[ CAS No. 3932-97-6 ]

Name: 3932-97-6|2,4-Dichloro-5-(trifluoromethyl)pyrimidine|98%
Brand: Ambeed
SKU: A178973
Rating: 97 (27 reviews)

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Quality Control of [ 3932-97-6 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 3932-97-6 ]

SDS Specification

Alternatived Products of [ 3932-97-6 ]

Product Details of [ 3932-97-6 ]

CAS No. :	3932-97-6	MDL No. :	MFCD03426408
Formula :	C₅HCl₂F₃N₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IDRUEHMBFUJKAK-UHFFFAOYSA-N
M.W :	216.98	Pubchem ID :	2782774
Synonyms :

Calculated chemistry of [ 3932-97-6 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.2
Num. rotatable bonds :	1
Num. H-bond acceptors :	5.0
Num. H-bond donors :	0.0
Molar Refractivity :	37.05
TPSA :	25.78 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) :	-5.49 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.85
Log Po/w (XLOGP3) :	3.01
Log Po/w (WLOGP) :	3.95
Log Po/w (MLOGP) :	1.92
Log Po/w (SILICOS-IT) :	3.3
Consensus Log Po/w :	2.81

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.39
Solubility :	0.0893 mg/ml ; 0.000412 mol/l
Class :	Soluble
Log S (Ali) :	-3.22
Solubility :	0.132 mg/ml ; 0.000608 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.78
Solubility :	0.0362 mg/ml ; 0.000167 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.82

Safety of [ 3932-97-6 ]

Signal Word:	Danger	Class:	8,6.1
Precautionary Statements:	P264-P270-P280-P301+P310+P330-P301+P330+P331-P303+P361+P353-P304+P340+P310-P305+P351+P338+P310-P363-P405-P501	UN#:	2922
Hazard Statements:	H301-H314	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 3932-97-6 ]

* 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 [ 3932-97-6 ]
Downstream synthetic route of [ 3932-97-6 ]

[ 3932-97-6 ] Synthesis Path-Upstream 1~4

1
[ 54-20-6 ]
[ 3932-97-6 ]

Yield	Reaction Conditions	Operation in experiment
95%	at 85 - 100℃; for 20 h;	Preparation of 2.4-dichloro-5-trifluoromethylpyrimidine (3) 5-Trifluoromethyluracil (250 g, 1.39 mol) and phosphorous oxychloride (655 mL, 6.94 mol, 5 equiv) were charged to a 3 L 4-neck flask equipped with overhead stirrer, a reflux condenser, an addition funnel and an internal theromocouple. The contents were maintained under a nitrogen atmosphere as concentrated phosphoric acid (85 wt percent, 9.5 mL, 0.1 equiv) was added in one portion to the slurry, resulting in a moderate exotherm. Diisopropylethylamine (245 mL, 1.39 mol, 1 equiv) was then added dropwise over 15 minutes at such a rate that the internal temperature of the reaction reached 85-90° C. by the end of the addition. By the end of the amine addition the reaction mixture was a homogenous light-orange solution. Heating was initiated and the orange solution was maintained at 100° C. for 20 hours, at which time HPLC analysis of the reaction mixture indicated that the starting material was consumed. External heating was removed and the contents of the flask were cooled to 40° C. and then added dropwise to a cooled mixture of 3N HCl (5 L, 10 equiv) and diethyl ether (2 L) keeping the temperature of the quench pot between 10 and 15° C. The layers were separated, and the aqueous layer was extracted once with ether (1 L). The combined organic layers were combined, washed with water until the washes were neutral (5*1.5 L washes), dried with MgSO₄ and concentrated to provide 288 g (95percent yield) of a light yellow-orange oil of 96percent purity (HPLC). This material can be further purified by distillation (bp 109° C. at 79 mmHg).
95%	With phosphoric acid; N-ethyl-N,N-diisopropylamine; trichlorophosphate In water at 85 - 100℃; for 20.25 h;	5-Trifluoromethyluracil (250 g, 1.39 mol) and phosphorous oxychloride (655 mL, 6.94 mol, 5 equiv) were charged to a 3 L 4-neck flask equipped with overhead stirrer, a reflux condenser, an addition funnel and an internal theromocouple. The contents were maintained under a nitrogen atmosphere as concentrated phosphoric acid (85 wt percent, 9.5 mL, 0.1 equiv) was added in one portion to the slurry, resulting in a moderate exotherm. Diisopropylethylamine (245 mL, 1.39 mol, 1 equiv) was then added dropwise over 15 min at such a rate that the internal temperature of the reaction reached 85-90° C. by the end of the addition. By the end of the amine addition the reaction mixture was a homogenous light-orange solution. Heating was initiated and the orange solution was maintained at 100° C. for 20 h, at which time HPLC analysis of the reaction mixture indicated that the starting material was consumed. External heating was removed and the contents of the flask were cooled to 40° C. and then added dropwise to a cooled mixture of 3NHCl (5 L, 10 equiv) and diethyl ether (2 L) keeping the temperature of the quench pot between 10 and 15° C. The layers were separated, and the aqueous layer was extracted once with ether (1 L). The combined organic layers were combined, washed with water until the washes were neutral (5.x.1.5 L washes), dried with MgSO₄and concentrated to provide 288 g (95percent yield) of a light yellow-orange oil of 96percent purity (HPLC). This material can be further purified by distillation (bp 109° C. at 79 mmHg).
95%	at 85 - 100℃; for 20.25 h;	5-Trifluoromethyluracil (250 g, 1.39 mol) and phosphorous oxychloride (655 mL, 6.94 mol, 5 equiv) were charged to a 3 L 4-neck flask equipped with overhead stirrer, a reflux condenser, an addition funnel and an internal theromocouple. The contents were maintained under a nitrogen atmosphere as concentrated phosphoric acid (85 wt percent, 9.5 mL, 0.1 equiv) was added in one portion to the slurry, resulting in a moderate exotherm. Diisopropylethylamine (245 mL, 1.39 mol, 1 equiv) was then added dropwise over 15 minutes at such a rate that the internal temperature of the reaction reached 85-90° C. by the end of the addition. By the end of the amine addition the reaction mixture was a homogenous light-orange solution. Heating was initiated and the orange solution was maintained at 100° C. for 20 hours, at which time HPLC analysis of the reaction mixture indicated that the starting material was consumed. External heating was removed and the contents of the flask were cooled to 40° C. and then added dropwise to a cooled mixture of 3N HCl (5 L, 10 equiv) and diethyl ether (2 L) keeping the temperature of the quench pot between 10 and 15° C. The layers were separated, and the aqueous layer was extracted once with ether (1 L). The combined organic layers were combined, washed with water until the washes were neutral (5.x.1.5 L washes), dried with MgSO₄and concentrated to provide 288 g (95percent yield) of a light yellow-orange oil of 96percent purity (HPLC). This material can be further purified by distillation (bp 109° C. at 79 mmHg).

