH+) for C7HGCINO3S

Reference： [1]Heterocycles,1985,vol. 23,p. 611 - 616
[2]Patent: WO2005/26149,2005,A1 .Location in patent: Page/Page column 86

10
[ 27467-92-1 ]
[ 1005-38-5 ]
[ 81587-41-9 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1982,vol. 30,p. 302 - 318

11
[ 4083-64-1 ]
[ 1005-38-5 ]
[ 133030-35-0 ]

Reference： [1]Australian Journal of Chemistry,1991,vol. 44,p. 129 - 134

12
[ 33761-31-8 ]
[ 1005-38-5 ]
[ 81587-39-5 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1982,vol. 30,p. 302 - 318

13
[ 1005-38-5 ]
[ 16182-04-0 ]
[ 133030-34-9 ]

Reference： [1]Australian Journal of Chemistry,1991,vol. 44,p. 129 - 134

14
[ 1005-38-5 ]
[ 74619-77-5 ]

Reference： [1]Heterocycles,1985,vol. 23,p. 611 - 616

15
[ 1005-38-5 ]
[ 66380-47-0 ]

Yield	Reaction Conditions	Operation in experiment
94.9%	With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 4h;	To a stirred solution of 10.0 g (57.2 mmol) of 6-chloro-2-(methylthio)pyrimidine-4-amine in 300 ml of dichloromethane were added during 30 minutes a solution of 15.3 g (68.6 mmol) of m-chloroperbenzoic acid (77 percent ) (Aldrich) dissolved in 200 ml of DCM. The reaction mixture was stirred at room temperature for 4 hours. The white precipitate formed was filtered, washed several times with DCM and then after drying gave 10.4 g (94.9 percent) of the intermediate 1.1H-RMN (300 MHz, DMSO-d6): 8 = 3.28 (s, 3H), 6.64 (s, 1H), 8.1 1 (s, 2H).
1 g	With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 4h;	To a solution of 1.0 g (5.7 mmol) of 6-chloro-2- (methylthio) pyrimidin-4-amine in 50 mL of methylene chloride was added 1.5 g (6.9 mmol) M-chloroperbenzoic acid (77percent) solution.The reaction mixture was stirred for 4 hours at room temperature.The resulting white precipitate was filtered, washed with methylene chloride several times, dried,1.0 g of intermediate (F) was obtained

Reference： [1]Patent: WO2011/121418,2011,A1 .Location in patent: Page/Page column 24
[2]Heterocycles,1985,vol. 23,p. 611 - 616
[3]Patent: CN107286146,2017,A .Location in patent: Paragraph 0139; 0142-0144

17
ammonium hydroxide [ No CAS ]
[ 1005-38-5 ]
[ 1005-39-6 ]

Reference： [1]American Chemical Journal,1905,vol. 34,p. 190

18
[ 7726-95-6 ]
[ 1005-38-5 ]
[ 63931-22-6 ]

Reference： [1]American Chemical Journal,1905,vol. 34,p. 190

20
[ 6299-25-8 ]
[ 7664-41-7 ]
[ 1005-38-5 ]

Reference： [1]American Chemical Journal,1904,vol. 32,p. 353

21
4-oxy-2-methylsulfanyl-6-amino-pyrimidine [ No CAS ]
[ 1005-38-5 ]

Reference： [1]American Chemical Journal,1905,vol. 34,p. 190

22
[ 1074-41-5 ]
[ 1005-38-5 ]

Yield	Reaction Conditions	Operation in experiment
83%	With N,N-dimethyl-aniline; trichlorophosphate; for 1h;Reflux;	General procedure: 2-Alkylthio-4-amino-6-hydroxylpyrimidine (2a,b) (27 mmol), POCl3 (15 mL, 162 mmol), and PhNMe2 (6.8 mL, 54 m mol) were refluxed together for 1 h. The excess POCl3 was removed in vacuo, and then the residue was poured into 60 mL (1:1, v/v) of cooled concentrated ammonium hydroxide and chloroform. The solution was kept stirring at room temperature. After POCl3 was dissolved completely, the aqueous phase was extracted with CHCl3 (3.x.20 mL), the combined organic phases were dried with MgSO4, concentrated, and purified by flash column chromatography (Et3N-neutralized silica gel, gradient elution separation with EtOAc/P.E., 1:50-1:2, v/v) and then by recrystallization from cyclohexane to afford the product as colorless crystals.

Reference： [1]Tetrahedron,2011,vol. 67,p. 5156 - 5161
[2]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 6336 - 6352
[3]Phosphorus, Sulfur and Silicon and the Related Elements,2012,vol. 187,p. 650 - 659

23
[ 1005-38-5 ]
4-amino-2-methylsulfanyl-6-[2-(phosphonomethoxy)ethoxy]pyrimidine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2002,vol. 45,p. 1918 - 1929

24
[ 1005-38-5 ]
[ 99357-36-5 ]

Reference： [1]Journal of the Chemical Society,1943,p. 383,384
Journal of the Chemical Society,1944,p. 318,321
[2]Journal of Organic Chemistry,2016,vol. 81,p. 3780 - 3789

25
[ 1005-38-5 ]
[ 858798-64-8 ]

Reference： [1]Journal of the Chemical Society,1943,p. 383,384
Journal of the Chemical Society,1944,p. 318,321

26
[ 1005-38-5 ]
N⁶-ethyl-N⁴,N⁴-dimethyl-2-methylsulfanyl-pyrimidine-4,6-diyldiamine [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1954,vol. 19,p. 631,635

27
[ 1005-38-5 ]
[ 856971-81-8 ]

Reference： [1]Journal of Organic Chemistry,1954,vol. 19,p. 631,635

28
resin bound 3-[4-(3,5-dichloropyrid-4-ylcarboxamido)phenyl]-2-diazopropanoic acid [ No CAS ]
[ 1005-38-5 ]
3-[4-(3,5-dichloropyrid-4-ylcarboxamido)phenyl]-2-[4-chloro-2-(methylthio)pyrimidin-6-yl amino]propanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 124 3-[4-(3,5-Dichloropyrid-4-ylcarboxamido)phenyl]-2-[4-chloro-2-(methylthio)pyrimidin-6-yl amino]propanoic acid 6-Amino-4-chloro-2-(methylthio)pyrimidine gave the title compound (1.4mg) HPLC-MS Retention time 2.63 min; MH+ 512.

