[ CAS No. 33097-11-9 ]

Name: 33097-11-9|4,6-Dichloro-2-(methylthio)pyrimidine-5-carbaldehyde|97%
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SKU: A144896
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Quality Control of [ 33097-11-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 33097-11-9 ]

Product Details of [ 33097-11-9 ]

CAS No. :	33097-11-9	MDL No. :	MFCD00194954
Formula :	C₆H₄Cl₂N₂OS	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MRHGOAKYYORQGQ-UHFFFAOYSA-N
M.W :	223.08	Pubchem ID :	4614004
Synonyms :

Calculated chemistry of [ 33097-11-9 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	49.16
TPSA :	68.15 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.94 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.6
Log Po/w (XLOGP3) :	2.43
Log Po/w (WLOGP) :	2.32
Log Po/w (MLOGP) :	0.79
Log Po/w (SILICOS-IT) :	2.89
Consensus Log Po/w :	2.01

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.99
Solubility :	0.227 mg/ml ; 0.00102 mol/l
Class :	Soluble
Log S (Ali) :	-3.5
Solubility :	0.0699 mg/ml ; 0.000313 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.34
Solubility :	0.102 mg/ml ; 0.000458 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.72

Safety of [ 33097-11-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280	UN#:	N/A
Hazard Statements:	H302-H317	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 33097-11-9 ]

* 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 [ 33097-11-9 ]
Downstream synthetic route of [ 33097-11-9 ]

[ 33097-11-9 ] Synthesis Path-Upstream 1~7

1
[ 1979-98-2 ]
[ 33097-11-9 ]

Yield	Reaction Conditions	Operation in experiment
61%	Stage #1: With trichlorophosphate In Trichloroethylene at 5 - 20℃; Stage #2: at 80℃;	Example 1; 3-[2-r4-Amino-l-piperidinylV8-r2.6-difluorophenyl)-7-oxo-5,6.7,8- tetrahvdropyrimido[4,5-0C to 10 ⁰C. The solution was then warmed up to room temperature before 6-hydroxy-2-(methylthio)-4(lH)-pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 ⁰C overnight followed by concentration under vacuum. The resulting slurry like residue was poured into ice, stirred for about 2 hours then filtered to afford the crude product. EPO <DP n="115"/>The crude product was further purified by recrystalization with hexane to afford 4,6- dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (21.3 g , 61percent). ¹H-NMR (CDCl₃) δ 2.66 (s, 3 H), 10.4 (s, 1 H).
61%	Stage #1: With trichlorophosphate In N,N-dimethyl-formamide at 5 - 20℃; Stage #2: at 80℃;	To the solution of phosphorus oxy chloride (65 mL, 0.70 mol) in trichloroethylene (46.5 mL) was added DMF (25 mL, 0.32 mol) slowly to keep the temperature between 5 ⁰C to 10 ⁰C. The solution was then warmed up to room temperature before 6-hydroxy-2-(methylthio)-4(lH)- pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 ⁰C overnight followed by concentration under vacuum. The resulting slurry like residue was poured into ice, stirred for 2 hours then filtered to afford the crude product. The crude product was further purified by recrystalization with hexane to afford 4,6-dichloro-2-(methylthio)-5- pyrimidinecarbaldehyde (21.3 g , 61percent). ¹H-NMR (CDCl₃) δ 2.66 (s, 3 η), 10.4 (s, 1 η).To a solution of 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (10.0 g, 44.8 mmol) in TηF (250 mL) was added 2,6-difluoroaniline (5.35 mL, 49.3 mmol, 1.1 eq) followed by Et₃N (12.6 mL, 89.6 mmol, 2 eq). The reaction mixture was heated to 55⁰C for about 22 h before <n="109"/>concentrated. The slurry was re-dissolved in DCM (250 mL) and washed with H₂O (2 x 100 mL), then concentrated and further washed with acetone (2 x 10 mL) to give 9.87 g (70 percent) of pure 4- chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5-pyrimidinecarbaldehyde. LC-MS m/z 316 (M+H)⁺.A solution of 4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5- pyrimidinecarbaldehyde (200 mg, 0.63 mmol) in DMF (4.0 mL) and acetic anhydride (2.0 mL) was heated with a microwave (16O⁰C) for about 30 minutes. The resultant mixture was then concentrated. Flash chromatography (EtOAc / Hexane, 1 : 5) provided the title compound (109 mg, 51percent): LC-MS m/z 340 (M+H)⁺.

Reference： [1] Patent: WO2006/104889, 2006, A2, . Location in patent: Page/Page column 113-114
[2] Patent: WO2007/147103, 2007, A2, . Location in patent: Page/Page column 107-108

2
[ 1979-98-2 ]
[ 68-12-2 ]
[ 33097-11-9 ]

Yield	Reaction Conditions	Operation in experiment
61%	With trichlorophosphate In Trichloroethylene at 5 - 80℃;	To the solution of phosphorus oxychloride (65 mL, 0.70 mol) in trichloroethylene(46.5 mL) was added DMF (25 mL, 0.32 mol) slowly to keep the temperature between 5 ⁰C to 10 ⁰C. The solution was then warmed up to room temperature before 6-hydroxy-2- (methylthio)-4(lH)-pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 ⁰C overnight followed by concentration under vacuum.The resulting slurry like residue was poured into ice, stirred for about 2 hours then filtered to afford the crude product. The crude product was further purified by recrystalization with hexane to afford 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (21.3 g , 61percent). ¹H- NMR (CDCl₃) δ 2.66 (s, 3 H), 10.4 (s, 1 H). To the mixture of hydroxylamine hydrochloride (139 mg, 2.0 mmol), HOAc (0.113 mL, 2.0 mmol) and EtOH (5 mL) was added 4,6-dichloro-2-(methylthio)-5- <n="80"/>pyrimidinecarbaldehyde (223 mg, 1.0 mol) to room temperature. The solution was then heated at 50 ⁰C for about 1 hour, 60 ⁰C for about 30 minutes and 70 ⁰C for about 30 minutes before it was concentrated under vacuum and washed with H₂O (10-20 mL) to afford 4,6- dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (190 mg, 80percent). LC-MS m/z 238 (M + H)⁺ 1.57 minute, 1.65 minute; ¹H-NMR (CDCl₃) δ 2.62, 2.65 (3 H), 7.53, 8.30 (1 H). To 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (2.38 g, 10 mmol) was added SOCl₂ (21.8 mL, 0.30 mol) slowly at room temperature. The solution was then heated at 75 ⁰C for about 3 hours before it was concentrated under vacuum. The residue SOCl₂ was removed by evaporation with toluene (5 mL) under vacuum. The resulting solid was washed with EtOH/H₂O (1OmL, 1 : 1) to afford 4,6-dichloro-2-(methylthio)-5- pyrimidinecarbonitrile (2.04 g, 93percent). LC-MS m/z 220 (M + H)⁺1.99 minute; ¹H-NMR (CDCl₃) δ 2.64(3 H).To the solution of 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbonitrile (2.20 g, 10.0 mmol) in DMF (10 mL) was added 2,6-difluoroaniline (2.17 mL, 20.0 mmol). The solution was stirred at 50 ⁰C for about 60 minutes. The mixture was slowly added into a solution of MeOH (20 mL) and water (30 mL). The resultant solid was filtered and washed with MeOH / H₂O (20 mL, 1 :1) to give 4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5- pyrimidinecarbonitrile as a white solid (2.82 g, 90 percent). LC-MS m/z 313 (M + H)⁺; ¹H-NMR (CDCl₃) δ 2.33 (s, 3 H), 6.94 (s, 1 H), 7.04 (m, 2 H), 7.35 (m, 1 H).
61%	With trichlorophosphate In Trichloroethylene at 5 - 80℃;	To the solution of phosphorus oxychloride (65 mL, 0.70 mol) in trichloroethylene(46.5 mL) was added DMF (25 mL, 0.32 mol) slowly to keep the temperature between 5 ⁰C to 10 ⁰C. The solution was then warmed up to room temperature before 6-hydroxy-2- (methylthio)-4(lH)-pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 ⁰C overnight followed by concentration under vacuum. The resulting slurry like residue was poured into ice, stirred for about 2 hours then filtered to afford the crude product. The crude product was further purified by recrystalization with hexane to afford 4, 6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (21.3 g , 61percent). ¹H- NMR (CDCl₃) δ 2.66 (s, 3 H), 10.4 (s, 1 H).To the mixture of hydroxylamine hydrochloride (139 mg, 2.0 mmol), HOAc (0.113 rnL, 2.0 mmol) and EtOH (5 mL) was added 4,6-dichloro-2-(methylthio)-5- pyrimidinecarbaldehyde (223 mg, 1.0 mol) to room temperature. The solution was then heated at 50 ⁰C for about 1 hour, 60 ⁰C for about 30 minutes and 70 ⁰C for about 30 minutes before it was concentrated under vacuum and washed with H₂O (10-20 mL) to afford 4,6- dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (190 mg, 80percent). LC-MS m/z 238 (M + H)⁺ 1.57 minute, 1.65 minute; ¹H-NMR (CDCl₃) δ 2.62, 2.65 (3 H), 7.53, 8.30 (1 H). To 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (2.38 g, 10 mmol) was added SOCl₂ (21.8 mL, 0.30 mol) slowly at room temperature. The solution was then heated at 75 ⁰C for about 3 hours before it was concentrated under vacuum. The residueSOCl₂ was removed by evaporation with toluene (5 mL) under vacuum. The resulting solid was washed with EtOH/H₂O (1OmL, 1 : 1) to afford 4,6-dichloro-2-(methylthio)-5- pyrimidinecarbonitrile (2.04 g, 93percent). LC-MS m/z 220 (M + H)⁺1.99 minute; ¹H-NMR (CDCl₃) δ 2.64(3 H). To the solution of 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbonitrile (2.20 g, 10.0 mmol) in DMF (10 mL) was added 2,6-difluoroaniline (2.17 mL, 20.0 mmol). The solution was stirred at 50 ⁰C for about 60 minutes. The mixture was slowly added into a solution of MeOH (20 mL) and water (30 mL). The resultant solid was filtered and washed with MeOH / H₂O (20 mL, 1 :1) to give 4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5- pyrimidinecarbonitrile as a white solid (2.82 g, 90 percent). LC-MS m/z 313 (M + H)⁺; ¹H-NMR (CDCl₃) δ 2.33 (s, 3 H), 6.94 (s, 1 H), 7.04 (m, 2 H), 7.35 (m, 1 H).