72.9%	at 110 - 120℃;	10060] To a jacket reactor (500 mE) is added 5-trifluorom- ethyluracil (5-TFU, 40 g, 70percent assay, .-0.16 mol, 1.0 eq.), H3P04 (2.4 g; 0.02 mol, 0.13 eq.) andPOCl3 (128 g; 0.83 mol, 5.2 eq.) (a white suspension is formed). DIPEA (35 g, 0.27 mol, 1.69 eq.) is addedto the suspension dropwise in about 10 mm and then the reaction mixture is heated to 110-120° C. (clear solution). The reaction is monitored with HPEC until ratio 5-TFU:5-TFP<5 :95 (reactionnormally finished in 7-8 h; if reaction is not complete, additional P0C13 (5 g, 0.032 mol, 0.2 eq) and DIPEA (1.3 g, 0.01 mol, 0.06 eq) are charged and stirred for another 1-2 h). The reaction is then cooled tort and n-butyl acetate (80 mE) is added to the reaction mixture. About 60 mE of distillate (POC13 and some n-butyl acetate) is collected at 63-65° C./450-500 mbar. The resulting dark solution is slowly added to a mixture of conc. HC1 (165 g, 27 weight percent, 1.23 mol, 7.7 eq.) and methyl tertiary butyl ether (MTBE, 120 mE) while the temperature is maintained below 20° C. The organic phase is separated and the aqueous phase is extracted with MTBE (2x120 mE). The organic phase is gathered, washed with water until the pH value reaches ca. 5-6. MTBE is removed under reduced pressure (.-42° C./200 mbar), the final product is purified through distillation (87- 89° C./55 mbar) to afford 5-TFP as colorless oil (25.3 g, yield72.9percent; purity 98percent).2,4-dichloro-5-trifluoromethylpyrimidine (5-TFP)10061] Colorless to light yellow oil10062] ‘H NMR (CD3COCD3): ö 8.8 (s, 1 H),10063] ‘9F NMR (CD3COCD3): ö —63.710064] ESI MS (m/z) 216 [M—1]
72.9%	at 110 - 120℃;	To a jacket reactor (500 mL) is added 5-trifluoromethyluracil (5-TFU, 40 g, ~ 70 percent assay, ~ 0.16 mol, 1 .0 eq.), H₃PO4 (2.4 g; 0.02 mol, 0.13 eq.) and POCI₃ (128 g; 0.83 mol, 5.2 eq.) (a white suspension is formed). DIPEA (35 g, 0.27 mol, 1 .69 eq.) is added to the suspension dropwise in about 10 min and then the reaction mixture is heated to 1 10-120 °C (clear solution). The reaction is monitored with HPLC until ratio 5-TFU:5-TFP < 5:95 (reaction normally finished in 7-8 h; if reaction is not complete, additional POCI₃ (5 g, 0.032 mol, 0.2 eq) and DIPEA (1 .3 g, 0.01 mol, 0.06 eq) are charged and stirred for another 1 -2 h). The reaction is then cooled to rt and n-butyl acetate (80 mL) is added to the reaction mixture. About 60 mL of distillate (POCI₃ and some n-butyl acetate) is collected at 63-65 °C/450-500 mbar. The resulting dark solution is slowly added to a mixture of cone. HCI (165 g, 27 weight percent, 1 .23 mol, 7.7 eq.) and methyl tertiary butyl ether (MTBE, 120 mL) while the temperature is maintained below 20 °C. The organic phase is separated and the aqueous phase is extracted with MTBE (2 x 120 mL). The organic phase is gathered, washed with water until the pH value reaches ca. 5-6. MTBE is removed under reduced pressure (~ 42 °C/200 mbar), the final product is purified through distillation (87-89 °C/55 mbar) to afford 5-TFP as colorless oil (25.3 g, yield 72.9 percent; purity 98 percent). 2,4-dichloro-5-trifluoromethylpyrimidine (5-TFP) Colorless to light yellow oil 1H NMR (CD₃COCD₃): δ 8.8 (s, 1 H), 1⁹F NMR (CD₃COCD₃): δ -63.7 ESI MS (m/z) 216 [M-1 ]^"
61%	at 25 - 90℃; for 5.16667 - 6.16667 h;	48 g (267 mmol) 5-trifluoromethyluracil is suspended in 210 mL phosphorus oxychloride (POCl₃) while moisture is excluded. 47.7 g (320 mmol, 1.2 eq) diethylaniline is slowly added dropwise to this suspension, such that the temperature remains between 25° C. and 30° C. After the addition has ended the mixture is stirred for another 5-10 min in the water bath and the mixture is heated for 5-6 h at 80-90° C. while moisture is excluded. The excess POCl₃is destroyed by stirring-into about 1200 g sulphuric acid containing ice water and the aqueous phase is immediately extracted 3.x. with in each case 500 ml ether or t-butyl-methyl-ether. The combined ethereal extracts are washed 2.x. with 300 mL sulphuric acid-containing ice water (about 0.1 M) and with cold saline solution and immediately dried on sodium sulphate. The drying agent is filtered off and the solvent is eliminated in vacuo. The residue is distilled in vacuo (10 mbar) through a short column (20 cm) (head temperature: 65-70° C.), to obtain 35.3 g (0.163 mol, 61percent) of a colourless liquid which is poured off and stored under argon. DC: R_f=0.83 (cHex:EE=3:1)
17.7%	at 85 - 100℃; for 36 h; Inert atmosphere	5- (trifluoromethyl) pyrimidine -2,2- (1H, 3H) - dione (18g, 0.1mol) was added to a 250ml three-necked flask, was added phosphorus oxychloride (45.8ml, 5eq), phosphoric acid (O.leq) under nitrogen, was heated in an oil bath, was slowly added dropwise diisopropylethyl amine (16ml) between 85 ~ 90 , temperature was raised to 100 dropwise completed reaction was refluxed 36h, evaporated to dryness under reduced pressure The solvent, i.e. by column chromatography an oily liquid 2,4-dichloro-5- (trifluoromethyl) pyrimidine (3.8 g of, yield 17.7percent).

Reference： [1] Patent: US2005/256145, 2005, A1, . Location in patent: Page/Page column 43
[2] Patent: US2005/256125, 2005, A1, . Location in patent: Page/Page column 29
[3] Patent: US2005/256144, 2005, A1, . Location in patent: Page/Page column 20
[4] Patent: US2014/135497, 2014, A1, . Location in patent: Paragraph 0060; 0061; 0062; 0063; 0064
[5] Patent: WO2014/76085, 2014, A1, . Location in patent: Page/Page column 9-10
[6] Patent: US2007/32514, 2007, A1, . Location in patent: Page/Page column 10
[7] Patent: CN105461695, 2016, A, . Location in patent: Paragraph 0136; 0137
[8] Patent: WO2004/48343, 2004, A1, . Location in patent: Page 74
[9] Patent: WO2008/77885, 2008, A2, . Location in patent: Page/Page column 13
[10] Patent: WO2009/63240, 2009, A1, . Location in patent: Page/Page column 43-44
[11] Patent: US2009/163467, 2009, A1, . Location in patent: Page/Page column 8
[12] Patent: WO2009/71535, 2009, A1, . Location in patent: Page/Page column 22-23
[13] Patent: WO2010/55117, 2010, A1, . Location in patent: Page/Page column 29
[14] Patent: WO2010/106097, 2010, A1, . Location in patent: Page/Page column 29-30
[15] Patent: WO2010/136559, 2010, A1, . Location in patent: Page/Page column 34
[16] Patent: US2011/33441, 2011, A1, . Location in patent: Page/Page column 8
[17] Journal of Fluorine Chemistry, 2015, vol. 179, p. 150 - 158

2
[ 3932-97-6 ]
[ 69034-12-4 ]

Reference： [1] Patent: WO2009/150240, 2009, A1, . Location in patent: Page/Page column 132

3
[ 3932-97-6 ]
[ 939791-38-5 ]

Reference： [1] Patent: US2011/33441, 2011, A1,

4
[ 3932-97-6 ]
[ 1374640-70-6 ]

Reference： [1] Patent: WO2013/138495, 2013, A1,
[2] Patent: WO2013/138502, 2013, A1,
[3] Patent: WO2014/182593, 2014, A1,

[ 3932-97-6 ] Synthesis Path-Downstream 1~68

1
[ 6002-83-1 ]
[ 3932-97-6 ]
[ 22517-60-8 ]

Reference： [1]Patent: CH441366,1968,
    Chem.Abstr.,1968,vol. 69
[2]Patent: BE618638,1962,
    Chem.Abstr.,1963,vol. 59
[3]Patent: US3830840,1974,
    Chem.Abstr.,vol. 84

2
[ 54-20-6 ]
[ 3932-97-6 ]