Reference： [1]Patent: US6348463,2002,B1 .Location in patent: Page column 50

29
[ 1177479-05-8 ]
[ 1005-38-5 ]
6-[3-(2-methoxy-phenyl)-2,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-2-methylsulfanyl-pyrimidin-4-ylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 115℃; for 12h;	A 25 mL round-bottomed flask was charged with 50 mg of crude amine (0.22 mmol, [1] equivalent), 46 mg of 6-chloro-2-methylsulfanyl- pyrimidin-4-yl amine (0.26 mmol, 1.2 equiv), 50 mg of [K2CO3] and 5 mL of dimethyl formamide. The reaction mixture was stirred at [115 °C] for 12 hours and quenched with 10 [ML] of water. The resulting slurry was extracted with 2 x 20 mL of ethyl acetate. The organic layers were combined and concentrated to a oil which was purified by silica gel chromatography [(CH2C12] to EtOAc to [ETOH)] yielding 23 mg of compound [I-7] as a white solid (0.062 mmol, 24 percent [YIELD).APOS;H] NMR (500 MHz, CDC13) [8] 7.33 (1 H, d, J = 7 Hz), 7.26 [(1] [H,] [T, T = 8 HZ),] 6.99 [(1 H,] t, J = 7 Hz), 6.95 [(1 H,] d, [J = 8 HZ),] 5.34 [(1 H,] s), 4.83 (2 H, br s), 4.63 (2 H, br s), 3.90 (2 H, m), 3.86 (3 H, s), 2.37 (3 H, s) ppm. FIA MS: 369.2 [(M+H)] [HPLC] : Rt = 2.731 min. purity >95percent.

Reference： [1]Patent: WO2003/101989,2003,A1 .Location in patent: Page 28

30
[ 696-59-3 ]
[ 1005-38-5 ]
[ 321330-23-8 ]

Yield	Reaction Conditions	Operation in experiment
	In acetic acid;Heating / reflux;	According to Scheme 20, <strong>[1005-38-5]4-amino-6-chloro-2-methylthiopyrimidine</strong> 151 was reacted with 1 equivalent of 2,5-dimethoxytetrahydrofuran in refluxing acetic acid to provide 6-chloro-2-methylthio-4-(1-pyrrolyl)pyrimidine 152: 1H NMR (CDCl3) delta2.75 (s,3H), 6.55 (d,2H), 7.05 (s,1H), 7.65 (d,2H).

Reference： [1]Patent: US2003/229092,2003,A1 .Location in patent: Page 32; 33

31
[ 1005-38-5 ]
[ 73874-95-0 ]
[ 848498-96-4 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In 1-methyl-pyrrolidin-2-one; at 150℃; for 1.5h;Microwave;	TEA (0.243 ML, 1.74 mmol) and 6-CHLORO-2-(METHYLTHIO) pyrimidin-4-amine (0.309 g, 1.74 mmol) were added to a solution of tert-butyl piperidin-4-ylcarbamate (0.35 g, 1.74 mmol) in NMP (4 ML). Using a Smith Microwave Synthesizer, the mixture was subjected to single- mode microwave at 150 °C for 90 minutes. The mixture was partitioned between water and EtOAc and washed (x2) with water. The organic phase was dried over magnesium sulphate and concentrated to give the title compound (0.294 g). MS (ES) (MH+) : 340 for CL6H26N402S

Reference： [1]Patent: WO2005/26149,2005,A1 .Location in patent: Page/Page column 87

32
[ 107-20-0 ]
[ 1005-38-5 ]
[ 872059-27-3 ]

Yield	Reaction Conditions	Operation in experiment
60%	In N,N-dimethyl-formamide; at 100℃;	Referring to Scheme 1, 4-amino-6-chloro-2-(methylthio)-pyrimidine (1.0 g, 5.7 mmol) and chloroacetaldehyde (2 ml, 14.2 mmol) were mixed in DMF (5 ml). The solution was stirred overnight at 100° C. DMF was removed in vacuo and the residue was purified by flash chromatography with 1:10 MeOH:DCM to leave 7-chloro-5-(methylthio)imidazo[1,2-f]pyrimidine as a brown solid (68 mg, 60percent). 1H NMR (400 MHz, CD3OD) delta 7.93 (s, 1H) 7.74 (d, J=1.5 Hz, 1H) 7.62 (s, 1H) 3.27 (s, 3H). [M+H] calc'd for C7H6ClN3S, 200; found, 200.
	In ethanol; for 2.5h;Heating / reflux;	A mixture of 6-chloro-2-methylsulfanyl-pyrimidin-4-ylamine (0.9 g, 5.14 mmol) and chloroacetaldehyde (6.5 mL, 51.4 mmol) in ethanol (10 mL) was heated to reflux for 2.5 h and brought to RT. The mixture was concentrated and the residue obtained was dissolved in dichloromethane, washed with saturated NaHCO3, brine, dried, concentrated and purified by column chromatography chromatography on silica gel using 0-4percent MeOH/CH2Cl2 to give as a white solid. MS m/z 200 (MH)+.