Reference： [1] Patent: WO2007/147104, 2007, A2, . Location in patent: Page/Page column 78-79
[2] Patent: WO2007/147109, 2007, A2, . Location in patent: Page/Page column 101-102

3
[ 68-12-2 ]
[ 1979-98-2 ]
[ 33097-11-9 ]

Yield	Reaction Conditions	Operation in experiment
42%	Stage #1: at -5 - 20℃; for 1 h; Stage #2: at 20℃; for 3.5 h; Heating / reflux	POCI₃ (7OmL, 0.75mol) was cooled to -5°C and DMF (23mL, 0.3mol) was added slowly. The resultant mixture was allowed to stand at 2O⁰C for 1 hour. 4,6-dihydroxy-2-methyl- mercaptopyrimidine (15.8 g., 0.1 mol) was added using a solid addition funnel. The reaction mixture was first stirred at room temperature for 30 minutes and then heated at reflux for 3 hours. Following removal of excess POCI₃ and DMF in vacuo, the residue was poured into <n="107"/>ice. The solid obtained was filtered and washed with cold water. After treating the solid with hexanes (sonication). the desired product was obtained as a white solid (9.3g, 42percent). ¹H NMR (CDCl₃, 300 MHz) δ 10.34 (s, IH), 2.64 (s, 3H); CHN Calc'd for C₆H₄Cl₂N₂OS: C, 32.30; H, 1.81; N, 12.56. Found: C, 32.44; H, 1.69; N, 12.51.
13%	at 10 - 100℃;	Reference Example 69 Production of 4,6-dichloro-2-(methylsulfanyl)pyrimidine-5-carbaldehyde To ice-cooled phosphorus oxychloride (77.62 g, 506 mmol) was added dropwise DMF (9.29 mL, 120 mmol), and the mixture was stirred at room temperature for 1 hr. 2-(Methylsulfanyl)pyrimidine-4,6-diol (15.8 g, 100 mmol) was added thereto by small portions, and the mixture was stirred at room temperature for 1 hr, at 40-50°C for 1 hr, and then at 100°C overnight. After cooling, the reaction mixture was poured into ice, and the mixture was extracted twice with ethyl acetate. The extract was washed successively with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate, hexane:ethyl acetate=95:5-->85:15) to give the title compound (2.97 g, 13percent) as a pale-yellow solid. ¹H NMR (300 MHz, CDCl₃) δ:2.64 (3 H, s), 10.38 (1 H, s).

Reference： [1] Patent: WO2007/84560, 2007, A2, . Location in patent: Page/Page column 105-106
[2] ACS Combinatorial Science, 2014, vol. 16, # 4, p. 168 - 175
[3] Patent: EP2471793, 2012, A1, . Location in patent: Page/Page column 57-58
[4] Patent: US2005/197340, 2005, A1, . Location in patent: Page/Page column 73-74
[5] Patent: US2005/203091, 2005, A1, . Location in patent: Page/Page column 52-53
[6] Patent: WO2007/2248, 2007, A2, . Location in patent: Page/Page column 88

4
[ 1979-98-2 ]
[ 33097-11-9 ]

Yield	Reaction Conditions	Operation in experiment
61%	Stage #1: With trichlorophosphate In Trichloroethylene at 5 - 20℃; Stage #2: at 20 - 80℃; Stage #3: With water In Trichloroethylene at 0℃; for 2 h;	57a) 4-chloro-6-[(2,6-difluorophenyDamino]-2-(methylthio^')-5- pyrimidinecarbonitrile; To the solution of phosphorus oxychloride (65 mL, 0.70 mol) in trichloroethylene (46.5 mL) was added DMF (25 mL, 0.32 mol) slowly to keep the temperature between 5 ⁰C to 10 ⁰C. The solution was then warmed up to room temperature before 6-hydroxy-2-(methylthio)-4(l/i)-pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 ⁰C overnight followed by concentration under vacuum. The resulting slurry like residue was poured into ice, stirred for about 2 hours then filtered to afford the crude product. The crude product was further purified by recrystalization with hexane to afford 4,6- dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (21.3 g , 61percent). ¹H-NMR (CDCl₃) δ 2.66 (s, 3 H), 10.4 (s, I H).
61%	Stage #1: With trichlorophosphate In Trichloroethylene at 5 - 10℃; Stage #2: at 20 - 80℃;	Example 1; N-CcvclopropylmethylV3-r8-r2,6-difluoroρhenylV2-(r2-hvdroxy-l- rhvdroxymethvπethyl^"\|amino)-7-oxo-7₁8-dihvdropyridor2,3-dlpyrimidin-4-yl)-4- methylbenzamidela) 4-chloro-8-(2.6-difluorophenyl)-2-(^'methylthio)pyridor2.3-^)pyrimidin-7r8H^r)- oneTo the solution of phosphorus oxychloride (65 mL, 0.70 mol) in trichloroethylene (46.5 mL) was added DMF (25 mL, 0.32 mol) slowly to keep the temperature between 5 ⁰C to 10 ⁰C. The solution was then warmed up to room temperature before 6-hydroxy-2- (methylthio)-4(lH)-pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 ⁰C overnight followed by concentration under vacuum. The resulting slurry like residue was poured into ice, stirred for 2 hours then filtered to afford the crude product. The crude product was further purified by recrystalization with hexane to afford 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (21.3 g , 61percent). ¹H-NMR (CDCl₃) δ 2.66 (s, 3 H), 10.4 (s, 1 H).

Reference： [1] Patent: WO2006/104917, 2006, A2, . Location in patent: Page/Page column 81-82
[2] Patent: WO2006/104915, 2006, A2, . Location in patent: Page/Page column 122
[3] Patent: WO2007/23105, 2007, A1, . Location in patent: Page/Page column 53; 69-70

5
[ 91759-32-9 ]
[ 68-12-2 ]
[ 33097-11-9 ]

Reference： [1] Patent: EP1970373, 2008, A1, . Location in patent: Page/Page column 35

6
[ 33097-11-9 ]
[ 33097-13-1 ]

Reference： [1] Patent: WO2006/104889, 2006, A2,
[2] Patent: WO2007/147109, 2007, A2,
[3] Patent: WO2007/147104, 2007, A2,

7
[ 33097-11-9 ]
[ 313339-35-4 ]

Reference： [1] Patent: EP2471793, 2012, A1, . Location in patent: Page/Page column 58

[ 33097-11-9 ] Synthesis Path-Downstream 1~62

1
[ 151693-45-7 ]
[ 33097-11-9 ]
[ 180298-94-6 ]

Reference： [1]Synthetic Communications,2000,vol. 30,p. 3719 - 3730
[2]Chemistry of Heterocyclic Compounds,1996,vol. 32,p. 371 - 372

2
[ 2349-58-8 ]
[ 33097-11-9 ]
4-chloro-2-methylthio-7,8-diphenyl-5H-imidazo[2,1-b]pyrimido[5,4-e][1,3]thiazin-5-ol [ No CAS ]

Reference： [1]Chemistry of Heterocyclic Compounds,2000,vol. 36,p. 751 - 753

3
[ 3179-31-5 ]
[ 33097-11-9 ]
[ 321660-52-0 ]

Reference： [1]Chemistry of Heterocyclic Compounds,2000,vol. 36,p. 751 - 753

4
[ 123-75-1 ]
[ 33097-11-9 ]
[ 445040-59-5 ]

Reference： [1]Polish Journal of Chemistry,2002,vol. 76,p. 725 - 728

5
[ 110-89-4 ]
[ 33097-11-9 ]
[ 445040-60-8 ]

Reference： [1]Polish Journal of Chemistry,2002,vol. 76,p. 725 - 728
[2]Chemistry of Heterocyclic Compounds,2008,vol. 44,p. 442 - 450
[3]Chemistry of Heterocyclic Compounds,2004,vol. 40,p. 1352 - 1358

6
[ 62-53-3 ]
[ 33097-11-9 ]
[ 444605-10-1 ]

Yield	Reaction Conditions	Operation in experiment
76%	With sodium hydride; In dimethyl sulfoxide; at 23℃; for 3h;	4-Chloro-2-methylsulfanyl-6-phenylamino-pyrimidine-5-carbaldehyde To a solution of aniline (550 microliter (hereinafter "muL" or "UL"), 6 millimoles (hereinafter "mmol"), 1.2 equivalents (hereinafter "eq")) in dry DMSO (100 ML) was added NaH as a 60% suspension in mineral oil (240 milligrams (hereinafter "mg"), 6 mmol, 1.2 eq) and the reaction mixture was stirred for 1 hour (hereinafter "h").To the red solution was then added <strong>[33097-11-9]4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde</strong> (1.11 grams (hereinafter "g"), 5 mmol) [Santilli, et al., J. Heterocycl. Chem. 1971, 8, 445-45] dissolved in anhydrous DMSO (20 milliliters (hereinafter "ML")).The reaction mixture turned yellow and was stirred 2 h at 23, H2O (250 ML) was added followed by EtOAc (500 ML).The layers were separated; the organic layer was washed with saturated (hereinafter sat'd) aq. NaCl, dried (MgSO4) and filtered.The organic layer was evaporated and the crude residue was dissolved in isopropanol (50 ML) and heated to 60, H2O (50 ML) was added and the solution was cooled slowly to 23.The product was isolated by filtration and dried in vacuo to afford 1.06 g (76% yield) of pure 4-chloro-2-methylsulfanyl-6-phenylamino-pyrimidine-5-carbaldehyde. 1H-NMR delta 2.59 (s, 3H), 7.21 (m, 1H), 7.44 (m, 2H), 7.68 (m, 2H), 10.37 (s, 1H), 11.38 (br s, 1H). LC MS (m/e)=280 (MH+).

Reference： [1]Patent: US2004/116697,2004,A1 .Location in patent: Page 22
[2]Tetrahedron Letters,2003,vol. 44,p. 4567 - 4570

7
[ 110-91-8 ]
[ 33097-11-9 ]
[ 587878-87-3 ]

Yield	Reaction Conditions	Operation in experiment
67%	In methanol; at 0 - 20℃; for 2h;Cooling with ice;	a) 2-methylthio-4-chloro-6-morpholinylpyrimidine-5-carboxaldehyde <strong>[33097-11-9]2-(methylthio)-4,6-dichloropyrimidine-5-carboxaldehyde</strong> (1.5 g, 6.76 mmol) was dissolved in 50 mL of methanol, added dropwisely with morpholine (590 g, 6.76 mmol) dissolved in 2 mL of methanol under ice bath, reacted at room temperature for 2 hours, and filtered. The solid was washed with methanol to give 1.24 g of the title compound as a yellow solid with a yield of 67%. MS (ESI): m/z 274[M+H]+. 1H NMR (400 MHz, CDCl3) delta 10.21 (s, 1H), 3.88-3.76 (m, 4H), 3.72-3.54 (m, 4H), 2.52 (s, 3H).

Reference： [1]Heterocyclic Communications,2003,vol. 9,p. 89 - 94
[2]Patent: US2015/368274,2015,A1 .Location in patent: Paragraph 0117-0121

8
[ 623-51-8 ]
[ 33097-11-9 ]
[ 200627-20-9 ]

Yield	Reaction Conditions	Operation in experiment
75%	With triethylamine; In tetrahydrofuran; at 0℃; for 1h;	To a solution of pyrimidine (1.55 g, 7.0 mmol) from step (a) in THF (20 mL) was added Et3N (1.5 equiv, 10.5 mmol, 1.5 mL). The solution was then cooled to 00C, followed by dropwise addition of ethyl-2-mercapto -acetate (1 equiv, 0.77 mL). The mixture was stirred for Ih at 00C. After this time, the reaction was concentrated, triturated with hexanes and filtered. The mother liquor was concentrated and subjected to silica gel chromatography (88:12 hexanes/ethyl acetate). Concentration of the desired fractions afforded 1.6g of the desired compound as a white solid (5.2 mmol, 75%). 1H NMR (CDCl3, 300 MHz) delta 10.43 (s, IH), 4.22 (q, 2H, J=7.2 Hz), 3.90 (s, 2H), 2.60 (s, 3H), 1.28 (t, 3H, J=7.2 Hz). CHN CaIcM fOr CiOHi1ClN2O3S2: C, 39.15; H, 3.61; N, 9.13. Found: C, 39.29; H, 3.50; N, 9.05.