Yield	Reaction Conditions	Operation in experiment
95%	With phosphoric acid; N-ethyl-N,N-diisopropylamine; trichlorophosphate; at 85 - 100℃; for 20h;	Preparation of 2.4-dichloro-5-trifluoromethylpyrimidine (3) 5-Trifluoromethyluracil (250 g, 1.39 mol) and phosphorous oxychloride (655 mL, 6.94 mol, 5 equiv) were charged to a 3 L 4-neck flask equipped with overhead stirrer, a reflux condenser, an addition funnel and an internal theromocouple. The contents were maintained under a nitrogen atmosphere as concentrated phosphoric acid (85 wt %, 9.5 mL, 0.1 equiv) was added in one portion to the slurry, resulting in a moderate exotherm. Diisopropylethylamine (245 mL, 1.39 mol, 1 equiv) was then added dropwise over 15 minutes at such a rate that the internal temperature of the reaction reached 85-90 C. by the end of the addition. By the end of the amine addition the reaction mixture was a homogenous light-orange solution. Heating was initiated and the orange solution was maintained at 100 C. for 20 hours, at which time HPLC analysis of the reaction mixture indicated that the starting material was consumed. External heating was removed and the contents of the flask were cooled to 40 C. and then added dropwise to a cooled mixture of 3N HCl (5 L, 10 equiv) and diethyl ether (2 L) keeping the temperature of the quench pot between 10 and 15 C. The layers were separated, and the aqueous layer was extracted once with ether (1 L). The combined organic layers were combined, washed with water until the washes were neutral (5*1.5 L washes), dried with MgSO4 and concentrated to provide 288 g (95% yield) of a light yellow-orange oil of 96% purity (HPLC). This material can be further purified by distillation (bp 109 C. at 79 mmHg).
95%	With phosphoric acid; N-ethyl-N,N-diisopropylamine; trichlorophosphate; In water; at 85 - 100℃; for 20.25h;	5-Trifluoromethyluracil (250 g, 1.39 mol) and phosphorous oxychloride (655 mL, 6.94 mol, 5 equiv) were charged to a 3 L 4-neck flask equipped with overhead stirrer, a reflux condenser, an addition funnel and an internal theromocouple. The contents were maintained under a nitrogen atmosphere as concentrated phosphoric acid (85 wt %, 9.5 mL, 0.1 equiv) was added in one portion to the slurry, resulting in a moderate exotherm. Diisopropylethylamine (245 mL, 1.39 mol, 1 equiv) was then added dropwise over 15 min at such a rate that the internal temperature of the reaction reached 85-90 C. by the end of the addition. By the end of the amine addition the reaction mixture was a homogenous light-orange solution. Heating was initiated and the orange solution was maintained at 100 C. for 20 h, at which time HPLC analysis of the reaction mixture indicated that the starting material was consumed. External heating was removed and the contents of the flask were cooled to 40 C. and then added dropwise to a cooled mixture of 3NHCl (5 L, 10 equiv) and diethyl ether (2 L) keeping the temperature of the quench pot between 10 and 15 C. The layers were separated, and the aqueous layer was extracted once with ether (1 L). The combined organic layers were combined, washed with water until the washes were neutral (5×1.5 L washes), dried with MgSO4 and concentrated to provide 288 g (95% yield) of a light yellow-orange oil of 96% purity (HPLC). This material can be further purified by distillation (bp 109 C. at 79 mmHg).
95%	With N-ethyl-N,N-diisopropylamine; trichlorophosphate;phosphoric acid; at 85 - 100℃; for 20.25h;	5-Trifluoromethyluracil (250 g, 1.39 mol) and phosphorous oxychloride (655 mL, 6.94 mol, 5 equiv) were charged to a 3 L 4-neck flask equipped with overhead stirrer, a reflux condenser, an addition funnel and an internal theromocouple. The contents were maintained under a nitrogen atmosphere as concentrated phosphoric acid (85 wt %, 9.5 mL, 0.1 equiv) was added in one portion to the slurry, resulting in a moderate exotherm. Diisopropylethylamine (245 mL, 1.39 mol, 1 equiv) was then added dropwise over 15 minutes at such a rate that the internal temperature of the reaction reached 85-90 C. by the end of the addition. By the end of the amine addition the reaction mixture was a homogenous light-orange solution. Heating was initiated and the orange solution was maintained at 100 C. for 20 hours, at which time HPLC analysis of the reaction mixture indicated that the starting material was consumed. External heating was removed and the contents of the flask were cooled to 40 C. and then added dropwise to a cooled mixture of 3N HCl (5 L, 10 equiv) and diethyl ether (2 L) keeping the temperature of the quench pot between 10 and 15 C. The layers were separated, and the aqueous layer was extracted once with ether (1 L). The combined organic layers were combined, washed with water until the washes were neutral (5×1.5 L washes), dried with MgSO4 and concentrated to provide 288 g (95% yield) of a light yellow-orange oil of 96% purity (HPLC). This material can be further purified by distillation (bp 109 C. at 79 mmHg).