Reference： [1]Patent: US2006/84650,2006,A1 .Location in patent: Page/Page column 87
[2]Patent: US2005/288502,2005,A1 .Location in patent: Page/Page column 20
[3]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 42 - 46

33
[ 110-91-8 ]
[ 7440-44-0 ]
[ 1005-38-5 ]
[ 96225-91-1 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; hexane; benzene;	EXAMPLE 35 A mixture of 5.2 g (0.02 mole) of <strong>[1005-38-5]4-amino-6-chloro-2-methylthiopyrimidine</strong> and 5.3 g (0.06 mole) of morpholine in 40 ml of ethanol was heated at reflux for fifteen hours. The mixture was then cooled and evaporated. The residue thereby obtained was diluted with water and extracted with dichloromethane. The extracts were dried over magnesium sulfate to provide a residue which was recrystallized with treatment with decolorizing charcoal from a benzene/hexane mixture to provide 4-amino-2-methylthio-6-(4-morpholino)pyrimidine, m.p. 125°-128° C. The structural assignment was supported by nuclear magnetic resonance spectral analysis.

Reference： [1]Patent: US4503050,1985,A

34
[ 109-01-3 ]
[ 1005-38-5 ]
[ 96225-86-4 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 37 Using the method of Example 35, 4-methyl-piperazine was reacted with 4-amino-6-chloro-2-methylthio-pyrimidine to provide white solid 4-amino-6-[1-(4-methyl-piperazino)]-2-methylthiopyrimidine, m.p. 165°-167° C. The structural assignment was supported by infrared and nuclear magnetic resonance spectral analyses.

Reference： [1]Patent: US4503050,1985,A

35
[ 123-90-0 ]
[ 1005-38-5 ]
[ 96225-88-6 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 36 Using the method of Example 35, thiomorpholine was reacted with <strong>[1005-38-5]4-amino-6-chloro-2-methylthiopyrimidine</strong> to provide 4-amino-2-methylthio-6-(4-thiomorpholino)pyrimidine as a yellow solid, m.p. 144°-145° C. The structural assignment was supported by nuclear magnetic resonance spectral analysis.

Reference： [1]Patent: US4503050,1985,A

36
[ 1005-38-5 ]
[ 1423-26-3 ]
[ 932046-86-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In toluene; for 10h;Heating / reflux;Product distribution / selectivity;	Example 11: 4-(3,3,4-Trimethyl-4-oxy-piperazin-1-yl)-6-(3-trifluoromethyl-phenyl)- pyrimidine-2-carbonitrile A: 2-Methylsulfanyl-6-(3-trifluoromethylphenyl)-pyrimidin-4-ylamine To a stirred solution of <strong>[1005-38-5]4-amino-6-chloro-2-methylthiopyrimidine</strong> (3.5 g) in toluene (45 ml.) under a nitrogen atmosphere was added, sequentially, 3-(trifluoro- methyl)phenylboronic acid (4.15 g), potassium carbonate (25 ml_, 2M) and tetrakis- (triphenylphosphine)palladium(O) (1.16 g). The mixture was heated to reflux for ten hours. Ethyl acetate (15OmL) was added and the mixture washed with water (2 x 100 ml_). Organic layer was separated, washed with saturated sodium chloride (100 ml_), dried over sodium sulphate and solvent was evaporated under reduced pressure to yield crude product. Purification by flash chromatography yielded product 2-methyl- sulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-ylamine (3.45 g) 1H NMR (CDCI3): delta 8.25 (s, 1 H), 8.19 (d, 1 H), 7.70 (d, 1 H), 7.58 (t, 1 H), 6.56 (s, 1 H), 4.92 (s, 2H), 2.61 (s, 3H). MS m/z: 286.3 (M+1 ).
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; at 20℃;Heating / reflux;Product distribution / selectivity;	To a stirred solution of <strong>[1005-38-5]4-amino-6-chloro-2-methylthiopyrimidine</strong> (3.5 g) in toluene (45 mL) under a nitrogen atmosphere was added, sequentially, 3-(trifluoromethyl)phenylboronic acid (4.15 g), potassium carbonate (25 mL, 2M) and tetrakis(triphenylphosphine)palladium(0) (1.16 g). The mixture was heated to reflux for ten hours. Ethyl acetate (150 mL) was added and the mixture washed with water (2.x.100 mL). Organic layer was separated, washed with saturated sodium chloride (100 mL), dried over sodium sulphate and solvent was evaporated under reduced pressure to yield crude product. Purification by flash chromatography yielded product 2-methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-ylamine (3.45 g) 1H NMR (CDCl3): delta 8.25 (s, 1H), 8.19 (d, 1H), 7.70 (d, 1H), 7.58 (t, 1H), 6.56 (s, 1H), 4.92 (s, 2H), 2.61 (s, 3H). MS m/z: 286.3 (M+1).; A: 2-Methylsulfanyl-6-(3-trifluoromethylphenyl)-pyrimidin-4-ylamine To a stirred solution of <strong>[1005-38-5]4-amino-6-chloro-2-methylthiopyrimidine</strong> (3.5 g) in toluene (45 mL) under a nitrogen atmosphere was added, sequentially, (3-trifluoromethylphenyl)boronic acid (4.15 g), potassium carbonate (25 mL, 2M) and tetrakis(triphenylphosphine)palladium(0) (1.16 g). The mixture was heated to reflux for ten hours and stirred at room temperature over the weekend. Ethyl acetate (150 mL) was added and the mixture washed with water (2.x.100 mL). Organics were separated, washed with saturated sodium chloride (100 mL), dried over sodium sulphate and solvent was evaporated under reduced pressure to yield crude product. Purification by flash chromatography yielded product 2-methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-ylamine (3.45 g) 1H NMR (CDCl3): 8.25 (s, 1H), 8.19 (d, 1H), 7.70 (d, 1H), 7.58 (t, 1H), 6.56 (s, 1H), 4.92 (s, 2H), 2.61 (s, 3H). MS m/z 286.3 (M+1).