Reference： [1]Patent: WO2007/84560,2007,A2 .Location in patent: Page/Page column 106
[2]Heterocyclic Communications,2003,vol. 9,p. 89 - 94

9
[ 623-51-8 ]
[ 33097-11-9 ]
4,6-bis(ethoxycarbonylmethylthio)-2-methylthiopyrimidine-5-carbaldehyde [ No CAS ]

Reference： [1]Heterocyclic Communications,2003,vol. 9,p. 89 - 94

10
[ 455-14-1 ]
[ 88738-78-7 ]
[ 33097-11-9 ]
[ 911370-02-0 ]

Reference： [1]Tetrahedron Letters,2007,vol. 48,p. 1205 - 1207

11
[ 5509-65-9 ]
[ 33097-11-9 ]
[ 444605-13-4 ]

Yield	Reaction Conditions	Operation in experiment
76%	With triethylamine; In chloroform; for 24h;Heating / reflux;	4-Chloro-6-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde To a solution of <strong>[33097-11-9]4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde</strong> (11.1 g, 50 mmol) in CHCl3 (100 ML) was added 2,6-difluoroaniline (8.07 ML, 75 mmol, 1.5 eq) followed by Et3N (10.43 ML, 75 mmol, 1.5 eq).The reaction mixture turned yellow and was heated to reflux for 24 h, H2O (50 ML) was added and the layers were separated.The organic layer was evaporated and the crude product was recrystallized from 200 ML of a methanol: H2O mixture (2:1) to give 12.03 g (76%) of pure 4-chloro-6-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: delta 2.21 (s, 3H), 6.91 (m, 2H), 7.24 (m, 1H), 10.29 (s, 1H), 10.35 (br s, 1H). LC MS (m/e)=316 (MH+).
76%	With triethylamine; In chloroform; for 24h;Heating / reflux;	EXAMPLE 1 4-Chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5-pirimidinecarbaldehyde To a solution of <strong>[33097-11-9]4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde</strong> (11.1 grams(hereinafter "g"), 50 millimoles (hereinafter "mmol")) in CHCl3 (100 milliliters (hereinafter "mL")) was added 2,6-difluoroaniline (8.07 mL, 75 mmol, 1.5 equivalents (hereinafter "eq")) followed by Et3N (10.43 mL, 75 mmol, 1.5 eq). The reaction mixture turned yellow and was heated to reflux for 24 h, H2O (50 mL) was added and the layers were separated. The organic layer was evaporated and the crude product was recrystallized from 200 mL of a methanol: H2O mixture (2:1) to give 12.03 g (76%) of pure 4-chloro-6-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: delta 2.21 (s, 3H), 6.91 (m, 2H), 7.24 (m, 1H), 10.29 (s, 1H), 10.35 (br s, 1H). LC MS (m/e)=316 (MH+).
70%	With triethylamine; In tetrahydrofuran; at 55℃; for 22h;	To a solution of 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (10.0 g, 44.8 mmol) in THF (250 mL) was added 2,6-difluoroaniline (5.35 mL, 49.3 mmol, 1.1 eq) followed by Et3N (12.6 mL, 89.6 mmol, 2 eq). The reaction mixture was heated to 550C for about 22 h before concentrated. The slurry was re-dissolved in DCM (250 mL) and washed with H2O (2 x 100 mL), then concentrated and further washed with acetone (2 x 10 mL) to give 9.87 g (70 %) of pure 4-chloro-6-[(2,6-difluorophenyl)amino]-2- (methylthio)-5-pyrimidinecarbaldehyde. LC-MS m/z 316 (M+H)+.

70%

With triethylamine; In tetrahydrofuran; at 55℃; for 22h;

To the solution of phosphorus oxy chloride (65 mL, 0.70 mol) in trichloroethylene (46.5 mL) was added DMF (25 mL, 0.32 mol) slowly to keep the temperature between 5 0C to 10 0C. The solution was then warmed up to room temperature before 6-hydroxy-2-(methylthio)-4(lH)- pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 0C overnight followed by concentration under vacuum. The resulting slurry like residue was poured into ice, stirred for 2 hours then filtered to afford the crude product. The crude product was further purified by recrystalization with hexane to afford 4,6-dichloro-2-(methylthio)-5- pyrimidinecarbaldehyde (21.3 g , 61%). 1H-NMR (CDCl3) delta 2.66 (s, 3 eta), 10.4 (s, 1 eta).To a solution of 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (10.0 g, 44.8 mmol) in TetaF (250 mL) was added 2,6-difluoroaniline (5.35 mL, 49.3 mmol, 1.1 eq) followed by Et3N (12.6 mL, 89.6 mmol, 2 eq). The reaction mixture was heated to 550C for about 22 h before <n="109"/>concentrated. The slurry was re-dissolved in DCM (250 mL) and washed with H2O (2 x 100 mL), then concentrated and further washed with acetone (2 x 10 mL) to give 9.87 g (70 %) of pure 4- chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5-pyrimidinecarbaldehyde. LC-MS m/z 316 (M+H)+.A solution of 4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5- pyrimidinecarbaldehyde (200 mg, 0.63 mmol) in DMF (4.0 mL) and acetic anhydride (2.0 mL) was heated with a microwave (16O0C) for about 30 minutes. The resultant mixture was then concentrated. Flash chromatography (EtOAc / Hexane, 1 : 5) provided the title compound (109 mg, 51%): LC-MS m/z 340 (M+H)+.

Reference： [1]Patent: US2004/116697,2004,A1 .Location in patent: Page 22
[2]Patent: US2006/217401,2006,A1 .Location in patent: Page/Page column 30
[3]Tetrahedron Letters,2007,vol. 48,p. 1205 - 1207
[4]Tetrahedron Letters,2009,vol. 50,p. 370 - 372
[5]Patent: WO2006/104915,2006,A2 .Location in patent: Page/Page column 122
[6]Patent: WO2007/147103,2007,A2 .Location in patent: Page/Page column 107-108

12
[ 33097-11-9 ]
sarcosine t-butyl ester hydrochloride [ No CAS ]
[ 930300-65-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 1250 - 1253

13
[ 1979-98-2 ]
[ 68-12-2 ]
[ 33097-11-9 ]

Yield	Reaction Conditions	Operation in experiment
61%	With trichlorophosphate; In Trichloroethylene; at 5 - 80℃;	To the solution of phosphorus oxychloride (65 mL, 0.70 mol) in trichloroethylene(46.5 mL) was added DMF (25 mL, 0.32 mol) slowly to keep the temperature between 5 0C to 10 0C. The solution was then warmed up to room temperature before 6-hydroxy-2- (methylthio)-4(lH)-pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 0C overnight followed by concentration under vacuum.The resulting slurry like residue was poured into ice, stirred for about 2 hours then filtered to afford the crude product. The crude product was further purified by recrystalization with hexane to afford 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (21.3 g , 61%). 1H- NMR (CDCl3) delta 2.66 (s, 3 H), 10.4 (s, 1 H). To the mixture of hydroxylamine hydrochloride (139 mg, 2.0 mmol), HOAc (0.113 mL, 2.0 mmol) and EtOH (5 mL) was added 4,6-dichloro-2-(methylthio)-5- <n="80"/>pyrimidinecarbaldehyde (223 mg, 1.0 mol) to room temperature. The solution was then heated at 50 0C for about 1 hour, 60 0C for about 30 minutes and 70 0C for about 30 minutes before it was concentrated under vacuum and washed with H2O (10-20 mL) to afford 4,6- dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (190 mg, 80%). LC-MS m/z 238 (M + H)+ 1.57 minute, 1.65 minute; 1H-NMR (CDCl3) delta 2.62, 2.65 (3 H), 7.53, 8.30 (1 H). To 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (2.38 g, 10 mmol) was added SOCl2 (21.8 mL, 0.30 mol) slowly at room temperature. The solution was then heated at 75 0C for about 3 hours before it was concentrated under vacuum. The residue SOCl2 was removed by evaporation with toluene (5 mL) under vacuum. The resulting solid was washed with EtOH/H2O (1OmL, 1 : 1) to afford 4,6-dichloro-2-(methylthio)-5- pyrimidinecarbonitrile (2.04 g, 93%). LC-MS m/z 220 (M + H)+1.99 minute; 1H-NMR (CDCl3) delta 2.64(3 H).To the solution of 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbonitrile (2.20 g, 10.0 mmol) in DMF (10 mL) was added 2,6-difluoroaniline (2.17 mL, 20.0 mmol). The solution was stirred at 50 0C for about 60 minutes. The mixture was slowly added into a solution of MeOH (20 mL) and water (30 mL). The resultant solid was filtered and washed with MeOH / H2O (20 mL, 1 :1) to give 4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5- pyrimidinecarbonitrile as a white solid (2.82 g, 90 %). LC-MS m/z 313 (M + H)+; 1H-NMR (CDCl3) delta 2.33 (s, 3 H), 6.94 (s, 1 H), 7.04 (m, 2 H), 7.35 (m, 1 H).
61%	With trichlorophosphate; In Trichloroethylene; at 5 - 80℃;	To the solution of phosphorus oxychloride (65 mL, 0.70 mol) in trichloroethylene(46.5 mL) was added DMF (25 mL, 0.32 mol) slowly to keep the temperature between 5 0C to 10 0C. The solution was then warmed up to room temperature before 6-hydroxy-2- (methylthio)-4(lH)-pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 0C overnight followed by concentration under vacuum. The resulting slurry like residue was poured into ice, stirred for about 2 hours then filtered to afford the crude product. The crude product was further purified by recrystalization with hexane to afford 4, 6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (21.3 g , 61%). 1H- NMR (CDCl3) delta 2.66 (s, 3 H), 10.4 (s, 1 H).To the mixture of hydroxylamine hydrochloride (139 mg, 2.0 mmol), HOAc (0.113 rnL, 2.0 mmol) and EtOH (5 mL) was added 4,6-dichloro-2-(methylthio)-5- pyrimidinecarbaldehyde (223 mg, 1.0 mol) to room temperature. The solution was then heated at 50 0C for about 1 hour, 60 0C for about 30 minutes and 70 0C for about 30 minutes before it was concentrated under vacuum and washed with H2O (10-20 mL) to afford 4,6- dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (190 mg, 80%). LC-MS m/z 238 (M + H)+ 1.57 minute, 1.65 minute; 1H-NMR (CDCl3) delta 2.62, 2.65 (3 H), 7.53, 8.30 (1 H). To 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (2.38 g, 10 mmol) was added SOCl2 (21.8 mL, 0.30 mol) slowly at room temperature. The solution was then heated at 75 0C for about 3 hours before it was concentrated under vacuum. The residueSOCl2 was removed by evaporation with toluene (5 mL) under vacuum. The resulting solid was washed with EtOH/H2O (1OmL, 1 : 1) to afford 4,6-dichloro-2-(methylthio)-5- pyrimidinecarbonitrile (2.04 g, 93%). LC-MS m/z 220 (M + H)+1.99 minute; 1H-NMR (CDCl3) delta 2.64(3 H). To the solution of 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbonitrile (2.20 g, 10.0 mmol) in DMF (10 mL) was added 2,6-difluoroaniline (2.17 mL, 20.0 mmol). The solution was stirred at 50 0C for about 60 minutes. The mixture was slowly added into a solution of MeOH (20 mL) and water (30 mL). The resultant solid was filtered and washed with MeOH / H2O (20 mL, 1 :1) to give 4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5- pyrimidinecarbonitrile as a white solid (2.82 g, 90 %). LC-MS m/z 313 (M + H)+; 1H-NMR (CDCl3) delta 2.33 (s, 3 H), 6.94 (s, 1 H), 7.04 (m, 2 H), 7.35 (m, 1 H).