72.9%	With trihydrogen phosphate; N-ethyl-N,N-diisopropylamine; trichlorophosphate; at 110 - 120℃;	10060] To a jacket reactor (500 mE) is added 5-trifluorom- ethyluracil (5-TFU, 40 g, 70% assay, .-0.16 mol, 1.0 eq.), H3P04 (2.4 g; 0.02 mol, 0.13 eq.) andPOCl3 (128 g; 0.83 mol, 5.2 eq.) (a white suspension is formed). DIPEA (35 g, 0.27 mol, 1.69 eq.) is addedto the suspension dropwise in about 10 mm and then the reaction mixture is heated to 110-120 C. (clear solution). The reaction is monitored with HPEC until ratio 5-TFU:5-TFP<5 :95 (reactionnormally finished in 7-8 h; if reaction is not complete, additional P0C13 (5 g, 0.032 mol, 0.2 eq) and DIPEA (1.3 g, 0.01 mol, 0.06 eq) are charged and stirred for another 1-2 h). The reaction is then cooled tort and n-butyl acetate (80 mE) is added to the reaction mixture. About 60 mE of distillate (POC13 and some n-butyl acetate) is collected at 63-65 C./450-500 mbar. The resulting dark solution is slowly added to a mixture of conc. HC1 (165 g, 27 weight %, 1.23 mol, 7.7 eq.) and methyl tertiary butyl ether (MTBE, 120 mE) while the temperature is maintained below 20 C. The organic phase is separated and the aqueous phase is extracted with MTBE (2x120 mE). The organic phase is gathered, washed with water until the pH value reaches ca. 5-6. MTBE is removed under reduced pressure (.-42 C./200 mbar), the final product is purified through distillation (87- 89 C./55 mbar) to afford 5-TFP as colorless oil (25.3 g, yield72.9%; purity 98%).2,4-dichloro-5-trifluoromethylpyrimidine (5-TFP)10061] Colorless to light yellow oil10062] ?H NMR (CD3COCD3): oe 8.8 (s, 1 H),10063] ?9F NMR (CD3COCD3): oe -63.710064] ESI MS (m/z) 216 [M-1]
72.9%	With phosphoric acid; N-ethyl-N,N-diisopropylamine; trichlorophosphate; at 110 - 120℃;	To a jacket reactor (500 mL) is added <strong>[54-20-6]5-trifluoromethyluracil</strong> (5-TFU, 40 g, ~ 70 % assay, ~ 0.16 mol, 1 .0 eq.), H3PO4 (2.4 g; 0.02 mol, 0.13 eq.) and POCI3 (128 g; 0.83 mol, 5.2 eq.) (a white suspension is formed). DIPEA (35 g, 0.27 mol, 1 .69 eq.) is added to the suspension dropwise in about 10 min and then the reaction mixture is heated to 1 10-120 C (clear solution). The reaction is monitored with HPLC until ratio 5-TFU:5-TFP < 5:95 (reaction normally finished in 7-8 h; if reaction is not complete, additional POCI3 (5 g, 0.032 mol, 0.2 eq) and DIPEA (1 .3 g, 0.01 mol, 0.06 eq) are charged and stirred for another 1 -2 h). The reaction is then cooled to rt and n-butyl acetate (80 mL) is added to the reaction mixture. About 60 mL of distillate (POCI3 and some n-butyl acetate) is collected at 63-65 C/450-500 mbar. The resulting dark solution is slowly added to a mixture of cone. HCI (165 g, 27 weight %, 1 .23 mol, 7.7 eq.) and methyl tertiary butyl ether (MTBE, 120 mL) while the temperature is maintained below 20 C. The organic phase is separated and the aqueous phase is extracted with MTBE (2 x 120 mL). The organic phase is gathered, washed with water until the pH value reaches ca. 5-6. MTBE is removed under reduced pressure (~ 42 C/200 mbar), the final product is purified through distillation (87-89 C/55 mbar) to afford 5-TFP as colorless oil (25.3 g, yield 72.9 %; purity 98 %). 2,4-dichloro-5-trifluoromethylpyrimidine (5-TFP) Colorless to light yellow oil 1H NMR (CD3COCD3): delta 8.8 (s, 1 H), 19F NMR (CD3COCD3): delta -63.7 ESI MS (m/z) 216 [M-1 ]"
61%	With N,N-diethylaniline; trichlorophosphate; at 25 - 90℃; for 5.16667 - 6.16667h;	48 g (267 mmol) <strong>[54-20-6]5-trifluoromethyluracil</strong> is suspended in 210 mL phosphorus oxychloride (POCl3) while moisture is excluded. 47.7 g (320 mmol, 1.2 eq) diethylaniline is slowly added dropwise to this suspension, such that the temperature remains between 25 C. and 30 C. After the addition has ended the mixture is stirred for another 5-10 min in the water bath and the mixture is heated for 5-6 h at 80-90 C. while moisture is excluded. The excess POCl3 is destroyed by stirring-into about 1200 g sulphuric acid containing ice water and the aqueous phase is immediately extracted 3× with in each case 500 ml ether or t-butyl-methyl-ether. The combined ethereal extracts are washed 2× with 300 mL sulphuric acid-containing ice water (about 0.1 M) and with cold saline solution and immediately dried on sodium sulphate. The drying agent is filtered off and the solvent is eliminated in vacuo. The residue is distilled in vacuo (10 mbar) through a short column (20 cm) (head temperature: 65-70 C.), to obtain 35.3 g (0.163 mol, 61%) of a colourless liquid which is poured off and stored under argon. DC: Rf=0.83 (cHex:EE=3:1)
17.7%	With phosphoric acid; N-ethyl-N,N-diisopropylamine; trichlorophosphate; at 85 - 100℃; for 36h;Inert atmosphere;	5- (trifluoromethyl) pyrimidine -2,2- (1H, 3H) - dione (18g, 0.1mol) was added to a 250ml three-necked flask, was added phosphorus oxychloride (45.8ml, 5eq), phosphoric acid (O.leq) under nitrogen, was heated in an oil bath, was slowly added dropwise diisopropylethyl amine (16ml) between 85 ~ 90 , temperature was raised to 100 dropwise completed reaction was refluxed 36h, evaporated to dryness under reduced pressure The solvent, i.e. by column chromatography an oily liquid 2,4-dichloro-5- (trifluoromethyl) pyrimidine (3.8 g of, yield 17.7%).
	With N,N-diethylaniline; trichlorophosphate; for 18h;Heating / reflux;	To 5-TRIFLUOROMETHYLURACIL (25 g) were sequentially added N, N-diethylaniline (25 g) and phosphoryl chloride (94 g), and the mixture was REFLUXED for 18 h. After cooling to r. t. the solution was poured onto ice (100 g), stirred for 10 min. and extracted with diethyl ether. The combined organic phases were washed with saturated aqueous sodium carbonate solution and water, dried (NA2SO4), and filtered. After removal of most of the ether, distillation of the residue at 190 C and 860 to 300 mbar gave the title compound (5.8 g). aH NMR (300 MHz, CDC13) : O/PPM = 8.83 (s, 1H).
	With N,N-diethylaniline; trichlorophosphate; at 25 - 90℃; for 5.16667 - 6.16667h;	A-I) 2,4-Dichloro-5-trifluoromethyl-pyrimidine48 g (267 mmol) <strong>[54-20-6]5-trifluoromethyluracil</strong> are suspended in 210 rnL phosphorus oxychloride (POCI3) while moisture is excluded. 47.7 g (320 mmol, 1.2 eq) diethylaniline are added dropwise to this suspension so slowly that the temperature remains between 25C and 300C. After the addition has ended the mixture is stirred for another 5 - 10 min in the water bath and heated for 5 - 6 h at 80 - 900C while moisture is excluded. The excess POCI3 is destroyed by stirring into approx. 1200 g sulphuric acid-containing ice water and the aqueous phase is immediately extracted 3 times with in each case 500 mL ether or tert- butyl-methyl-ether. The combined ethereal extracts are washed twice with 300 mL sulphuric acid-containing ice water (approx. 0.1 M) and with cold saline solution and immediately dried on sodium sulphate. The desiccant is filtered off and the solvent is eliminated in vacuo. The residue is distilled in vacuo (10 mbar) through a short column (20 cm) (head temperature: 65 - 700C), to obtain 35.3 g of a liquid which is poured off under protective gas and stored. TLC: Rf = 0.83 (cHex:EE = 3:1)
		5-Trifluoromethyluracil (5 g, 27.8 mmol) and phosphorous oxychloride (21.3 g, 0.136 mmol, 1.5 eq.) were stirred in a 3 neck flask, fitted with reflux condenser, internal thermometer and addition funnel under a nitrogen atmosphere. Concentrated phosphoric acid (200 muL) was added to the slurry followed by dropwise addition of di- °propylethylamine (3.6 g, 27.8 mmol, 1 eq.) at a rate that maintained the internal temperature below 90 0C. Once addition was complete, the solution was heated to 100 0C for 20 hours. After this time HPLC showed no more starting material to be present. The reaction was then allowed to cool before being added slowly to cooled, aqueous 3M hydrochloric acid (3 eq.) at a rate that maintained the temperature below 15 0C. The aqueous product was then twice extracted with diethyl ether (100 mL) and the combined organic extracts were washed with water until the extracts were neutral (5 x 100 mL). After drying with magnesium sulphate the solution was concentrated to produce a light orange oil. Further purification could either be achieved by distillation or solid phase extraction.
	With N,N-diethylaniline; trichlorophosphate; at 25 - 90℃; for 5.08333 - 6.16667h;	48g (267 mmol) <strong>[54-20-6]5-trifluoromethyluracil</strong> are suspended in 210 mL phosphorus oxychloride (POCl3) while moisture is excluded. 47.7 g (320 mmol, 1.2 eq) diethylaniline are added dropwise to this suspension so slowly that the temperature remains between 25 C. and 30 C. After the addition has ended the mixture is stirred for another 5-10 min in the water bath and heated for 5-6 h at 80-90 C. while moisture is excluded. The mixture obtained is stirred into approx. 1200 g sulphuric acid-containing ice water and the aqueous phase is immediately extracted 3 times with in each case 500 mL ether or tert-butyl-methyl-ether. The combined ethereal extracts are washed twice with 300 mL sulphuric acid-containing ice water (approx. 0.1 M) and with cold saline solution and dried. The desiccant is filtered off and the solvent is eliminated in vacuo. The residue is distilled in vacuo (10 mbar) through a short column (head temperature: 65-70 C.), to obtain 35.3 g of a liquid which is poured off under protective gas and stored.DC: Rf=0.83 (cHex:EE=3:1).
	With N,N-diethylaniline; trichlorophosphate; at 25 - 90℃; for 5.08333 - 6.16667h;	a) Procedure for synthesising 2,4-dichloro-5-trifluoromethyl-pyrimidine A-Ia; <strong>[54-20-6]5-trifluoromethyluracil</strong> (48.0 g, 267 mmol) is suspended in 210 mL phosphorus oxy- chloride (POCI3) while moisture is excluded. Diethylaniline (47.7 g, 320 mmol) is slowly added dropwise to this suspension such that the temperature remains between 25 0C and 30 0C. After the addition has ended the mixture is stirred for a further 5 - 10 min in the water bath and the mixture is heated for 5 - 6 h with the exclusion of moisture at 80 - 90 0C. The excess POCI3 is destroyed by stirring into approx. 1200 g of sulphuric acid mixed with ice water and the aqueous phase is immediately extracted 3 x with in each case 500 mL diethyl ether or te/t.-butylmethyl ether. The combined ethereal extracts are washed 2 x with 300 mL sulphuric acid mixed with ice water (approx. 0.1 M) and with cold saline solution and immediately dried on sodium sulphate. The desiccant is filtered off and the solvent is eliminated in vacuo. The residue is distilled in vacuo (10 mbar) through a short column (20 cm) (head temperature: 65 - 70 0C), to obtain a colourless liquid that is bottled and stored under argon. <n="24"/>TLC: Rf = 0.83 (chex:EE = 3:1)Analogously to this procedure further pyrimidines A-I are obtained from the corresponding intermediates/educts or the corresponding commercially obtainable educt.
	With N,N-diethylaniline; trichlorophosphate; at 25 - 90℃;	<strong>[54-20-6]5-trifluoromethyluracil</strong> (48.0 g, 267 mmol) is suspended in 210 mL phosphorus oxychloride (POCI3) while moisture is excluded. Diethylaniline (47.7 g, 320 mmol) is slowly added dropwise to this suspension such that the temperature remains between 250C and 300C. After the addition has ended the mixture is stirred for a further 5 - 10 min in the water bath and the mixture is heated for 5- 6 h with the exclusion of moisture at 80 - 900C. The excess POCI3 is destroyed by stirring into approx. 1200 g of sulphuric acid mixed with ice water and the aqueous phase is immediately extracted 3 x with in each case 500 mL diethyl ether or te/t.-butylmethyl ether. The combined ethereal extracts are washed 2 x with 300 mL sulphuric acid mixed with ice water (approx. 0.1 M) and with cold saline solution and immediately dried on sodium sulphate. The desiccant is filtered off and the solvent is eliminated in vacuo. The residue is distilled in vacuo (10 mbar) through a short column (20 cm) (head temperature: 65 - 700C), to obtain a colourless liquid that is bottled and stored under argon. TLC: Rf = 0.83 (chex:EE = 3:1)
	With N,N-diethylaniline; trichlorophosphate; at 25 - 90℃;	<strong>[54-20-6]5-trifluoromethyluracil</strong> (48.0 g, 267 mmol) is suspended in 210 ml. phosphorus oxychloride (POCI3) while moisture is excluded. Diethylamide (47.7 g, 320 mmol) is slowly added dropwise to this suspension such that the temperature remains between 25C and 300C. After the addition has ended the mixture is stirred for a further 5 - 10 min in the water bath and the mixture is heated for 5- 6 h with the exclusion of moisture at 80 - 900C. The excess POCI3 is destroyed by stirring into approx. 1200 g of sulphuric acid mixed with ice water and the aqueous phase is immediately extracted 3 x with in each case 500 ml. diethyl ether or te/f.-butylmethyl ether. The combined ethereal extracts are washed 2 x with 300 ml. sulphuric acid mixed with ice water (approx. 0.1 M) and with cold saline solution and immediately dried on sodium sulphate. The desiccant is filtered off and the solvent is eliminated in vacuo. The residue is distilled in vacuo (10 mbar) through a short column (20 cm) (head temperature: 65 - 700C), to obtain a colourless liquid that is bottled and stored under argon. TLC: Rf = 0.83 (cHex:EE = 3:1 )
		a) 2,4-dichloro-5-trifluoromethyl-pyrimidine (A-1a)A-1a<strong>[54-20-6]5-trifluoromethyluracil</strong> (48.0 g, 267 mmol) is suspended in 210 ml. phosphorus oxychloride (POCI3) while moisture is excluded. Diethylamide (47.7 g, 320 mmol) is slowly added dropwise to this suspension such that the temperature remains between 25C and 300C. After the addition has ended the mixture is stirred for a further 5 - 10 min in the water bath and the mixture is heated for 5 - 6 h with the exclusion of moisture at 80 - 900C. The excess POCI3 is destroyed by stirring into approx. 1200 g of sulphuric acid mixed with ice water and the aqueous phase is immediately extracted 3 x with in each case 500 mL diethyl ether or te/f.-butylmethyl ether. The combined ethereal extracts are washed 2 x with 300 mL sulphuric acid mixed with ice water (approx. 0.1 M) and with cold saline solution and immediately dried on sodium sulphate. The desiccant is filtered off and the solvent is eliminated in vacuo. The residue is distilled in vacuo (10 mbar) through a short column (20 cm) (head temperature: 65 - 700C), to obtain a colourless liquid that is bottled and stored under argon.(TLC: Rf = 0.83 (in cHex:EA = 3:1 )
	With phosphoric acid; N-ethyl-N,N-diisopropylamine; trichlorophosphate; In water; at 20 - 100℃; for 22h;Industry scale;	Trifluoromethyluracil (5.00 kg, 1 eq.), phosphorous oxychloride (21.50 kg, 5 eq.), and an 85 wt. % solution of phosphoric acid in water (320 g, 0.1 eq.) were charged to a reactor that was boiled out with ethanol and had a caustic scrubber attached. N,N-diisopropylethylamine (3.62 kg, 1 eq.) was separated into five charges, the first four being 1 liter and the fifth 0.9 liters and added at a rate keeping the temperature of the reaction mixture between 20 and 40 C. The reaction mixture was heated to 100 C. over 2 hours and held for 20 hours. After cooling to 20-30 C., the reaction mixture was transferred into a stirred 1:1 solution of hexanes/water (10 L/kg:10 L/kg) at a rate where the temperature did not exceed 50 C. and the time of transfer was at least 3 hours. The hexanes layer was washed twice with water (5 L/kg) and dried with magnesium sulfate (1.00 kg) followed by a filtration and rinse with hexanes (1 L/kg). Hexanes were removed by distillation at atmospheric pressure with a final distillate temperature of 75 C. and pot temperature of 100 C. GC headspace indicated 2.1% hexanes remained in the final product.