Reference： [1]Patent: WO2007/39470,2007,A1 .Location in patent: Page/Page column 19; 24
[2]Patent: US2007/111992,2007,A1 .Location in patent: Page/Page column 11; 13

37
[ 1005-38-5 ]
[ 372-09-8 ]
[ 1067232-90-9 ]

Reference： [1]Acta Crystallographica, Section C: Crystal Structure Communications,2008,vol. 64,p. o149-o154
[2]Tetrahedron Letters,2008,vol. 49,p. 5672 - 5675

38
[ 4198-90-7 ]
[ 1005-38-5 ]
[ 1039021-97-0 ]

Yield	Reaction Conditions	Operation in experiment
		step 1-Sodium hydride (1 mmol, 60percent in oil) was added portion wise to a solution of 70 in NMP at RT and the resulting solution was stirred for 10 min. To the sodium phenoxide solution was added 96 (1 mmol) and the resulting mixture was stirred for 30 h at 150° C. After the reaction was complete, the reaction was partitioned between EtOAc and H2O and the water phase was extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and the solvent was evaporated to afford 98a as an oil which was used in the next step without further purification.

Reference： [1]Patent: US2008/146595,2008,A1 .Location in patent: Page/Page column 28

39
[ 431-37-8 ]
[ 1005-38-5 ]
[ 1059191-44-4 ]

Yield	Reaction Conditions	Operation in experiment
45%	In N,N-dimethyl-formamide; at 120℃; for 16h;	Example 21A; 7-Chloro-5-(methylthio)-2-(trifluoromethyl)imidazo[1,2-c]pyrimidine 5 g (28.5 mmol) of 6-chloro-2-(methylthio)pyrimidine-4-amine and 6.26 g (42.7 mmol) of 3-chloro-1,1,1-trifluoropropanone are dissolved in 200 ml of DMF and heated at 120° C. for 16 h. After the reaction is complete, water is added and the mixture is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulphate and the product is purified by silica gel chromatography. Drying under high vacuum results in 3.5 g (45percent of theory) of the product as a solid.LCMS (method 5): Rt=3.40 min. (m/z=268 (M+H)+)1H-NMR (400 MHz, DMSO-d6): delta=8.65 (s, 1H), 7.75 (s, 1H), 2.78 (s, 3H).

Reference： [1]Patent: US2010/113441,2010,A1 .Location in patent: Page/Page column 30

40
[ 7252-83-7 ]
[ 1005-38-5 ]
[ 872059-27-3 ]

Yield	Reaction Conditions	Operation in experiment
66%	In 1,4-dioxane; water; for 24h;Reflux;	Example 9A; 7-Chloro-5-(methylthio)imidazo[1,2-c]pyrimidine 75 g (427 mmol) of 4-amino-6-chloro-2-(methylthio)pyrimidine are dissolved in 3000 ml of dioxane and 750 ml of water. 101.05 g (597.81 mmol) of bromoacetaldehyde dimethyl acetal are added, and the mixture is heated under reflux for 24 h. After the reaction is complete, the dioxane is removed in vacuo and the aqueous suspension is suspended in THF, filtered with suction and washed with some THF. Drying of the solid at 40° C. under high vacuum results in 56.5 g (66percent of theory) of the product.MS (ES+): m/z=200 (M+H)+.1H-NMR (400 MHz, DMSO-d6): delta=8.12 (s, 1H), 7.97 (s, 1H), 7.77 (s, 1H), 2.80 (s, 3H).

Reference： [1]Patent: US2010/113441,2010,A1 .Location in patent: Page/Page column 27

41
[ 1005-38-5 ]
[ 534-07-6 ]
[ 1059191-49-9 ]

Yield	Reaction Conditions	Operation in experiment
49%	With acetic acid; at 105℃; for 16h;	Example 26A; 7-Chloro-2-(chloromethyl)-5-(methylthio)imidazo[1,2-c]pyrimidine 8 g (45.5 mmol) of 6-chloro-2-(methylthio)pyrimidine-4-amine and 5.78 g (45.55 mmol) of 1,3-dichloroacetone are dissolved in 53 ml of glacial acetic acid and heated at 105° C. for 16 h. After the reaction is complete, water is added and the precipitate is filtered off with suction. The crude product is further purified by silica gel chromatography. Drying under high vacuum results in 5.53 g (49percent of theory) of product.LCMS (method 4): Rt=3.33 min. (m/z=248 (M+H)+)1H-NMR (400 MHz, DMSO-d6): delta=7.99 (s, 1H), 7.58 (s, 1H), 4.85 (s, 2H), 2.76 (s, 3H).
44%	With acetic acid; at 110℃; for 16h;	1,3-Dichloroacetone (2.89 g, 22.77 mmol) was added to a solution 6-chloro-2- methylsulfanyl-pyrimidin-4-ylamine (4 g, 22.77 mmol) in AcOH (15 mL) and the mixture was stirred at 110 °C for 16 hours. Then H20 was added and the solid formed was filtered off and dried in vacuo to yield 7-chloro-2-chloromethyl-5-methylsulfanyl-imidazo[l,2- c]pyrimidine (2.5 g, 44percent yield) as a pale brown solid that was used in the next step without further purification.
	With acetic acid; at 110℃; for 16h;	1,3-Dichloroacetone (2.89 g, 22.77 mmol) was added to a solution 6-chloro-2-methylsulfanyl-pyrimidin-4-ylamine (4 g, 22.77 mmol) in AcOH (15 mL) and the mixture was stirred at 110° C. for 16 hours. Then H2O was added and the solid formed was filtered off and dried in vacuo to yield 7-chloro-2-chloromethyl-5-methylsulfanyl-imidazo[1,2-c]pyrimidine (2.5 g, 44percent yield) as a pale brown solid that was used in the next step without further purification.