Reference： [1]Patent: WO2007/147104,2007,A2 .Location in patent: Page/Page column 78-79
[2]Patent: WO2007/147109,2007,A2 .Location in patent: Page/Page column 101-102

14
[ 33097-11-9 ]
4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With hydroxylamine hydrochloride; acetic acid; In ethanol; at 20 - 70℃; for 2h;	To the solution of phosphorus oxychloride (65 mL, 0.70 mol) in trichloroethylene(46.5 mL) was added DMF (25 mL, 0.32 mol) slowly to keep the temperature between 5 0C to 10 0C. The solution was then warmed up to room temperature before 6-hydroxy-2- (methylthio)-4(lH)-pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 0C overnight followed by concentration under vacuum.The resulting slurry like residue was poured into ice, stirred for about 2 hours then filtered to afford the crude product. The crude product was further purified by recrystalization with hexane to afford 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (21.3 g , 61%). 1H- NMR (CDCl3) delta 2.66 (s, 3 H), 10.4 (s, 1 H). To the mixture of hydroxylamine hydrochloride (139 mg, 2.0 mmol), HOAc (0.113 mL, 2.0 mmol) and EtOH (5 mL) was added 4,6-dichloro-2-(methylthio)-5- <n="80"/>pyrimidinecarbaldehyde (223 mg, 1.0 mol) to room temperature. The solution was then heated at 50 0C for about 1 hour, 60 0C for about 30 minutes and 70 0C for about 30 minutes before it was concentrated under vacuum and washed with H2O (10-20 mL) to afford 4,6- dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (190 mg, 80%). LC-MS m/z 238 (M + H)+ 1.57 minute, 1.65 minute; 1H-NMR (CDCl3) delta 2.62, 2.65 (3 H), 7.53, 8.30 (1 H). To 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (2.38 g, 10 mmol) was added SOCl2 (21.8 mL, 0.30 mol) slowly at room temperature. The solution was then heated at 75 0C for about 3 hours before it was concentrated under vacuum. The residue SOCl2 was removed by evaporation with toluene (5 mL) under vacuum. The resulting solid was washed with EtOH/H2O (1OmL, 1 : 1) to afford 4,6-dichloro-2-(methylthio)-5- pyrimidinecarbonitrile (2.04 g, 93%). LC-MS m/z 220 (M + H)+1.99 minute; 1H-NMR (CDCl3) delta 2.64(3 H).To the solution of 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbonitrile (2.20 g, 10.0 mmol) in DMF (10 mL) was added 2,6-difluoroaniline (2.17 mL, 20.0 mmol). The solution was stirred at 50 0C for about 60 minutes. The mixture was slowly added into a solution of MeOH (20 mL) and water (30 mL). The resultant solid was filtered and washed with MeOH / H2O (20 mL, 1 :1) to give 4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5- pyrimidinecarbonitrile as a white solid (2.82 g, 90 %). LC-MS m/z 313 (M + H)+; 1H-NMR (CDCl3) delta 2.33 (s, 3 H), 6.94 (s, 1 H), 7.04 (m, 2 H), 7.35 (m, 1 H).

Reference： [1]Patent: WO2007/147104,2007,A2 .Location in patent: Page/Page column 78-79

15
[ 367-25-9 ]
[ 33097-11-9 ]
[ 911370-03-1 ]

Yield	Reaction Conditions	Operation in experiment
40%	With triethylamine; In tetrahydrofuran; for 20h;	To a solution of <strong>[33097-11-9]4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde</strong> (4.2g, 18.95mmol) and triethylamine (5.3ml, 38mmol) in TetaF (100ml) was added 2,4- difluoroaniline (2.1ml, 20.58mmol). The mixture was stirred for 2h, and methyl {bis[(2,2,2- trifluoroethyl)oxy]phosphoryl}acetate (6.Og, 18.95mmol) was added. The mixture was stirred for 18h, diluted with DCM (200ml) and washed with water (2 x 100ml). The dried (Na2SO4) organic phase was filtered and evaporated. Flash chromatography (EtOAc/ etaexane, 1 :5) provided the title compound as a cream solid (2.5g, 40%): LC-MS m/z 340 (M+eta)+ retention 3.24min.

Reference： [1]Patent: WO2007/147103,2007,A2 .Location in patent: Page/Page column 173

16
[ 159152-14-4 ]
[ 33097-11-9 ]
C₄₂H₄₂N₆Cl₂S [ No CAS ]

Reference： [1]Organic Letters,2007,vol. 9,p. 3165 - 3168

17
[ 159152-14-4 ]
[ 33097-11-9 ]
10-(4,6-dichloro-2-methylsulfanylpyrimidin-5-yl)-5,15-bis(2,4,6-trimethylphenyl)corrole [ No CAS ]
5,15-bis(4,6-dichloro-2-methylsulfanylpyrimidin-5-yl)-10,20-bis(2,4,6-trimethylphenyl)porphyrin [ No CAS ]

Reference： [1]Organic Letters,2007,vol. 9,p. 3165 - 3168
[2]Chemistry - A European Journal,2010,vol. 16,p. 5691 - 5705

18
[ 33097-11-9 ]
[ 911370-05-3 ]

Yield	Reaction Conditions	Operation in experiment
82%	With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; for 0.166667h;	Example 4; 4-Chloro-2-methylsulfinyl-8-("4-trifluoromethyl-phenvD-8H- pyridor23-<J1 pyrimidin-7-oneA solution of 4-Chloro-2-methylsulfanyl-8-(4- trifluoromethyl-phenyl)-8H-pyrido[2,3-d] pyrimidin-7-one (1.Og, 2.7mmol) in dichloromethane (5OmL) was mixed with m-CPBA (0.63g, 4.0mmol). The resultant mixture was stirred at room temperature for 10 minutes and concentrated under vacuum. Flash chromatography(EtOAc / Etaexane, 3 : 1) then provided the title compound (0.86g, 82%): MS (ES) m/z 388 (M+Eta)+. 1H-NMR(CDCl3) delta 2.80 (s, 3H), 7.03 (d, J= 9.9 Hz, IH), 7.39 (d, J=8.0 Hz, 2H), 7.86 (d, J= 8.0 Hz, 2H), 8.19 (d, J= 9.9 Hz, IH).

Reference： [1]Patent: WO2006/104917,2006,A2 .Location in patent: Page/Page column 62
[2]Tetrahedron Letters,2007,vol. 48,p. 1205 - 1207
[3]Patent: WO2007/147104,2007,A2

19
[ 108-91-8 ]
[ 33097-11-9 ]
4-Chloro-2-methylsulfanyl-6-cyclohexylaminopyrimidine-5-carboxaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	In acetonitrile; for 16h;	4-Chloro-2-methylsulfanyl -6-cyclohexylaminopyrimidine-5-carboxaldehyde 4,6-Dichloro-2-methylsulfanylpyrimidine-5-carboxaldehyde (4.0 g, 0.018 mol) in acetonitrile (65 ML) was treated with rapid stirring with cyclohexylamine (3.76 g, 4.3 ML, 0.038 mol) over 1 min.Reaction stirred 16 h then diluted with 3 volumes of H2O. The precipitated solid was collected, washed with H2O and dried in vacuo to afford 5.1 g. (99%) of the title compound as a white solid. LC MS (m/e)=286 (MH+). Rt=2.85 min.

Reference： [1]Patent: US2004/116697,2004,A1 .Location in patent: Page 67

20
[ 33097-11-9 ]
[ 5305-56-6 ]

Yield	Reaction Conditions	Operation in experiment
80%	With ammonia; In benzene; for 0.5h;	4-Amino-6-chloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde To the solution of <strong>[33097-11-9]4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde</strong> (2 g 7.36 mmol) in benzene (20 ML) was introduced NH3 gas for 30 minutes (hereinafter "min").The formed solid was then filtered and recrystallized from EtOAc (15 ML) to give 1.18 g (80%) of pure 4-amino-6-chloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: delta 2.50 (s, 3H), 7.28 (t, 3H, J=45 Hz, D2O exchangeable), 8.65 (d, 3H, J=41 Hz, D2O exchangeable), 10.11 (s, 1H).

Reference： [1]Patent: US2004/116697,2004,A1 .Location in patent: Page 24

21
[ 68-12-2 ]
[ 1979-98-2 ]
[ 33097-11-9 ]

Yield	Reaction Conditions	Operation in experiment
52%	With trichlorophosphate; at 5 - 100℃; for 20h;	POCI3 (3.2 mL) was cooled at 5C on an ice bath and supplemented dropwise by dimethylformamide (20 mL, 215 mmol). 2-(Methylthio)pyrimidine-4,6-diol (22e) (5 g, 31.6 mmol) was then added portion-wise and the mixture was stirred at 100C for 20 h. The mixture was poured on crushed ice and extracted with CH2CI2 (3 x 50 mL). The combined organic layers were dried and evaporated to dryness under vacuum.Yield: 52%.Melting point: 87-89C.H NMR (DMSO -d6) d 2.57 (s, 3H, S CH3), 10.07 (s, 1H, CO H).13C NMR (DMSO -d6) d 13.3 (SCH3), 112.9 (C-5), 159.3 (C-4/C-6), 168.2 (C-2), 186.6 (COH).
42%		POCI3 (7OmL, 0.75mol) was cooled to -5C and DMF (23mL, 0.3mol) was added slowly. The resultant mixture was allowed to stand at 2O0C for 1 hour. 4,6-dihydroxy-2-methyl- mercaptopyrimidine (15.8 g., 0.1 mol) was added using a solid addition funnel. The reaction mixture was first stirred at room temperature for 30 minutes and then heated at reflux for 3 hours. Following removal of excess POCI3 and DMF in vacuo, the residue was poured into <n="107"/>ice. The solid obtained was filtered and washed with cold water. After treating the solid with hexanes (sonication). the desired product was obtained as a white solid (9.3g, 42%). 1H NMR (CDCl3, 300 MHz) delta 10.34 (s, IH), 2.64 (s, 3H); CHN Calc'd for C6H4Cl2N2OS: C, 32.30; H, 1.81; N, 12.56. Found: C, 32.44; H, 1.69; N, 12.51.
13%	With trichlorophosphate; at 10 - 100℃;	Reference Example 69 Production of 4,6-dichloro-2-(methylsulfanyl)pyrimidine-5-carbaldehyde To ice-cooled phosphorus oxychloride (77.62 g, 506 mmol) was added dropwise DMF (9.29 mL, 120 mmol), and the mixture was stirred at room temperature for 1 hr. 2-(Methylsulfanyl)pyrimidine-4,6-diol (15.8 g, 100 mmol) was added thereto by small portions, and the mixture was stirred at room temperature for 1 hr, at 40-50C for 1 hr, and then at 100C overnight. After cooling, the reaction mixture was poured into ice, and the mixture was extracted twice with ethyl acetate. The extract was washed successively with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate, hexane:ethyl acetate=95:5?85:15) to give the title compound (2.97 g, 13%) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) delta:2.64 (3 H, s), 10.38 (1 H, s).