Reference： [1]Patent: US2005/256145,2005,A1 .Location in patent: Page/Page column 43
[2]Patent: US2005/256125,2005,A1 .Location in patent: Page/Page column 29
[3]Patent: US2005/256144,2005,A1 .Location in patent: Page/Page column 20
[4]Patent: US2014/135497,2014,A1 .Location in patent: Paragraph 0060; 0061; 0062; 0063; 0064
[5]Patent: WO2014/76085,2014,A1 .Location in patent: Page/Page column 9-10
[6]Patent: US2007/32514,2007,A1 .Location in patent: Page/Page column 10
[7]Patent: CN105461695,2016,A .Location in patent: Paragraph 0136; 0137
[8]Patent: WO2004/48343,2004,A1 .Location in patent: Page 74
[9]Patent: WO2008/77885,2008,A2 .Location in patent: Page/Page column 13
[10]Patent: WO2009/63240,2009,A1 .Location in patent: Page/Page column 43-44
[11]Patent: US2009/163467,2009,A1 .Location in patent: Page/Page column 8
[12]Patent: WO2009/71535,2009,A1 .Location in patent: Page/Page column 22-23
[13]Patent: WO2010/55117,2010,A1 .Location in patent: Page/Page column 29
[14]Patent: WO2010/106097,2010,A1 .Location in patent: Page/Page column 29-30
[15]Patent: WO2010/136559,2010,A1 .Location in patent: Page/Page column 34
[16]Patent: US2011/33441,2011,A1 .Location in patent: Page/Page column 8
[17]Journal of Fluorine Chemistry,2015,vol. 179,p. 150 - 158

3
[ 150544-04-0 ]
[ 3932-97-6 ]
6-(4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With triethylamine;zinc(II) chloride; In tetrahydrofuran; diethyl ether; at 20℃;	To a solution of 2,4-dichloro-5-trifluoromethylpyrimidine (3.51 g; 16.2 mmol) in THF (100 mL) was added a solution of ZnCl2 (1M in ether; 16.2 mL). After 15 minutes 6-aminooxindole (2 g; 13.5 mmol) was added in small portions, followed by the dropwise addition of Et3N (1.63 g; 16.2 mmol) in 10 mL of THF. The reaction was then stirred at RT overnight. Following removal of the solvent under reduced pressure, the crude reaction was triturated from methanol and the product filtered off as a yellow solid 2.2 g (50percent yield). 1H NMR (DMSO-d6, 400 MHz) delta 3.40 (s, 2H), 7.13 (d, J=8.3 Hz, 2H), 7.20 (d, J=7.9 Hz; 1H), 7.27 (br s, 1H), 8.75 (s, 1H), 10.41 (s, 1H), 10.62 (s, 1H); HPLC ret. time: 5.933 min. LRMS (M+) 329.1, 331.0.