Reference： [1]Patent: US2010/113441,2010,A1 .Location in patent: Page/Page column 31
[2]Patent: WO2012/125732,2012,A1 .Location in patent: Page/Page column 187
[3]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 1310 - 1317
[4]Patent: US2013/245043,2013,A1 .Location in patent: Paragraph 505; 506

42
[ 877874-79-8 ]
[ 1005-38-5 ]
[ 76-05-1 ]
C₂HF₃O₂*C₂₀H₁₆F₃N₇OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		4-(5-[3-(trifluromethyl)phenyl]amino}-4F-l,2,4-triazol-3-yl)phenol (100 mg, 0.31 mmol) was dissolved in 3 mL of anhydrous dioxane in 2-5 mL microwave vial (Personal Chemistry). Solid CS2CO3 (101.7 mg, 0.31 mmol) was added, followed by 4-amino-6-chloro-2-(methylthio)-pyrimidine (60.3 mg, 0.34 mmol). The vial was capped and microwaved at 200 °C for 10 min. Then ca. 3 mL of MeOH was added to dissolve the formed suspension. The resulting reddish-brown solution was transferred into a round-bottom flask and solvent was removed in vacuo. The residue was re-dissolved in 3 mL of DMF, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetontrile/water system with 0.01percent of TFA. The fractions, containing the product, were collected and partitioned between EtOAc and saturated aqueous NaHC03. Ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title compound as a white solid (39.5 mg).; ESI-MS: [M+H]+,461.0. lR NMR (DMSO-d6): 5 3.80 (s, 3H), 5.53 (s, 1H), 6.70 (s, 2H), 6.30 (s, 2H), (d, J= 8.6 Hz, 2H),

Reference： [1]Patent: WO2006/24034,2006,A1 .Location in patent: Page/Page column 96-97

43
[ 1005-38-5 ]
[ 1314704-89-6 ]

Reference： [1]Tetrahedron,2011,vol. 67,p. 5156 - 5161

44
[ 1005-38-5 ]
[ 1314704-90-9 ]

Reference： [1]Tetrahedron,2011,vol. 67,p. 5156 - 5161

45
[ 1005-38-5 ]
[ 629-19-6 ]
[ 1314704-84-1 ]

Yield	Reaction Conditions	Operation in experiment
81%	With copper(l) chloride; isopentyl nitrite; In acetonitrile; at 20 - 60℃; for 2h;Inert atmosphere;	General procedure: Compound 3a or 3b (5.85 mmol) was added into the dry acetonitrile (35 mL) containing appropriate dialkyl(aryl) disulfide (40.95 mmol) and CuCl (0.29 m mol). The mixture was purged thoroughly with N2 and stirred at room temperature for 30 min. Isoamyl nitrite (4.25 g, 36.3 mmol) was added to the solution immediately, the reaction was stirred for 30 min at room temperature, and then the mixture was heated at 60 °C. The reaction time was listed in Table 2. The disappearance of the starting material was monitored by TLC (EtOAc/P.E., 1:10, v/v). After removing CuCl, the solvent and other volatiles were removed under reduced pressure. The residue was purified by column chromatography (Et3N-neutralized silica gel, gradient elution separation with EtOAc/P.E., 1:40-1:20, v/v) to afford the product as colorless or yellow oil.

Reference： [1]Tetrahedron,2011,vol. 67,p. 5156 - 5161

46
[ 24424-99-5 ]
[ 1005-38-5 ]
[ 309256-03-9 ]
[ 1052714-60-9 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; potassium carbonate; In tetrahydrofuran; at 25 - 35℃;	6.1[00232] Reagents:[00233]; Experimental procedure; .bul. Charge 4-Amino-6-chloro-2-(methylthio)pyrimidine and THF into a clean and dry round bottom flask at 25-35 °C..bul. Add K2C03 lot wise at 25-35 ° C in 5-10 minutes..bul. Add Boc anhydride slowly at 25-35 °C in 15-30 minutes..bul. Stir at 25-35 °C for 15-30 minutes..bul. Add DMAP slowly in 5-10 minutes at 25-35 °C..bul. Maintain the reaction mass at 25-35 °C for 1-2 hours..bul. Check the progress of reaction by TLC..bul. Upon completion, charge ethyl acetate and water..bul. Stir the reaction mass at 25-35 °C for 10-15 minutes. .bul. Separate the aqueous layer and organic layer..bul. Wash the organic layer with saturated sodium chloride solution..bul. Dry the organic layer over sodium sulphate.bul. Filter sodium sulphate out.bul. Wash the sodium sulphate with Ethyl acetate..bul. Concentrate the organic layer completely under vacuum..bul. Yield: 632 g.bul. percent of Yield: 98.46..bul. Purity by HPLC: 77.98percent Di-Boc compound..bul. 11.49percent Mono Boc compound.Alternatively, compound 6.1 can be prepared by addition of (BOC)2NH anion to the corresponding 4,6-dichloropyrimidine or other suitable methods known in the art.