		Step 1. Preparation of 4,6-Dichloro-2-methylsulfsanyl-pyrimidine-5-carbaldehyde Phosphorous oxychloride (213 mL, 2.3 mol) was cooled in a sodium chloride-water ice bath to 1.8 C. under nitrogen. Dimethyl formamide (71.4 mL, 0.92 mol) was added dropwise over 45 minutes with stirring. The reaction mixture was allowed to warm up to room temperature and was stirred at room temperature for 30 minutes, and followed by stirring at 40 C. for 20 minutes. The reaction mixture was then heated to 57 C., and 2-Methylsulfanyl-pyrimidine-4,6-diol (50.0 g, 0.307 mol) was added in 5.0 g portions over 90 minutes. The reaction mixture was stirred for one hour at 55 C., and then heated to 110 C. with stirring for 17.5 hours. The reaction mixture was cooled and volatiles were removed under reduced pressure. The residue was poured into one lire of ice water. The resulting precipitate was isolated by filtration, washed with water, then with heptanes, and was dried to provide 25.2 g of crude 4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde. Mass Spec. M+H=224.
	With trichlorophosphate; at 1.8 - 110℃; for 20.5h;	Phosphorous oxychloride (213 mL, 2.3 mol) was cooled in a sodium chloride-water ice bath to 1.8 C. under nitrogen. Dimethyl formamide (71.4 mL, 0.92 mol) was added dropwise over 45 minutes with stirring. The reaction mixture was allowed to warm up to room temperature and was stirred at room temperature for 30 minutes, and followed by stirring at 40 C. for 20 minutes. The reaction mixture was then heated to 57 C., and 2-Methylsulfanyl-pyrimidine-4,6-diol (50.0 g, 0.307 mol) was added in 5.0 g portions over 90 minutes. The reaction mixture was stirred for one hour at 55 C., and then heated to 110 C. with stirring for 17.5 hours. The reaction mixture was cooled and volatiles were removed under reduced pressure. The residue was poured into one litre of ice water. The resulting precipitate was isolated by filtration, washed with water, then with heptanes, and was dried to provide 25.2 g of crude 4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde. Mass Spec. M+H=224.
	With trichlorophosphate; at 30℃; for 4h;Heating / reflux;	4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde. DMF (7 mL, 91 mmol) was slowly added to POCl3 (22 ml, 240 mmol) maintaining the temperature below 300C. To the resultant solution was added 2-methylsulfanyl-pyrimidine-4,6-diol (7.06 g, 44.6 mmol) maintaining the temperature below 300C. The resultant slurry was heated to reflux for 4 h. The solvent was removed and the residue was poured onto ice and extracted with EtOAc, dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (5% ethyl acetate in hexanes) gave the desired product. ESIMS calcd 224 (M+ + H), found 224 (M+ + H).

Reference： [1]Patent: WO2019/158655,2019,A1 .Location in patent: Page/Page column 87
[2]Patent: WO2007/84560,2007,A2 .Location in patent: Page/Page column 105-106
[3]ACS Combinatorial Science,2014,vol. 16,p. 168 - 175
[4]Patent: EP2471793,2012,A1 .Location in patent: Page/Page column 57-58
[5]Patent: US2005/197340,2005,A1 .Location in patent: Page/Page column 73-74
[6]Patent: US2005/203091,2005,A1 .Location in patent: Page/Page column 52-53
[7]Patent: WO2007/2248,2007,A2 .Location in patent: Page/Page column 88

22
[ 33097-11-9 ]
[ 85426-79-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	With hydrazine hydrate; triethylamine; In tetrahydrofuran; at 5℃; for 1h;	To a suspension of (27i) (2.5 g, 11.2 mmol) in THF (25 mL) cooled at 5C on an ice bath, were added dropwise hydrazine monohydrate (0.65 mL, 13 mmol) and triethylamine (1.8 mL, 13 mmol). After 1 hour stirring at 5C, the mixture was evaporated to dryness under vacuum and the residue was purified by silica gel column chromatography.Yield: 95%.Melting point: >300C.H NMR (DMSO -d6) d 2.59 (s, 3H, S CH3), 8.32 (s, 1H, CH), 14.25 (bs, 1H, N H).13C NMR (DMSO -d6) d 13.9 (SCH3), 109.6 (C-3a), 133.1 (C-3), 152.9-155.4 (C-4/C-7a), 168.7 (C- 6).
	With N-ethyl-N,N-diisopropylamine; hydrazine; In 1,4-dioxane; at 0℃; for 1088h;Heating / reflux;Product distribution / selectivity;	Step 2. Preparation of4-Chloro-6-methylsulfanyl-lH-pyrazolo[3,4-d]pyrimidine; 4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde (7.54 g, 0.0338 mol) was added to 80 mLof dioxane and stirred for 10 min at RT. Diisopropyl ethylamine (6.03 mL, 0.0340 mol) was added and the mixture was cooled in an ice bath with stirring for 10 min. Anhydrous hydrazine (1.08 mL, 0.0338 mmol) was added dropwise over three min, and stirring was continued for an additional five min. The ice bath was removed, and the reaction mixture was heated to reflux with stirring for 2 hours. The reaction mixture was then stirred at RT for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added to 20 mL of 2 N HCl and 100 mL EtOAc. The result- ing suspension was stirred and filtered, ad the solid was washed with water followed by EtOAc. The organic phase of the filtrate was collected, and the aqueous phase was extracted three times with 150 mL EtOAc. The combined organic phases were dried (MgSO4), filtered, and the filtrate was evaporated under reduced pressure. The resulting solid was washed with diethyl ether/hexanes (1:1) and the solid was dried to provide 3.13 g of crude 4-Chloro-6-methylsulfanyl-lH-pyrazolo[3,4-d]pyrimidine. Mass Spec. M-I-H = 201.Step 2. Preparation of4-Chloro-6-methylsulfanyl-lH-pyrazolo[3,4-d]pyrimidine; 4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde (7.54 g, 0.0338 mol) was added to 80 mL of dioxane and stirred for 10 min at RT. Diisopropyl ethylamine (6.03 mL,0.0340 mol) was added and the mixture was cooled in an ice bath with stirring for 10 min. Anhydrous hydrazine (1.08 mL, 0.0338 mmol) was added dropwise over three min, and stirring was continued for an additional five min. The ice bath was removed, and the reaction ixture was heated to reflux with stirring for two hours. The reaction mixture was then stirred at RT for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added to 20 mL of 2 N HCl and 100 mL EtOAc. The resulting suspension was stirred and filtered, ad the solid was washed with water followed by EtOAc. The organic phase of the filtrate was collected, and the aqueous phase was extracted three times with 150 mL EtOAc. The combined organic phases were dried (MgSO4), filtered, and the filtrate was evaporated under reduced pressure. The resulting solid was washed with diethyl ether/hexanes (1:1) and the solid was dried to provide 3.13 g of crude 4-Chloro-6-methylsulfanyl-lH-pyrazolo[3,4-d]pyrimidine. Mass Spec. M+H = 201.
		Step 2. Preparation of 4-Chloro-6-methylsulfanyl-]H-pyrazolo[3,4-d]pyrimidine 4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde (7.54 g, 0.0338 mol) was added to 80 mL of dioxane and stirred for 10 minutes at room temperature. Diisopropyl ethylamine (6.03 mL, 0.0340 mol) was added and the mixture was cooled in an ice bath with stirring for 10 minutes. Anhydrous hydrazine (1.08 mL, 0.0338 mmol) was added dropwise over three minutes, and stirring was continued for an additional five minutes. The ice bath was removed, and the reaction ixture was heated to reflux with stirring for two hours. The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added to 20 mL of 2 N HCl and 100 mL EtOAc. The resulting suspension was stirred and filtered, ad the solid was washed with water followed by EtOAc. The organic phase of the filtrate was collected, and the aqueous phase was extracted three times with 150 mL EtOAc. The combined organic phases were dried (MgSO4), filtered, and the filtrate was evaporated under reduced pressure. The resulting solid was washed with diethyl ether/hexanes (1:1) and the solid was dried to provide 3.13 g of crude 4-Chloro-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine. Mass Spec. M+H =201.

With N-ethyl-N,N-diisopropylamine; hydrazine; In 1,4-dioxane; ethyl acetate; at 0 - 20℃; for 18.5h;Heating / reflux;

4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde (7.54 g, 0.0338 mol) was added to 80 mL of dioxane and stirred for 10 minutes at room temperature. Diisopropyl ethylamine (6.03 mL, 0.0340 mol) was added and the mixture was cooled in an ice bath with stirring for 10 minutes. Anhydrous hydrazine (1.08 mL, 0.0338 mmol) was added dropwise over three minutes, and stirring was continued for an additional five minutes. The ice bath was removed, and the reaction ixture was heated to reflux with stirring for two hours. The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was added to 20 mL of 2 N HCl and 100 mL EtOAc. The resulting suspension was stirred and filtered, ad the solid was washed with water followed by EtOAc. The organic phase of the filtrate was collected, and the aqueous phase was extracted three times with 150 mL EtOAc. The combined organic phases were dried (MgSO4), filtered, and the filtrate was evaporated under reduced pressure. The resulting solid was washed with diethyl ether/hexanes (1:1) and the solid was dried to provide 3.13 g of crude 4-Chloro-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine. Mass Spec. M+H=201.

Reference： [1]ACS Combinatorial Science,2014,vol. 16,p. 168 - 175
[2]Patent: WO2019/158655,2019,A1 .Location in patent: Page/Page column 87; 88
[3]Patent: WO2007/23105,2007,A1 .Location in patent: Page/Page column 53; 70
[4]Patent: US2005/197340,2005,A1 .Location in patent: Page/Page column 74
[5]Patent: US2005/203091,2005,A1 .Location in patent: Page/Page column 53

23
[ 1979-98-2 ]
[ 33097-11-9 ]

Yield	Reaction Conditions	Operation in experiment
61%		57a) 4-chloro-6-[(2,6-difluorophenyDamino]-2-(methylthio')-5- pyrimidinecarbonitrile; To the solution of phosphorus oxychloride (65 mL, 0.70 mol) in trichloroethylene (46.5 mL) was added DMF (25 mL, 0.32 mol) slowly to keep the temperature between 5 0C to 10 0C. The solution was then warmed up to room temperature before 6-hydroxy-2-(methylthio)-4(l/i)-pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 0C overnight followed by concentration under vacuum. The resulting slurry like residue was poured into ice, stirred for about 2 hours then filtered to afford the crude product. The crude product was further purified by recrystalization with hexane to afford 4,6- dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (21.3 g , 61%). 1H-NMR (CDCl3) delta 2.66 (s, 3 H), 10.4 (s, I H).
61%		Example 1; N-CcvclopropylmethylV3-r8-r2,6-difluororhohenylV2-(r2-hvdroxy-l- rhvdroxymethv?ethyl"\|amino)-7-oxo-718-dihvdropyridor2,3-dlpyrimidin-4-yl)-4- methylbenzamidela) 4-chloro-8-(2.6-difluorophenyl)-2-('methylthio)pyridor2.3-^)pyrimidin-7r8Hr)- oneTo the solution of phosphorus oxychloride (65 mL, 0.70 mol) in trichloroethylene (46.5 mL) was added DMF (25 mL, 0.32 mol) slowly to keep the temperature between 5 0C to 10 0C. The solution was then warmed up to room temperature before 6-hydroxy-2- (methylthio)-4(lH)-pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 0C overnight followed by concentration under vacuum. The resulting slurry like residue was poured into ice, stirred for 2 hours then filtered to afford the crude product. The crude product was further purified by recrystalization with hexane to afford 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (21.3 g , 61%). 1H-NMR (CDCl3) delta 2.66 (s, 3 H), 10.4 (s, 1 H).
		Example 11: Synthesis of 6-(2,4-Difluoro-phenoxy)-3-iodo-lH-pyrazolo[3,4-d]pyri- midine; Step 1. Preparation of4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde; Phosphorous oxychloride (213 mL, 2.3 mol) was cooled in a sodium chloride- water ice bath to 1.8 0C under nitrogen. Dimethyl formamide (71.4 mL, 0.92 mol) was added drop- wise over 45 min with stirring. The reaction mixture was allowed to warm up to RT and was stirred at RT for 30 min, and followed by stirring at 400C for 20 min. The reaction mixture was then heated to 570C, and 2-Methylsulfanyl-pyrimidine-4,6-diol ( 50.0 g, 0.307 mol) was added in 5.0 g portions over 90 min. The reaction mixture was stirred for one hour at 55 0C, and then heated to 1100C with stirring for 17.5 hours. The reaction mixture was cooled and volatiles were removed under reduced pressure. The residue was poured into one litre of ice water. The resulting precipitate was isolated by filtration, washed with water, then with heptanes, and was dried to provide 25.2 g of crude 4,6-Dichloro-2- methylsulfanyl-pyrimidine-5-carbaldehyde. Mass Spec. M+H = 224.Example 19: Synthesis of (i?)-l-[6-(2,4-Difluoro-phenoxy)-3-(2-ethoxy-5-fluoro- phenyl)-lH-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-olStep 1.; Preparation of4,6-Dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde; Phosphorous oxychloride (213 mL, 2.3 mol) was cooled in a sodium chloride- water ice bath to 1.8 0C under nitrogen. Dimethyl formamide (71.4 mL, 0.92 mol) was added drop- wise over 45 min with stirring. The reaction mixture was allowed to warm up to RT and was stirred at RT for 30 min, and followed by stirring at 400C for 20 min. The reaction mixture was then heated to 570C, and 2-Methylsulfanyl-pyrimidine-4,6-diol ( 50.0 g, 0.307 mol) was added in 5.0 g portions over 90 min. The reaction mixture was stirred for one hour at 55 0C, and then heated to 1100C with stirring for 17.5 hours. The reaction mixture was cooled and volatiles were removed under reduced pressure. The residue was poured into one litre of ice water. The resulting precipitate was isolated by filtration, washed with EPO <DP n="71"/>water, then with heptanes, and was dried to provide 25.2 g of crude 4,6-Dichloro-2- methylsulfanyl-pyrimidine-5-carbaldehyde. Mass Spec. M+H = 224.