Reference： [1]Patent: US2005/256125,2005,A1 .Location in patent: Page/Page column 29

4
[ 25369-32-8 ]
[ 3932-97-6 ]
7-(4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With triethylamine;zinc(II) chloride; In diethyl ether; 1,2-dichloro-ethane; tert-butyl alcohol; at 0 - 20℃;	<strong>[25369-32-8]7-amino-oxindole</strong> (910 mg, 6.1 mmol) was added portionwise to a solution of 5-trifluoromethyl-2,4-dichloropyrimidine (1.33 g, 1 eq) and ZnCl2 (6.1 mL of a 1M solution in ether) in 1:1 DCE/t-butanol (30 mL) at 0 C. After 15 minutes a solution of Et3N (0.94 mL, 1.1 eq) in 1:1 DCE/t-butanol (10 mL) was added dropwise. The reaction was allowed to warm to RT overnight. The reaction was then concentrated and the product triturated from methanol as a green solid 1.61 g (81%). 1H NMR (DMSO-d6, 400 MHz) delta 3.51 (s, 2H), 6.92 (m, 1H), 7.08 (d, J=7.5 Hz, 2H), 8.66 (s, 1H), 10.10 (s, 1H), 10.17 (s, 1H); HPLC ret. time: 5.870 min. LRMS (M+) 329.1, 331.1.

Reference： [1]Patent: US2005/256125,2005,A1 .Location in patent: Page/Page column 30

5
[ 3932-97-6 ]
[ 5188-07-8 ]
[ 919116-35-1 ]
[ 919116-36-2 ]
2,4-bis-methylsulphanyl-5-trifluoromethylpyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%; 30%; 4%	In tetrahydrofuran; at -25 - 20℃; for 1h;	5 g (23 mmol) 2,4-dichloro-5-trifluoromethyl-pyrimidine is dissolved in 40 mL THF, the solution is adjusted to -25 C. and 1.8 g (25.3 mmol, 1.1 eq) sodium thiomethoxide is added. The mixture is stirred for 1 h at -25 C. and then without cooling stirred overnight at RT. Then it is diluted with dichloromethane and washed 3× with 1 N HCl. The organic phase is dried on magnesium sulphate and evaporated down in vacuo. The crude product is purified by column chromatography (silica gel, cyclohexane/dichloromethane; from 90/10 to 80/20% in about 20 min). 1.56 g (6.8 mmol, 30%) of the product A-3 and 1.46 g (6.4 mmol, 28%) of the product A-2 are isolated as colourless oils. In addition 0.24 g (4%) of 2,4-bis-methylsulphanyl-5-trifluoromethyl-pyrimidine may be isolated as a colourless solid. product A-3 product A-2 Rf (cHex:CH2Cl2 1:1) 0.48 0.40 The structural analysis is carried out by chemical derivatisation and subsequent NMR spectroscopy. For this, A-2 and A-3 are first of all dehalogenated separately in THF at 100 C., 5 bar H2, Pd/C and Pd(OH)2 in a ratio of 1:1 in each case. Thanks to the different symmetry characteristics of the products formed it is possible to identify the regioisomers clearly.

Reference： [1]Patent: US2007/32514,2007,A1 .Location in patent: Page/Page column 10-11

6
[ 19008-43-6 ]
[ 3932-97-6 ]
[ 919116-55-5 ]
C₁₉H₁₃ClF₃N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 20 - 60℃;	C-1a) benzyl 4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-benzoate 10 g (44 mmol) <strong>[19008-43-6]benzyl 4-aminobenzoate</strong> is dissolved in 200 mL DMA, 8 mL Hünig base (0.97 eq) is added and 10.4 g (48.21 mmol) 2,4-dichloro-5-trifluoromethylpyrimidine, dissolved in 50 mL DMA, are added dropwise at RT to the clear solution. The reaction solution is stirred overnight at 60 C., then combined with 300 mL dichloromethane and extracted with distilled water (3*300 mL). The organic phase is dried on sodium sulphate and the solvent is eliminated in vacuo. The crude product is combined with 100 mL MeOH, digested and left to stand for 2 h. Then the mixture is stirred for 10 min, the precipitate is filtered off and washed with methanol (methanolic filtrate contains the unwanted regioisomer of the nucleophilic substitution). Finally the crude product is once more suspended in methanol, filtered off, washed with a little methanol and dried at 60 C. in the vacuum dryer. 8.5 g (20.7 mmol, 43%) of C-1a is obtained in the form of a light yellow solid. Rf=0.71 (silica gel, cHex:EE 1:2) MS-ESI+: 408 (M+H)+

Reference： [1]Patent: US2007/32514,2007,A1 .Location in patent: Page/Page column 15

7
[ 19008-43-6 ]
[ 3932-97-6 ]
[ 919116-55-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 20 - 60℃;	D-2) Benzyl 4-(4-chloro-5-trifluoromethvtøyrimidin-2-ylamino)-benzoate <n="31"/>1O g (44 mmol) <strong>[19008-43-6]benzyl 4-aminobenzoate</strong> D-I are dissolved in 200 mL DMA, 8 rnL of Hnig base (0.97 eq) are added and 10.4 g (48.21 mmol) of 2,4-dichloro-5- trifluoromethylpyrimidine, dissolved in 50 mL DMA, are added dropwise to this solution at RT. The reaction solution is stirred overnight at 600C, then combined with 300 mL DCM and extracted with distilled water (3 times 300 mL). The organic phase is dried and the solvent is eliminated in vacuo. The crude product is combined with 100 mL MeOH, digested and left to stand for 2 h. Then it is stirred for 10 min, the precipitate is filtered off and washed with MeOH. Finally the crude product is suspended again in MeOH, filtered off, washed with a little MeOH and dried at 600C in the vacuum dryer. 8.5 g of D-2 are obtained.Rf = 0.71 (silica gel, cHex:EE 1 :2) MS-ESI+: 408 (M+H)+
	With N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 20 - 60℃;	10g (44 mmol) <strong>[19008-43-6]benzyl 4-aminobenzoate</strong> are dissolved in 200 mL DMA, 8 mL Hünig base (0.97 eq) are added and 10.4 g (48.21 mmol) 2,4-dichloro-5-trifluoromethylpyrimidine, dissolved in 50 mL DMA, are added dropwise at RT to this solution. The reaction mixture is stirred at 60 C. overnight, then combined with 300 mL DCM and extracted with water (3 times 300 mL). The organic phase is dried and the solvent is eliminated in vacuo. The crude product is combined with 100 mL MeOH, digested and left to stand for 2 h. Then it is stirred for 10 min, the precipitate is filtered off and washed with MeOH. Finally the crude product is again suspended in MeOH, filtered off, washed with a little MeOH and dried in the vacuum dryer at 60 C. 8.5 g A-2a are obtained.Rf=0.71 (silica gel, cHex:EE 1:2)MS-ESI+: 408 (M+H)+

Reference： [1]Patent: WO2008/77885,2008,A2 .Location in patent: Page/Page column 29-30
[2]Patent: US2009/163467,2009,A1 .Location in patent: Page/Page column 8

8
[ 92146-82-2 ]
[ 3932-97-6 ]
[ 1073160-25-4 ]

Yield	Reaction Conditions	Operation in experiment
53%	With N-ethyl-N,N-diisopropylamine; zinc dibromide In 1,2-dichloro-ethane; <i>tert</i>-butyl alcohol at 25℃; for 16h;	9.1 Example 9; Preparation of tert-butyl 3-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzoate (9) Step 1. Preparation of tert-butyl 3-({4-chloro-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzoate (C8) A solution of pyrimidine (24.8 g, 115 mmol) in tert-butanol (150 mL) and DCE (150 mL) was treated with ZnBr2 (25.8 g, 115 mmol), and the resultant mixture was stirred at 25° C. until all the ZnBr2 dissolved. The resultant solution was cooled to 0° C. and treated drop-wise with aniline (22.13 g, 115 mmol). The resultant brown mixture was then treated drop-wise with DIEA (40.1 mL, 230 mmol). The mixture was allowed to warm to 25° C. and stirred for 16 hours under N2 atmosphere. The mixture was concentrated, and the resultant residue was suspended in MeOH. The resultant white solids were collected to provide C8 as a white solid. Yield: 22.7 grams, 53%. APCI m/z 371.8/373.8 (M-); 1H NMR (d6-DMSO) δ: 10.84 (bs, 1H), 8.85 (s, 1 h), 8.37 (bs, 1H), 7.92 (d, J=7.8 Hz., 1 h), 7.62 (d, J=7.8 Hz., 1H), 7.48 (t, J=7.8 Hz, 1H), 1.56 (s, 9H) ppm.