Reference： [1]Patent: WO2011/97594,2011,A2 .Location in patent: Page/Page column 100; 102-103

47
[ 1005-38-5 ]
KG₅ [ No CAS ]

Reference： [1]Patent: WO2011/97594,2011,A2

48
[ 1005-38-5 ]
[ 1321594-53-9 ]

Reference： [1]Patent: WO2011/97594,2011,A2

49
[ 1005-38-5 ]
2CH₄O₃S*C₂₀H₁₆F₃N₇OS [ No CAS ]

Reference： [1]Patent: WO2011/97594,2011,A2

50
[ 1005-38-5 ]
[ 1321594-54-0 ]

Reference： [1]Patent: WO2011/97594,2011,A2

51
[ 1005-38-5 ]
[ 1321594-55-1 ]

Reference： [1]Patent: WO2011/97594,2011,A2

52
[ 1005-38-5 ]
[ 1337962-39-6 ]

Reference： [1]Patent: WO2011/121418,2011,A1
[2]Patent: WO2014/114695,2014,A1
[3]Patent: CN107286146,2017,A
[4]Patent: WO2018/146612,2018,A1

53
[ 107-20-0 ]
[ 1005-38-5 ]
[ 1339891-11-0 ]

Yield	Reaction Conditions	Operation in experiment
70.96%	In 1,4-dioxane; water; at 95℃; for 14h;	Step A: Preparation of 7-chloro-5-(methylthio)imidazo[1.2-clpyrimidine hydrochloride: A solution of 6-chloro-2-(methylthio)pyrimidin-4-amine (25.17 g, 143.3 mmol) and 2-chloroacetaldehyde (27.73 mL, 215.0 mmol) (50 percent aqueous) in 1 ,4-dioxane (50 mL) was heated at 95 °C for 14 hours. The reaction mixture was allowed to cool to ambient temperature and then cooled in an ice bath. The reaction mixture was filtered and the solids washed with dioxane to afford 7-chloro-5-(methylthio)imidazo[l ,2-c]pyrimidine hydrochloride (24.01 g, 101.7 mmol, 70.96percent yield) as a tan powder. MS (apci) m/z = 200.0 (M+H).
70.96%	In 1,4-dioxane; water; at 95℃; for 14h;	A solution of 6-chloro-2-(methylthio)pyrimidin-4-amine (25.17 g, 143.3 mmol) and 2-chloroacetaldehyde (27.73 mL, 215.0 mmol) (50 percent> aqueous) in 1,4-dioxane (50 mL) was heated at 95 °C for 14 hours. The reaction mixture was allowed to cool to ambient temperature and then cooled in an ice bath. The reaction mixture was filtered and the solids washed with dioxane to afford 7-chloro-5-(methylthio)imidazo[l,2-c]pyrimidine hydrochloride (24.01 g, 101.7 mmol, 70.96percent yield) as a tan powder. MS (apci) m/z = 200.0 (M+H).
70%	In 1,4-dioxane; at 95℃;	[00549] To a stirred solution of 6-chloro-2-(methylsulfanyL)pyrimidin-4-amine (1.5 g, 8.54 mmol) in dioxane (4 mL) was added chloroacetaldehyde (50percent, 1.63 mL, 12.8 mmol) and stirred at 95 °C overnight. The reaction mixture was cooled in an ice bath and the resulting precipitate filtered and washed with dioxane to afford the title compound (1.41 g, 70percent) as a colourless powder. [00550] Method A: LC-MS m/z = 199.8 [M + H]+; RT = 0.93 min

Reference： [1]Patent: WO2011/130146,2011,A1 .Location in patent: Page/Page column 86-87
[2]Patent: WO2013/55645,2013,A1 .Location in patent: Paragraph 00370
[3]Patent: WO2017/59191,2017,A1 .Location in patent: Paragraph 00547-00550

54
[ 1005-38-5 ]
[ 1339892-21-5 ]

Reference： [1]Patent: WO2011/130146,2011,A1

55
[ 437-81-0 ]
[ 1005-38-5 ]
[ 68-11-1 ]
[ 1350308-15-4 ]

Yield	Reaction Conditions	Operation in experiment
78.8%	In toluene;Reflux;	General procedure: The appropriate (hetero) aromatic amine (1.0 mmol) and 2',6'-/3',5'-dihalo-substituted (hetero/aromatic) aldehyde (1.5 mmol) were stirred in dry toluene under reflux condition followed by addition of mercaptoaceticacid (2.0 mmol). The reaction mixture was refluxed with a Dean-Stark trap for 24-48 h until the complete consumption of (hetero) aromatic amine. The reaction mixture was concentrated to dryness under reduced pressure and the residue was taken up in ethyl acetate. The organic layer was successively washed with 5percent aq citric acid, water, 5percent aq sodium hydrogen carbonate, and then finally with brine. The organic layer was dried over sodium sulfate and solvent was removed under reduced pressure to get a crude product that was purified by column chromatography on silica-gel (230-400 mesh) using hexane-ethyl acetate as eluent. The structures of synthesized compounds were characterized by means of TLC, IR, ESI-MS, 1H NMR, 13C NMR, elemental analyses and HRMS.