Reference： [1]Patent: WO2006/104917,2006,A2 .Location in patent: Page/Page column 81-82
[2]Patent: WO2006/104915,2006,A2 .Location in patent: Page/Page column 122
[3]Patent: WO2007/23105,2007,A1 .Location in patent: Page/Page column 53; 69-70

24
[ 88738-78-7 ]
[ 33097-11-9 ]
[ 911370-02-0 ]

Yield	Reaction Conditions	Operation in experiment
70%		Example 1; 4-Chloro-2-methylsulfanyl-8-(4-trifluoromethyl-phenyl)-8H- A solution of 4,<5-dichloro-2-methylsulfanyl-pyrimidine-5~ carbaldehyde (LOg, 4.5mmol) and Et3N (1.26mL, 9.0mmol) in TEtaF (25mL) was mixed with 4~trifluoromethylaniline (0.62mL, 4.9mmol). The resultant mixture was stirred at room temperature for 2 hours before bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)- EPO <DP n="62"/>phosphonate (0.95mL, 4.5mmol) was added. After stirring at room temperature for additional 12 hours, the mixture was diluted with dichloromethane (5OmL) and washed with H2O (2 x 25mL). The organic layer was dried over Na2SO4, filtered and concentrated. This crude product was further purified by washing with a mixture of THF / Hexane (1 : 3, 2 x 1OmL) to provide the title compound (1.17g, 70%): MS (ES) m/z 372 (M+H)+; 1H-NMR(CDCl3) delta 2.18 (s, 3H), 6.79 (d, J= 9.8 Hz, IH), 7.40(d, J= 8.4 Hz, 2H), 7.83 (d, J= 8.4 Hz, 2H), 8.03 (d, J= 9.8 Hz, IH).
70%		A solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5- carbaldehyde (1.Og, 4.5mmol) and Et3N (1.26mL, 9.0mmol) in TetaF (25mL) was mixed with 4-trifluoromethylaniline (0.62mL, 4.9mmol). The resultant mixture was stirred at room temperature for 2 hours before bis(2,2,2- trifluoroethyl)(methoxycarbonylmethyl)-phosphonate (0.95mL, 4.5mmol) was added. After stirring at room temperature for additional 12 hours, the mixture was diluted with dichloromethane (5OmL) and washed with H2O (2 x 25mL). The organic layer was dried over Na2SO4, filtered and concentrated. This crude product was further purified by washing with a mixture of THF / Hexane (1 : 3, 2 x 1OmL) to provide the title compound (1.17g, 70%): MS (ES) m/z 372 (M+H)+; 1H-NMR(CDCl3) delta 2.18 (s, 3H), 6.79 (d, J= 9.8 Hz, IH),7.40 (d, J= 8.4 Hz, 2H), 7.83 (d, J= 8.4 Hz, 2H), 8.03 (d, J= 9.8 Hz, IH).

Reference： [1]Patent: WO2006/104917,2006,A2 .Location in patent: Page/Page column 60-61
[2]Patent: WO2007/147104,2007,A2 .Location in patent: Page/Page column 59

25
[ 88738-78-7 ]
[ 33097-11-9 ]
[ 911370-03-1 ]

Yield	Reaction Conditions	Operation in experiment
52%		Example 2; 4-Chloro-2-methylsulfanyl-8-('2,4-difluoro-rhohenylV8H"-rJyridor2.3-6? pyrimidin-7-oneA solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5- carbaldehyde (1.Og, 4.5mmol) and Et3N (1.26mL, 9.0mmol) in TEtaF(25mL) was mixed with 2,4-difluoroaniline (0.5OmL, 4.9mmol). The resultant mixture was stirred at room temperature for 2 hours before bis(2,2,2-trifluoroethyl) (methoxycarbonyl-methyl)phosphonate (0.95mL, 4.5mmol) was added. After stirring at room temperature for additional 48 hours, the mixture was diluted with dichloromethane (5OmL) and then washed with H2O (2 x 25mL). The organic layer was dried over Na2SO4, filtered and concentrated. This crude product was applied to flash chromatography (EtOAc / Hexane, 1 : 5) to provide the title compound (0.79g, 52%): MS (ES) m/z 340 (M+H)+; 1H-NMR(CDCl3) delta 2.24(s, 3H), 6.79 (d, J= 9.8 Hz, IH), 7.06 (m, 2H), 7.29 (m, IH), 8.03 (d, J= 9.8 Hz, IH).
52%		A solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5- carbaldehyde (1.Og, 4.5mmol) and Et3N (1.26mL, 9.0mmol) in TetaF (25mL) was mixed with 2,4-difluoroaniline (0.5OmL, 4.9mmol). The resultant mixture was stirred at room temperature for 2 hours before bis(2,2,2- trifluoroethyl) (methoxycarbonyl-methyl)phosphonate (0.95mL, 4.5mmol) was added. After stirring at room temperature for additional 48 hours, the mixture was diluted with dichloromethane (5OmL) and then washed with H2O (2 x 25mL). The organic layer was dried over Na2SO4, filtered and concentrated. This crude product was applied to flash chromatography (EtOAc / Hexane, 1 : 5) to provide the title compound (0.79g, 52%): MS (ES) m/z 340 (M+H)+; 1H-NMR(CDCl3) delta 2.24 (s, 3H), 6.79 (d, J= 9.8 Hz, IH), 7.06 (m, 2H),7.29 (m, IH), 8.03 (d, J= 9.8 Hz, IH).
40%		Example 96; 3-(8-(2,4-difluorophenylV2-(r2-hvdroxy-l-(Tivdroxymethyl)ethyllamino>-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)benzoic acid96a) 4-chloro-8-(2,4-difluorophenylV2-rmethylthio)pyridof2.3-(/1Pyrimidin-7(8/D- oneTo a solution of <strong>[33097-11-9]4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde</strong> (4.2g, 18.95mmol) and triethylamine (5.3ml, 38mmol) in THF (100ml) was added 2,4-difluoroaniline (2.ImI5 20.58mmol). The mixture was stirred for 2h, and methyl {bis[(2,2,2-trifluoroethyl)oxy]phosrhohoryl} acetate (6.Og, 18.95mmol) was added. The mixture was stirred for 18h, diluted with DCM (200ml) and washed with water EPO <DP n="196"/>(2 x 100ml). The dried (Na2SO4) organic phase was filtered and evaporated. Flash chromatography (EtOAc/ Hexane, 1 :5) provided the title compound as a cream solid (2.5g5 40%): LC-MS m/z 340 (M+H)+ retention 3.24min.

Reference： [1]Patent: WO2006/104917,2006,A2 .Location in patent: Page/Page column 61
[2]Patent: WO2007/147104,2007,A2 .Location in patent: Page/Page column 59
[3]Patent: WO2006/104915,2006,A2 .Location in patent: Page/Page column 194-195

26
[ 33097-11-9 ]
[ 33097-12-0 ]

Yield	Reaction Conditions	Operation in experiment
80%	With hydroxylamine hydrochloride; acetic acid; In ethanol; at 20 - 60℃; for 2h;	To the mixture of hydroxylamine hydrochloride (139 mg, 2.0 mmol), HOAc (0.113 mL, 2.0 mmol) and EtOH (5 mL) was added 4,6-dichloro-2-(methylthio)-5- pyrimidinecarbaldehyde (223 mg, 1.0 mol) to room temperature. The solution was then heated at 50 0C for about 1 hour, 60 0C for about 30 minutes and 70 0C for about 30 minutes before it was concentrated under vacuum and washed with H2O (10-20 mL) to afford 4,6-dichloro-2-(memylthio)-5-pyrimidinecarbaldehyde.oxime (190 mg, 80%). LC-MS m/z 238 (M + H)+ 1.57 minute, 1.65 minute; 1H-NMR (CDCl3) delta 2.62, 2.65 (3 H), 7.53, 8.30 (1 H).
80%	With hydroxylamine hydrochloride; acetic acid; In ethanol; at 20 - 70℃; for 2h;	To the mixture of hydroxylamine hydrochloride (139 mg, 2.0 mmol), HOAc (0.113 rnL, 2.0 mmol) and EtOH (5 mL) was added 4,6-dichloro-2-(methylthio)-5- pyrimidinecarbaldehyde (223 mg, 1.0 mol) to room temperature. The solution was then heated at 50 0C for about 1 hour, 60 0C for about 30 minutes and 70 0C for about 30 minutes before it was concentrated under vacuum and washed with H2O (10-20 mL) to afford 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (190 mg, 80%). LC-MS m/z 238 (M + H)+ 1.57 minute, 1.65 minute; 1H-NMR (CDCl3) delta 2.62, 2.65 (3 H), 7.53, 8.30 (1 H).
80%	With hydroxylamine hydrochloride; acetic acid; In ethanol; at 20 - 70℃; for 2h;	To the solution of phosphorus oxychloride (65 mL, 0.70 mol) in trichloroethylene(46.5 mL) was added DMF (25 mL, 0.32 mol) slowly to keep the temperature between 5 0C to 10 0C. The solution was then warmed up to room temperature before 6-hydroxy-2- (methylthio)-4(lH)-pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 0C overnight followed by concentration under vacuum. The resulting slurry like residue was poured into ice, stirred for about 2 hours then filtered to afford the crude product. The crude product was further purified by recrystalization with hexane to afford 4, 6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (21.3 g , 61%). 1H- NMR (CDCl3) delta 2.66 (s, 3 H), 10.4 (s, 1 H). <n="103"/>To the mixture of hydroxylamine hydrochloride (139 mg, 2.0 mmol), HOAc (0.113 rnL, 2.0 mmol) and EtOH (5 mL) was added 4,6-dichloro-2-(methylthio)-5- pyrimidinecarbaldehyde (223 mg, 1.0 mol) to room temperature. The solution was then heated at 50 0C for about 1 hour, 60 0C for about 30 minutes and 70 0C for about 30 minutes before it was concentrated under vacuum and washed with H2O (10-20 mL) to afford 4,6- dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (190 mg, 80%). LC-MS m/z 238 (M + H)+ 1.57 minute, 1.65 minute; 1H-NMR (CDCl3) delta 2.62, 2.65 (3 H), 7.53, 8.30 (1 H). To 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde oxime (2.38 g, 10 mmol) was added SOCl2 (21.8 mL, 0.30 mol) slowly at room temperature. The solution was then heated at 75 0C for about 3 hours before it was concentrated under vacuum. The residueSOCl2 was removed by evaporation with toluene (5 mL) under vacuum. The resulting solid was washed with EtOH/H2O (1OmL, 1 : 1) to afford 4,6-dichloro-2-(methylthio)-5- pyrimidinecarbonitrile (2.04 g, 93%). LC-MS m/z 220 (M + H)+1.99 minute; 1H-NMR (CDCl3) delta 2.64(3 H). To the solution of 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbonitrile (2.20 g, 10.0 mmol) in DMF (10 mL) was added 2,6-difluoroaniline (2.17 mL, 20.0 mmol). The solution was stirred at 50 0C for about 60 minutes. The mixture was slowly added into a solution of MeOH (20 mL) and water (30 mL). The resultant solid was filtered and washed with MeOH / H2O (20 mL, 1 :1) to give 4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5- pyrimidinecarbonitrile as a white solid (2.82 g, 90 %). LC-MS m/z 313 (M + H)+; 1H-NMR (CDCl3) delta 2.33 (s, 3 H), 6.94 (s, 1 H), 7.04 (m, 2 H), 7.35 (m, 1 H).