Reference： [1]Current Patent Assignee: PFIZER INC; VERASTEM INC - US2009/54395, 2009, A1 Location in patent: Page/Page column 51

9
[ 6274-22-2 ]
[ 3932-97-6 ]
[ 1073160-19-6 ]

Yield	Reaction Conditions	Operation in experiment
40%		Preparation of 4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)-N-methylbenzamide (B20) ; A solution of 2,4-dichloro-5-trifluoromethyl-pyrimidine (8.63 mmol) in 1:1 t-BuOH/DCE (10 mL) was cooled to 5 C., treated with solid ZnBr2 (22.5 mmol), and stirred at 5 C. for 30 minutes. The resultant solution was maintained at 5 C. and treated first with solid <strong>[6274-22-2]4-amino-N-methyl-benzamide</strong> (7.5 mmol) followed by TEA (16.5 mmol). The resultant white mixture was allowed to warm 25 C., and it was mixed at 25 C. for 20 hours. The mixture was adsorbed onto silica gel, and the fraction eluting 0-10% methanol/DCM was collected and concentrated. The resultant residue was triturated with water and filtered to provide B20. Yield: 3.0 mmol, 40%. LCMS 2.3 min, MZ+=331.1 1H NMR (500 MHz, d6-DMSO) delta ppm 10.89 (s, 1H), 8.87 (s, 1H), 8.34 (d, J=4.67 Hz, 1H), 7.73-7.89 (m, 3H), 2.78 (d, J=4.67 Hz, 3H).

Reference： [1]Patent: US2009/54395,2009,A1 .Location in patent: Page/Page column 46

10
[ 3932-97-6 ]
[ 70654-85-2 ]
[ 1152262-37-7 ]

Yield	Reaction Conditions	Operation in experiment
69%	With triethylamine; zinc(II) chloride; In 1,2-dichloro-ethane; tert-butyl alcohol; at 0 - 20℃;	2,4-Dichloro-5-triflouromethylpyrimidine (2.80 g, 13.04 mmol) and anhydrous ZnCl2 (1.76 g, 13.04 mmol) were stirred in tert-butanol:l,2-dichloroethane (1:1, 90 mL) for 1 h at room temperature before cooling to 0 0C. 2,2-Dioxo-l,3-dihydrobenzo[c]thiophene-5-yl amine (1.56 g, 8.52 mmol, 80% purity) was then added in a single portion, followed by the dropwise addition Of Et3N (1.87 mL, 13.04 mmol) in tert-butanol:l,2-dichloroethane (1:1, 6.3 mL). The reagents were allowed to stir and warm to room temperature overnight. The solvent was then removed in vacuo and the tan solid suspended in methanol (200 mL) for 2 h before being filtered off, washed with methanol (10 mL) and diethyl ether (20 mL) and dried to produce a pale tan powder (1.7 g, 69%). Rt = 2.32 min; M-H = 362.

Reference： [1]Patent: WO2009/63240,2009,A1 .Location in patent: Page/Page column 45

11
[ 222036-66-0 ]
[ 3932-97-6 ]
[ 1141380-38-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 6071 - 6077

12
[ 102308-97-4 ]
[ 3932-97-6 ]
[ 1141371-17-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 6071 - 6077

13
[ 20876-36-2 ]
[ 3932-97-6 ]
[ 717907-76-1 ]

Yield	Reaction Conditions	Operation in experiment
82%		To a solution of 5-trifluoromethyl-2,4-dichloropyrimidine (214.8 g; 0.921 mol) in 1:1 DCE/tBuOH (1.240 L) was added Zinc chloride 1 M solution in ether (1 eq; 0.921 L). After 0.5 hour, 5-amino-oxindole (124 g; 0.837 mol) was added followed by triethylamine (129.4 ml; 0.921 mol) keeping temperature at 25° C. The reaction was allowed to stir at room temperature overnight, then was concentrated and the product triturated from methanol as a yellow solid (224.3 g; 82percent). 1H NMR (DMSO-d6, 400 MHz) delta 3.29 (s, 2H), 6.76 (d, J=7.9 Hz, 2H), 7.39 (d, J=8.3 Hz), 7.51 (br s, 1H), 8.71 (s, 1H), 10.33 (s, 1H), 10.49 (s, 1H). 13C NMR (DMSO-d6, 100 MHz) delta 177.0, 161.3, 158.7 (br), 140.7, 132.8, 126.9, 123.7 (q, J=268 Hz), 121.0, 118.7, 111.2 (q, J=32 Hz), 109.6, 36.7; HPLC ret. time: 5.759 min. LRMS (M+) 329.1, 331.1.
		T-butyl alcohol (3 L/kg) and zinc dibromide (5.07 kg) were charged to the reactor then stirred for 10 minutes. 5-Aminooxindole (3.00 kg) and dichloroethane (3 L/kg) were then added followed by stirring 30 minutes. The product from Step 1 was added then the triethylamine was added over 30 minutes keeping the temperature below 35° C., and the reaction mixture was stirred overnight. Methanol (13.5 L) was added to the reaction mixture. The reaction mixture was then filtered through two Buchner funnels over several hours, filtration was aided by constantly moving the filter cake. The filter cakes were rinsed with methanol (6.4 L). The reactor was charged with methanol (15 L) and the wet cake was returned to the reactor and stirred for 1 hour, filtered over two Buchner funnels and washed with methanol (2.5 L). Trituration and filtration were repeated and the product was dried in the vacuum dried at 33° C. for 12 hours. GC headspace showed 0.1percent methanol remained in the product.

Reference： [1]Patent: US2005/256144,2005,A1 .Location in patent: Page/Page column 20
[2]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 6071 - 6077
[3]Patent: US2011/33441,2011,A1 .Location in patent: Page/Page column 8

14
[ 1709-52-0 ]
[ 3932-97-6 ]
[ 1141378-43-9 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2,4-dichloro-5-trifluoromethylpyrimidine With zinc(II) chloride In diethyl ether; dichloromethane; <i>tert</i>-butyl alcohol at -5℃; for 1h; Stage #2: N-methyl-4-aminobenzenesulfonamide With triethylamine In diethyl ether; dichloromethane; <i>tert</i>-butyl alcohol at -5 - 40℃;

Reference： [1]Location in patent: scheme or table Walker, Daniel P.; Christopher Bi; Kalgutkar, Amit S.; Bauman, Jonathan N.; Zhao, Sabrina X.; Soglia, John R.; Aspnes, Gary E.; Kung, Daniel W.; Klug-McLeod, Jacquelyn; Zawistoski, Michael P.; McGlynn, Molly A.; Oliver, Robert; Dunn, Matthew; Li, Jian-Cheng; Richter, Daniel T.; Cooper, Beth A.; Kath, John C.; Hulford, Catherine A.; Autry, Christopher L.; Luzzio, Michael J.; Ung, Ethan J.; Roberts, W. Gregory; Bonnette, Peter C.; Buckbinder, Leonard; Mistry, Anil; Griffor, Matthew C.; Han, Seungil; Guzman-Perez, Angel [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 23, p. 6071 - 6077]