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 6919 - 6926

56
[ 1005-38-5 ]
[ 1373127-44-6 ]
[ 1373127-49-1 ]

Reference： [1]Phosphorus, Sulfur and Silicon and the Related Elements,2012,vol. 187,p. 650 - 659

57
[ 1005-38-5 ]
[ 1373127-44-6 ]

Reference： [1]Phosphorus, Sulfur and Silicon and the Related Elements,2012,vol. 187,p. 650 - 659

58
[ 1005-38-5 ]
[ 6898-84-6 ]
[ 1373127-37-7 ]

Reference： [1]Phosphorus, Sulfur and Silicon and the Related Elements,2012,vol. 187,p. 650 - 659

59
[ 1005-38-5 ]
[ 1400633-90-0 ]

Reference： [1]Patent: WO2012/125732,2012,A1
[2]Patent: US2013/245043,2013,A1
[3]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 1310 - 1317

60
[ 1005-38-5 ]
[ 75-04-7 ]
[ 78448-99-4 ]

Yield	Reaction Conditions	Operation in experiment
75.3%	In water; dimethyl sulfoxide; at 65℃; for 48h;Sealed tube;	A mixture of 1 .00 g (5.69 mmol) of 6-chloro-2-(methylthio)pyrimidine-4-amine and 4.5 ml (57 mmol) of ethylamine (70percent in water) in 3 ml of DMSO was stirred for 48 hours at 65 °C in a closed glass tube. The solution was poured onto 20 ml of cold water. The formed precipitate was filtered, washed several times with cold water and dried. 0.79 g (75.3percent) of a white solid were obtained. 1H-NMR (400 MHz, DMSO-d6): delta = 1 .06 (t, 3H), 2.31 (s, 3H), 3.13 (m, 2H), 5.07 (s, 1 H), 6.03 (s, 2H), 6.52 (t, 1 H). HPLC-MS: Rt 2.355 m/z 185.0 (MH+).

Reference： [1]Patent: WO2014/114695,2014,A1 .Location in patent: Page/Page column 29

61
[ 1005-38-5 ]
[ 1620910-79-3 ]

Reference： [1]Patent: WO2014/114695,2014,A1

62
[ 1005-38-5 ]
[ 1620910-81-7 ]

Reference： [1]Patent: WO2014/114695,2014,A1

63
[ 1005-38-5 ]
[ 1620910-82-8 ]

Reference： [1]Patent: WO2014/114695,2014,A1

64
[ 1005-38-5 ]
[ 1620910-63-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-chloro-succinimide; In dichloromethane; at 20℃; for 1h;	General procedure: To a cold stirring solution of 10 g (52.2 mmol) 6-chloro-2- (methylsulfinyl)pyrimidine-4-amine in 450 ml of DCM, 10 g (56.2 mmol) of N- bromosuccinimide were added, and stirring was continued for 1 hour at room temperature to provide 5-bromo-6-chloro-2-(methylthio)pyrimidine-4-amine, which was used without further purification in the next step (see intermediate 3). The end of the reaction is followed by thin layer chromatography. The following intermediate was synthesized using the procedure described for intermediate 1 , but using N-chlorosuccinimide. Intermediate 2: 5,6-dichloro-2-(methylthio)pyrimidine-4-amine 1H-NMR (400 MHz, DMSO-d6): delta = 2.40 (s, 3H), 7.46 (s, 1 H), 7.98 (s, 1 H).

Reference： [1]Patent: WO2014/114695,2014,A1 .Location in patent: Page/Page column 26

65
[ 1005-38-5 ]
[ 1005-39-6 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 10080 - 10100

66
[ 1005-38-5 ]
[ 52222-43-2 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 10080 - 10100

67
[ 1005-38-5 ]
6-amino-2-(methylthio)-7H-purine-8(9H)-thione [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 10080 - 10100
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 10080 - 10100

68
[ 1005-38-5 ]
2-(6-amino-2-(methylthio)-9H-purin-8-ylthio)-N-(3,4-dimethoxyphenyl)acetamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 10080 - 10100
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 10080 - 10100

69
[ 24424-99-5 ]
[ 1005-38-5 ]
[ 1052714-60-9 ]

Yield	Reaction Conditions	Operation in experiment
66%	With dmap; In dichloromethane; at 20℃; for 12.5h;	Step 1. A solution of <strong>[1005-38-5]4-amino-6-chloro-2-methylthiopyrimidine</strong> (8.64 g, 49.2mmol) and 4-dimethylaminopyridine (636 mg, 5.21 mmol) in dichloromethane (60 mL) was treated with di-tert-butyl dicarbonate (23.6 g, 108 mmol) in small portions over 30 minutes. The solution was allowed to stir at ambient temperature for 12 hours, was diluted with dichloromethane (150 mL), washed twice with water (200 mL) followed by saturated brine (100 mL), dried over Na2SO4, then filtered and the remaining liquid evaporated. Theresulting solid was triturated with 1:1 pentane:ether, collected by filtration and dried under vacuum to afford 4-bis(tert-butoxycarbonyl)amino-6-chloro-2-methylthiopyrimidine as a waxy off-white solid (12.19 g, 32.4 mmol, 66percent); m.p. 90-9 1 °C; TLC RF 0.30 (10:90 ethyl acetate-hexane). 1H NMR (500 MHz, CDC13) oe 7.48 (1H, s), 2.49 (3H, s), 1.55 (18H, s).