With sodium hydroxide; hydroxylamine hydrochloride; In ethanol; water;

4,6- Dichloro-2-methylsuIfanyl-pyrimidine-5-carbaldehyde (9.3g., 42 mmol; prepared according to 5.2.1, Step a) was suspended in 95% EtOH (10OmL) was warmed until a solution was obtained. Hydroxylamine hydrochloride (3.5g, 105 mmol) dissolved in water (10 mL) was added to this solution followed by an addition of NaOH (2.5 g.s 63 mmol) dissolved in water (25 mL). The reaction was stirred overnight. Concentration of the crude reaction mixture caused a precipitation, which was allowed to stand for 1 hr before being filtered off. The precipitate was then dried under high vacuum to yield the crude product (LC-MS: MH+ 238/240).

Reference： [1]Patent: WO2006/104917,2006,A2 .Location in patent: Page/Page column 81-82
[2]Tetrahedron Letters,2009,vol. 50,p. 370 - 372
[3]Patent: WO2006/104889,2006,A2 .Location in patent: Page/Page column 114
[4]Patent: WO2007/147109,2007,A2 .Location in patent: Page/Page column 102
[5]Patent: WO2007/84560,2007,A2 .Location in patent: Page/Page column 111

27
[ 1979-98-2 ]
[ 33097-11-9 ]

Yield	Reaction Conditions	Operation in experiment
61%		Example 1; 3-[2-r4-Amino-l-piperidinylV8-r2.6-difluorophenyl)-7-oxo-5,6.7,8- tetrahvdropyrimido[4,5-<f\|pyrimidin-4-yll-N-cvclobutyl-4-methylbenzamide; To the solution of phosphorus oxychloride (65 mL, 0.70 mol) in trichloroethylene (46.5 mL) was added DMF (25 mL, 0.32 mol) slowly to keep the temperature between 5 0C to 10 0C. The solution was then warmed up to room temperature before 6-hydroxy-2-(methylthio)-4(lH)-pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 0C overnight followed by concentration under vacuum. The resulting slurry like residue was poured into ice, stirred for about 2 hours then filtered to afford the crude product. EPO <DP n="115"/>The crude product was further purified by recrystalization with hexane to afford 4,6- dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (21.3 g , 61%). 1H-NMR (CDCl3) delta 2.66 (s, 3 H), 10.4 (s, 1 H).
61%		To the solution of phosphorus oxy chloride (65 mL, 0.70 mol) in trichloroethylene (46.5 mL) was added DMF (25 mL, 0.32 mol) slowly to keep the temperature between 5 0C to 10 0C. The solution was then warmed up to room temperature before 6-hydroxy-2-(methylthio)-4(lH)- pyrimidinone (25 g, 0.16 mol) was added in portions. The resultant reaction mixture was heated at 80 0C overnight followed by concentration under vacuum. The resulting slurry like residue was poured into ice, stirred for 2 hours then filtered to afford the crude product. The crude product was further purified by recrystalization with hexane to afford 4,6-dichloro-2-(methylthio)-5- pyrimidinecarbaldehyde (21.3 g , 61%). 1H-NMR (CDCl3) delta 2.66 (s, 3 eta), 10.4 (s, 1 eta).To a solution of 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (10.0 g, 44.8 mmol) in TetaF (250 mL) was added 2,6-difluoroaniline (5.35 mL, 49.3 mmol, 1.1 eq) followed by Et3N (12.6 mL, 89.6 mmol, 2 eq). The reaction mixture was heated to 550C for about 22 h before <n="109"/>concentrated. The slurry was re-dissolved in DCM (250 mL) and washed with H2O (2 x 100 mL), then concentrated and further washed with acetone (2 x 10 mL) to give 9.87 g (70 %) of pure 4- chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5-pyrimidinecarbaldehyde. LC-MS m/z 316 (M+H)+.A solution of 4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5- pyrimidinecarbaldehyde (200 mg, 0.63 mmol) in DMF (4.0 mL) and acetic anhydride (2.0 mL) was heated with a microwave (16O0C) for about 30 minutes. The resultant mixture was then concentrated. Flash chromatography (EtOAc / Hexane, 1 : 5) provided the title compound (109 mg, 51%): LC-MS m/z 340 (M+H)+.

Reference： [1]Patent: WO2006/104889,2006,A2 .Location in patent: Page/Page column 113-114
[2]Patent: WO2007/147103,2007,A2 .Location in patent: Page/Page column 107-108

28
[ 2365-48-2 ]
[ 33097-11-9 ]
[ 918628-99-6 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -10℃; for 0.25h;	(6-Chloro-5-formyI-2-methylsulfanyl-pyrimidin-4-ylsulfanyl)-acetic acid methyl ester. To an ice- cooled solution (-100C) of <strong>[33097-11-9]4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde</strong> (2.0 g, 8.97 mmol) and iPr2EtN (0.82 mL, 8.97 mmol) in DCM (40 mL) was added methyl thioglycolate (1.56 mL, 8.97 mmol) in DCM (20 mL) over 15 min. The reaction mixture was let warm to RT, then washed with sat. NaHCO3, dried over MgSO4, filtered, and concentrated. The product was used without further purification. ESEVlS calcd 293 (M+ + H), found 293 (M+ + H).

Reference： [1]Patent: WO2007/2248,2007,A2 .Location in patent: Page/Page column 88

29
[ 925981-73-3 ]
[ 33097-11-9 ]
[ 925981-74-4 ]

Reference： [1]Russian Journal of Organic Chemistry,2008,vol. 44,p. 288 - 291

30
[ 68572-18-9 ]
[ 33097-11-9 ]
[ 890095-72-4 ]

Reference： [1]Russian Journal of Organic Chemistry,2008,vol. 44,p. 288 - 291

31
[ 155405-64-4 ]
[ 33097-11-9 ]
[ 925981-75-5 ]
[ 1065273-77-9 ]

Reference： [1]Russian Journal of Organic Chemistry,2008,vol. 44,p. 288 - 291

32
[ 91759-32-9 ]
[ 68-12-2 ]
[ 33097-11-9 ]

Yield	Reaction Conditions	Operation in experiment
		(1) Phosphorous oxychloride(144.1 g) was cooled to 0C and DMF(28 mL) was added dropwise. The mixture was stirred at room temperature for 30 minutes, and 4,6-dihydroxy-2-mercaptopyrimidine(20 g) was added thereto. After stirring at room temperature for an hour, the reaction solution was stirred under reflux for 6 hours. The reaction solution was concentrated, toluene was added to the residue and the mixture was concentrated again. Water and ethyl acetate were added to the residue and the organic layer was separated and dried. The solvent was concentrated, the residue was purified with silica gel column chromatography(hexane/ethyl acetate=95/5 to 80/20) to give 4,6-dichloro-2-methyl-sulfanylpyridine-5-carboaldehyde(11.62 g) as a colorless powder. GC-MS:222/224[M].

Reference： [1]Patent: EP1970373,2008,A1 .Location in patent: Page/Page column 35

33
[ 33097-11-9 ]
[ 95-00-1 ]
[ 939979-05-2 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In methanol; at 0 - 20℃; for 1h;	(2) A solution of 2,4-dichlorobenzylamine(1.89 g) and triethylamine(1.36 g) in methanol(10 mL) was added dropwise to a solution of 4,6-dichloro-2-methylsulfanylpyridine-5-carboaldehyde(2.0 g) in methanol(80 mL) cooled at 0C. The reaction mixture was stirred at room temperature for an hour, an aqueous saturated sodium bicarbonate solution and ethyl acetate were added thereto, and the organic layer was separated. The organic layer was dried and the solvent was concentrated. Diisopropyl ether and hexane were added to the residue and the precipitates were filtered and dried to give 4-chloro-6-(2,4-dichlorobenzylamino)-2-methylsulfanylpyrimidine-5-carboaldehyde(2.88 g) as a colorless powder. APCI-MS(m/e):362/364[M+H]+.

Reference： [1]Patent: EP1970373,2008,A1 .Location in patent: Page/Page column 35

34
[ 33097-11-9 ]
[ 98-80-6 ]
4-chloro-2-methylthio-6-phenylpyrimidine-5-carbaldehyde [ No CAS ]

Reference： [1]Journal of Heterocyclic Chemistry,2009,vol. 46,p. 960 - 964

35
[ 496-30-0 ]
[ 33097-11-9 ]
[ 1217361-23-3 ]

Reference： [1]Letters in Organic Chemistry,2009,vol. 6,p. 526 - 528

36
[ 109-84-2 ]
[ 33097-11-9 ]
[ 1220517-89-4 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 18 - 25℃;	Intermediate 27; 2-[4-Chloro-6-(methylsulfanyl)-lH-pyrazolo[3,4-(i1pyrimidin-l -yl]ethanolTo a solution of 4,6-dichloro-2-(methylthio)pyrimidine-5-carbaldehyde (500 mg, 2.24 mmol) in THF were added triethylamine (0.469 mL, 3.36 mmol) and 2-hydrazinylethanol (0.152 mL, 2.24 103496-1Pmmol, drop-wise). The reaction mixture was allowed to stir at room temperature overnight. The volatiles were removed under reduced pressure to give the title product (0.429g) that was used in the subsequent step without any further purification. LCMS: 245 [M+H]+.