Reference： [1]Patent: WO2015/30847,2015,A1 .Location in patent: Page/Page column 157; 158

70
[ 1005-38-5 ]
4-bis(tert-butoxycarbonyl)amino-6-(3,5-dimethylisoxazol-4-yl)-2-(methylthio)pyrimidine [ No CAS ]

Reference： [1]Patent: WO2015/30847,2015,A1

71
[ 1005-38-5 ]
4-bis(tert-butoxycarbonyl)amino-6-(3,5-dimethylisoxazol-4-yl)-2-(methylsulfonyl)pyrimidine [ No CAS ]

Reference： [1]Patent: WO2015/30847,2015,A1

72
[ 79-36-7 ]
[ 1005-38-5 ]
2,2-dichloro-N-(2-chloropyrimidin-5-yl)acetamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 3562 - 3568

73
[ 1005-38-5 ]
[ 66380-45-8 ]

Reference： [1]Journal of Organic Chemistry,2016,vol. 81,p. 3780 - 3789

74
[ 1005-38-5 ]
4-methoxy-2-(methylthio)-5-nitrosopyrimidin-6-amine [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2016,vol. 81,p. 3780 - 3789

75
[ 124-41-4 ]
[ 1005-38-5 ]
[ 3289-53-0 ]

Reference： [1]Journal of Organic Chemistry,2016,vol. 81,p. 3780 - 3789

76
[ 1005-38-5 ]
[ 486-74-8 ]
N-(6-chloro-2-(methylthio)pyrimidine-4-one)quinoline-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11%	With pyridine; trichlorophosphate; at 80℃; for 1h;	Quinoline-4-carboxylic acid (36.4 mg, 0.226 mmol),3-chloro-5-(methylthio)benzene amine (50.0 mg, 0.205 mmol)and POCl3 (34.6 mg, 0.226 mmol)Dissolved in pyridine (1 mL)and stirred at 80°C for 1 hour. Thin film chromatography (TLC) in verifying, new spot the system is moved, and adding water to the composition, a reaction mixture of a, die chloro methane at extracted times 2. The organic layer extracted are dried, using magnesium sulfate, after, concentrating it under reduced pressure, organic for extract of moisture MgSO4removal of filtering the concentrate and a thin silica gel fraction is concentrated to after chromatography (preparative TLC, n/ethyl acetate = 1/1-hexanediol) for purifying the white solid thereby, a desired compound (11percent) is obtained.
11%	With pyridine; trichlorophosphate; at 80℃; for 1h;	quinoline-4-carboxylic acid ( 36.4 mg , 0.226 mmol ) ,6-chloro-2-(methylsulfanyl)pyrimidin-4-amine( 50.0 mg , 0.205 mmol ) and POCl3 ( 34.6 mg , 0.226 mmol ) in pyridine (1 mL) and stirred at 80°C for 1 hour. When the thin film check chromatography (TLC), when a new spot is confirmed , water was added to the reaction mixture twice with dichloromethane It was extracted . The extracted organic layer was dried using magnesium sulfate, and then concentrated under reduced pressure , the water content of the organic extractAfter removing MgSO4 by filtration and then concentrated by preparative silica gel thin layer chromatography ( preparative TLC , ethyl acetate/ N- hexane = 1/ 1) to obtain the title compound ( 11percent) as a white solid
11%	With pyridine; trichlorophosphate; at 80℃; for 1h;	Quinoline-4-carboxylic acid (36.4 mg, 0.226 mmol),3-chloro-5 - (methylthio) benzene amine (50.0 mg, 0.205 mmol) and POCl3 (34.6 mg, 0.226 mmol), pyridine (1 mL) was dissolved in, 80 was stirred for 1 hour dongan. When thin layer chromatography (TLC) check when, a new spot is confirmed, water was added to the reaction mixture, and extracted twice with dichloromethane. And the extracted organic layer was dried using magnesium sulfate, vacuum concentrated and, after the water was removed by filtration of the organic extract over MgSO4 and concentrated by silica gel preparative thin layer chromatography (preparative TLC, ethyl acetate / n- hexane = l / l ) to give to give the title compound (11percent) of a white solid.

Reference： [1]Patent: KR2016/21163,2016,A .Location in patent: Paragraph 0729-0732
[2]Patent: KR2015/134301,2015,A .Location in patent: Paragraph 0729; 0730; 0731
[3]Patent: KR2015/25531,2015,A .Location in patent: Paragraph 0729; 0730; 0731

77
[ 1005-38-5 ]
[ 486-74-8 ]
N-(6-(3-aminophenyl)-2-(methylthio)pyrimidine-4-one)quinoline-4-carboxamide [ No CAS ]

Reference： [1]Patent: KR2016/21163,2016,A
[2]Patent: KR2015/25531,2015,A

78
[ 1005-38-5 ]
[ 1620910-80-6 ]

Reference： [1]Patent: WO2018/146612,2018,A1

79
[ 1005-38-5 ]
[ 1620910-83-9 ]

Reference： [1]Patent: WO2018/146612,2018,A1

80
[ 1005-38-5 ]
[ 150255-96-2 ]
3-(6-amino-2-(methylthio)pyrimidin-4-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); caesium carbonate; In water; toluene; at 115℃; for 16h;	Bis(di-/er/-butyl(4-dimethylamiiiophenyl)phosphine)dichloropalladium(II) (1.0 g, 5 mol%) ws added to a mixture of 6-chloro-2-(methylthio)pyrimidin-4-amine (Combi-Blocks, cat ST-1384) (5.0 g, 29 mmol), (3-cyanophenyl)boronic acid (8.4 g, 57 mmol) and cesium carbonate (37 g, 114 mmol) in toluene (100 mL) and water (10 mL) The mixture was purged with nitrogen, and then stirred at 115 C for 16 h. The reaction mixture was cooled to room temperature, filtered through a Celite plug with DCM and concentrated under reduced pressure. Water (200 mL) was added to the residue and the resulting solid was collected by filtration, and then dried to give the desired product (6.5 g, 94 %), which was used in the next step without further purification. LC-MS calculated for CnHi N+S (M+H)+: m/z = 243.1; found 243.2.

Reference： [1]Patent: WO2019/168847,2019,A1 .Location in patent: Page/Page column 166; 167

81
[ 1005-38-5 ]
[ 98-80-6 ]
[ 77766-06-4 ]