Reference： [1]Patent: WO2010/38060,2010,A1 .Location in patent: Page/Page column 78-79

37
[ 6629-60-3 ]
[ 33097-11-9 ]
[ 1220517-81-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In ethanol; at 18 - 25℃; for 1h;	Intermediate 17; 4-Chloro-l-Ethyl-6-(methylsulfanyl)-lH-pyrazolo[3,4-(i1pyrimidine4,6-Dichloro-2-(methylthio)pyrimidine-5-carbaldehyde (500 mg, 2.24 mmol) and ethylhydrazine oxalate (336 mg, 2.24 mmol) were dissolved in ethanol (6.222 mL) and TEA (1.250 mL, 8.97 mmol) was added. The reaction was stirred at rt for 1 hour. The reaction mixture was concentrated in vacuo leaving a yellow solid. This material was separated between EtOAc and water, washed with brine, aq. NaHCO3 and dried with MgSO4. Concentration in vacuo provided the title product as a yellow solid (480 mg). LCMS: 229 [M+H]+. 103496-1P

Reference： [1]Patent: WO2010/38060,2010,A1 .Location in patent: Page/Page column 73

38
[ 109-97-7 ]
[ 33097-11-9 ]
[ 1217353-51-9 ]

Reference： [1]Journal of Organic Chemistry,2010,vol. 75,p. 2127 - 2130

39
[ 5509-65-9 ]
[ 139911-29-8 ]
[ 33097-11-9 ]
[ 444605-29-2 ]

Yield	Reaction Conditions	Operation in experiment
		4,6-Dich.loro-2-(methylthio)pyrimidin.e-5-carboxaldehyde (40kg) was dissolved in anhydrous THF (200L) at room temperature. Triethylamine (20kg) was added followed by 2,6-difluoroan.iline (26kg) and the reaction mixture was heated at 60-650C for 12h. The mixture was cooled to room temperature. To the mixture was added water (160L) followed by triethylamine (25.6kg), 4-fluoro-2-mcthylbcnzcncboronic acid (33.2kg), palladium acetate (0.8kg, 2mol%) and. triphenylphosphine (1.88kg, 4mol%). The reaction mixture was heated to 65C and stirred vigorously at this temperature for 3h. The mixture was cooled to 55-600C and THF (160L) was added. The bottom aqueous phase was separated at 55-600C. The organic phase was concentrated to200L, methanol (400L) was added and the THF was removed (until <3mol% THF by NMR) by atmospheric distillation, keeping the volume of the solution at ca.600L by adding methanol (600- 800L). The solution was cooled to 55-6O0C and seeded with the title compound (0.16kg). The slurry was stirred at 55C for at least 30 min and then cooled to 2O0C over Ih. The slurry was stirred at 2O0C for at least 2h and filtered. The cake was washed with methanol (160L) followed by MeOH:water (4: 1,120L) and dried in vacuo at 60-650C <n="87"/>overnight to give the title compound (43.8kg) 400MHzNMR in CDCb. Tetramethylsilane as reference at 0.00 ppm. delta(ppm): 2.29 (3 H) s, 2.33 (3 H) s, 6.97 - 7.05 (4 H) m, 7.24 - 7.32 (3 H) m, 9.64 (1 H) s, 10.38 (1 H) s.

Reference： [1]Patent: WO2007/59500,2007,A2 .Location in patent: Page/Page column 85-86

40
[ 138-37-4 ]
[ 33097-11-9 ]
[ 1254784-12-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 7413 - 7421

41
C₁₄H₂₀N₃O₃Pol [ No CAS ]
[ 33097-11-9 ]
C₂₀H₂₃ClN₅O₄PolS [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2011,vol. 133,p. 676 - 679
[2]Organic and Biomolecular Chemistry,2012,vol. 10,p. 4229 - 4235

42
[ 31230-17-8 ]
[ 33097-11-9 ]
[ 1361961-49-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; potassium iodide; In N,N-dimethyl-formamide; at 20℃; for 3h;	To a mixture of 5-methyl-lH-pyrazol-3-amine (1.44 g, 14.84 mmol), DIEA (2.19 mL, 12.57 mmol) and KI (380 mg, 2.28 mmol) in DMF (13 mL) was added 4,6-dichloro-2-(methylthio)pyrimidine-5-carbaldehyde (2.55 g, 1 1.43 mmol). The mixture was stirred at rt for 3 h and then water was added. The suspended solid was collected by filtration and dried to afford crude 4-chloro-6-((5- methyl-lH-pyrazol-3-yl)amino)-2-(methylthio)pyrimidine-5-carbaldehyde (3.74 g, quantitative) as a light orange powder, which was used without further purification.

Reference： [1]Patent: WO2012/30924,2012,A1 .Location in patent: Page/Page column 162

43
[ 159152-14-4 ]
[ 33097-11-9 ]
C₄₈H₄₄Cl₄N₈S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With boron trifluoride diethyl etherate; In dichloromethane; at 20℃; for 1h;Inert atmosphere;	To stirred CH2Cl2 (400 mL), purged with Ar for 15 min, 5-mesityldipyrromethane (1)[1] (1.209 g, 4.57 mmol) and <strong>[33097-11-9]4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde</strong> (2) (1.020 g, 4.57 mmol) were added, immediately followed by the addition of BF3·OEt2 (0.4 mL, 3.20 mmol, 0.7 equiv), and the resulting solution was stirred at rt for 1 h (under Ar and protected from light). p-Chloranil (1.124 g, 4.57 mmol) was subsequently added and the mixture was heated at reflux during 1 h. The solvent was evaporated and, after column chromatographic purification (silica, eluent CH2Cl2-petroleum ether 2:1), A2B2-porphyrin 3 was obtained as a purple solid (1.382 g, 65%).

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 2406 - 2409

44
[ 33097-11-9 ]
[ 313339-35-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium chlorite; aminosulfonic acid; In tetrahydrofuran; water; tert-butyl alcohol; at -10 - 35℃; for 0.166667h;	Reference Example 70 Production of ethyl 4,6-dichloro-2-(methylsulfanyl)pyrimidine-5-carboxylate To a solution of the compound of Reference Example 69 (4.02 g, 18 mmol), amidosulfuric acid (3.50 g, 36 mmol), tert-butanol (72 mL), THF (72 mL) and water (36 mL) was added a solution of sodium chlorite (2.03 g, 18 mmol) in water (36 mL) at -10C, and the mixture was stirred for 10 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1% aqueous sodium thiosulfate solution and brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 4,6-dichloro-2-(methylsulfanyl)pyrimidine-5-carboxylic acid as a crude product. To a solution of this crude product in THF (50 mL) were added oxalyl chloride (2.36 mL, 27 mmol) and DMF (1 drop), and the mixture was stirred at room temperature for 1 hr. Water was added thereto, and the mixture was extracted twice with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. To the residue were added ethanol (50 mL) and triethylamine (3.76 mL, 27 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted twice with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate, hexane:ethyl acetate=99:1?90:10) to give the title compound (3.28 g, 68%) as a pale-yellow oil. 1H NMR (300 MHz, CDCl3) delta:1.41 (3 H, t, J = 7.2 Hz), 2.59 (3 H, s), 4.45 (2 H, q, J = 7.1 Hz).

Reference： [1]Patent: EP2471793,2012,A1 .Location in patent: Page/Page column 58

45
[ 33097-11-9 ]
[ 959070-42-9 ]

Reference： [1]Patent: EP2471793,2012,A1

46
[ 627-37-2 ]
[ 33097-11-9 ]
C₁₀H₁₂ClN₃OS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 20℃; for 2h;	N-methylallylamine (1.88 mL, 19.8 mmol) and triethylamine (3.01 mL, 21.6 mmol) were added to a solution of 4,6-dichloro-2-(methylthio)pyrimidine-5-carbaldehyde (4.02 g, 18.0 mmol) in CH2Cl2 (50 mL) at room temperature. After stirring for 2 hours, sat. NH4Cl solution was added, and the layers separated. The organic phase was dried over Na2SO4 and concentrated. The residue (3.87 g, 15.0 mmol) was dissolved in anhydrous THF (35 mL) and cooled to -78 oC. Vinylmagnesium bromide solution (1 M, 15.75 mL) was added dropwise and the reaction was stirred for 30 min before being warmed to 0 oC. The reaction was quenched by addition of sat. NH4Cl solution and extracted with EtOAc (x 2). The combined organics were dried over Na2SO4 and concentrated to give the product 10 as a pale yellow oil (4.10 g, 96%)

Reference： [1]Tetrahedron Letters,2013,vol. 54,p. 993 - 997

47
[ 645-36-3 ]
[ 33097-11-9 ]
[ 1476056-79-7 ]

Yield	Reaction Conditions	Operation in experiment
75%	With triethylamine; In isopropyl alcohol; for 0.166667h;	2,2-Diethoxyethylamine (3.6 mL, 24.7 mmol) was added to a suspensionof <strong>[33097-11-9]4,6-dichloro-2-(methylsulfanyl)pyrimidine-5-carbaldehyde</strong>16 (5.0 g, 22.4 mmol) in i-PrOH (100 mL), and the mixture was stirred until all the crystals had dissolved. Et3N (3.4 mL24.3 mmol) was then added. After 10 min, the solvent was evaporated under reduced pressure, and the product was extracted with CH2Cl2 (50 mL). The soln was washed with H2O (2 × 50 mL), dried(Na2SO4), and concentrated. The crude product was crystallized from hexane at -15 C to give a yellowish solid; yield: 5.34 g(75%); mp 104-106 C. IR (KBr): 3268 (NH), 1654 (C=O) cm-1.1H NMR (300 MHz, CDCl3): delta = 1.28 (t, J = 6.9 Hz, 6 H, 2 × CH3),2.56 (s, 3 H, SCH3), 3.61 (dq, 2J = 9.3 Hz, 3J = 6.9 Hz, 2 H,2 × CHAHBCH3), 3.72-3.84 (m, 4 H, NCH2 and 2 × CHAHBCH3),4.67 (t, J = 5.4 Hz, 1 H, OCH), 9.42 (br s, 1 H, NH), 10.27 (s, 1 H,CHO).13C NMR (75 MHz, CDCl3): delta = 14.7, 15.6, 43.6, 63.1, 100.5,105.0, 160.4, 164.6, 177.0, 190.5.Anal. Calcd for C12H18ClN3O3S: C, 45.07; H, 5.67. Found: C,45.29; H, 5.67.

Reference： [1]Synthesis,2013,vol. 45,p. 2438 - 2446

48
[ 924-50-5 ]
[ 33097-11-9 ]
[ 1610890-91-9 ]

Yield	Reaction Conditions	Operation in experiment
54%	In N,N-dimethyl-formamide; at 20℃; for 0.333333h;	A mixture of aldehyde 1 (540 mg, 2.42 mmol) and methyl 3-aminocrotonate 2 (610 mg, 5.30 mmol) in absolute DMF (2 ml) was stirred at room temperature for 20 min, cooled to 0 C, filtered, washed with water and dried to afford 363 mg (54%) of 3, beige powder, mp 175-177 C (CH2Cl2-hexane, decomp.). 1H NMR (CDCl3) delta: 2.76 (s, 3 H, SMe),3.08 (s, 3 H, 7-Me), 4.02 (s, 3 H, CO2Me), 8.99 (s, 1H, H5). 13C NMR(DMSO-d6) delta: 15.2 (SMe), 26.6 (7-Me), 53.2 (CO2Me), 114.3 (C4a), 125.3(C6), 139.4 (C5), 159.5 (C8a), 162.8 (C4), 165.6 (CO2Me), 169.7 (C7), 175.5(C2). Signals assignment was made using fully coupled 13C spectrum. Thestructure of pyrido[2,3-d]pyrimidine (rather than [4,3-d]) is confirmed by HOESY spectrum containing cross-peak for H5 to C6. HRMS (ESI), m/z:284.0253 [M + H]+ (calc. for C11H10ClN3O2S, m/z: 284.0255).

Reference： [1]Mendeleev Communications,2014,vol. 24,p. 163 - 164

49
[ 70272-01-4 ]
[ 33097-11-9 ]
methyl 2-(methylsulfanyl)-4-oxo-7-phenyl-3,4-dihydropyrido[2,3-d]pyrimidine-6-carboxylate [ No CAS ]
methyl 4-(1-amino-3-methoxy-3-oxo-1-phenylprop-1-en-2-yl)-2-(methylsulfanyl)-7-phenylpyrido[2,3-d]pyrimidine-6-carboxylate [ No CAS ]