15
[ 33322-60-0 ]
[ 3932-97-6 ]
[ 1141379-20-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 6071 - 6077

16
[ 22245-92-7 ]
[ 3932-97-6 ]
[ 1141374-90-4 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2,4-dichloro-5-trifluoromethylpyrimidine With zinc(II) chloride In diethyl ether; dichloromethane; <i>tert</i>-butyl alcohol at -5℃; for 1h; Stage #2: 7-Amino-1,3,4,5-tetrahydro-2H-benz<b>azepin-2-on With triethylamine In diethyl ether; dichloromethane; <i>tert</i>-butyl alcohol at -5 - 40℃;

17
[ 3932-97-6 ]
[ 421595-81-5 ]
[ 1141379-48-7 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2,4-dichloro-5-trifluoromethylpyrimidine With zinc(II) chloride In diethyl ether; dichloromethane; <i>tert</i>-butyl alcohol at -5℃; for 1h; Stage #2: imidazo[1,2-a]pyridin-7-amine With triethylamine In diethyl ether; dichloromethane; <i>tert</i>-butyl alcohol at -5 - 40℃;

18
[ 3932-97-6 ]
[ 1201657-24-0 ]
[ 24101-09-5 ]

Yield	Reaction Conditions	Operation in experiment
1: 48% 2: 48%	With ammonia In tetrahydrofuran; water at 20℃; for 18h;	2-chloro-5-(trifluoromethyl)pyrimidin-4-amine 46.1 2-chloro-5-(trifluoromethyl)pyrimidin-4-amine 2,4-dichloro-5-(trifluoromethyl)pyrimidine (from Tosch) (40.0 g, 184 mmol) is dissolved in 300 mL of tetrahydrofuran and the mixture is cooled to 0° C. Ammonia (32% in water; 30.0 mL, 496 mmol) is added dropwise and the mixture is stirred at room temperature for 18 hours. Ethyl acetate is added and the reaction mixture is washed with a saturated aqueous sodium bicarbonate solution. The organic phase is concentrated under reduced pressure and purified by chromatography on silica gel (using a solvent gradient of cyclohexane/ethyl acetate from 100/0 to 50/50). Yield: 17.6 g (48% of theory) Mass spectrometry (ESI+): m/z=198 [M+H]+
1: 45% 2: 45%	With ammonia In methanol at 5 - 25℃;	With stirring, 1.0 g of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (Aldrich; order No. 684864) is added to a methanol ammonia solution (ca. 8 mol of ammonia in methanol), cooled to ca. 5° C., and the mixture is heated to 25° C. and stirred for two hours at the temperature. The mixture is concentrated by evaporation and added to water. Filtering with suction gives 0.56 g of a mixture of 4-amino-2-chloro-5-trifluoromethylpyrimidine (ca. 45%) and 2-amino-4-chloro-5-trifluoromethylpyrimidine (ca. 45%).
1: 45% 2: 45%	With ammonia In methanol at 5 - 25℃;	With stirring, 1.0 g of 2,4-dichloro-5-(trifluoromethyl)pyrimidine, Aldrich order no. 684864, is added to a methanolic ammonia solution (ca. 8 mol of ammonia in methanol) cooled to ca. 5° C., the mixture is heated to 25° C. and stirred for 2 hours at this temperature. The mixture is concentrated by evaporation and added to water. After filtering off with suction, 0.56 g of a mixture of 4-amino-2-chloro-5-trifluoromethylpyrimidine (ca. 45%) and 2-amino-4-chloro-5-trifluoromethylpyrimidine (ca. 45%) is obtained.

22.6%	With ammonia In methanol at 20℃; for 2h; Inert atmosphere;	[006101 General conditions for the preparation of 4-chloro-5-(trifluoromethyl)pyrimidin-2-amine: [006101 General conditions for the preparation of 4-chloro-5-(trifluoromethyl)pyrimidin-2-amine:[00611] To stirred neat 2,4-dichloro-5-(trifluoromethyl)pyrimidine (F-i) (5.0 g, 23.04 mmol) under argon, ammonia in methanol (7N solution, 15 mL) is added dropwise and the resulting mixture is stirred at RT for 2 h. The reaction mixture is quenched with water and then extracted with ethyl acetate (200 mL x 2). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo and the residue is purified by flash chromatography on silica gel eluting with 0-20% ethyl acetate/hexanes to afford the product, 4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (F-2) (1.03 g, 22.6% yield). The other regio-isomer, 2- chloro-5-(trifluoromethyl)pyrimidin-4-amine (F-3), can also be isolated.
22%	With ammonia In methanol at -10 - 20℃; for 3h;	1.A Step A: Preparation of 2-chloro-5-(trifluoromethyl)-4-pyrimidinamine To 2,4-dichloro-5-(trifluoromethyl)pyrimidine (5 g, 23 mmol) was slowly added 7 N ammonia in methanol (15 mL) at -10 °C and stirred at ambient temperature for 3 h, during which time an off-white precipitate formed in the reaction mixture. The reaction mixture was concentrated under reduced pressure to afford crude material. The crude material was purified by column chromatography on silica gel and eluted with ethyl acetate/petroleum ether (1: 10) to provide the title product as a white solid (1.0 g, 22% yield). The undesired regioisomer (i.e. 4-chloro-5-(trifluoromethyl)-2-pyrimidinamine) (1.2 g) was also obtained as a white solid. H NMR (CD3OD, 400 MHz) d 8.30 (s, 1H).
1: 22% 2: 1.2 g	With ammonia In methanol at -10 - 20℃; for 3h;	1.A Preparation of 2-chloro-5-(trifluoromethyl)-4-pyrimidinamine To 2,4-dichloro-5-(trifluoromethyl)-pyrimidine (5 g, 23 mmol) was slowly added 7 N ammonia in methanol (15 mL) at -10 °C and stirred at ambient temperature for 3 h, during which time an off-white precipitate formed in the reaction mixture. The reaction mixture was concentrated under reduced pressure to afford crude material. The crude material was purified by column chromatography on silica gel eluting with ethyl acetate/petroleum ether (1:10) to provide the title product as a white solid (1.0 g, 22% yield). The regioisomer (i.e.4-chloro-5- (trifluoromethyl)-2-pyrimidinamine) (1.2 g) was also obtained as a white solid. 1H NMR (CD3OD, 400 MHz) δ 8.30 (s, 1H).
	With ammonia In methanol at 20℃; for 2h; Inert atmosphere;	H Method HGeneral method for the synthesis of 4-chloro-5-(trifluoromethyl)pyrimidin-2-amine:[00379] Ammonia in methanol (7N solution, 15 mL) is added dropwise to the stirred neat 2,4-dichloro-5-(trifluoromethyl)pyrimidine (H-1) (5.0 g, 23.04 mmol) under argon, and the resulting mixture is stirred at RT for 2 h. The reaction mixture is quenched with water and then extracted with ethyl acetate (200 mL x 2). The combined organic layers are washed with brine, dried over Na2S04 and filtered. The filtrate is concentrated in vacuo and the residue is purified by flash chromatography on silica gel (0-20% ethyl acetate -hexanes) to afford the product, 4-chloro-5- (trifluoromethyl)pyrimidin-2-amine (H-2) as a white solid. The regional-isomer, 2-chloro-5-(trifluoromethyl)pyrimidin- 4-amine (H-3) can also be isolated as a white solid.
	With ammonia In methanol at 20℃; for 2h; Inert atmosphere;	78 Example 78 Ammonia in methanol (7 N solution, 15 mL) was added dropwise to stirred neat 2,4-dichloro-5-(trifluoromethyl)pyrimidine 131 (5.0 g, 23.04 mmol) under argon, and the resulting mixture was stirred at RT for 2 h. The reaction mixture was quenched with water and then extracted with ethyl acetate (2*200 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (0-20% ethyl acetate-hexanes) to afford the product 4-chloro-5-(trifluoromethyl)pyrimidin-2-amine 132. The regio-isomer 2-chloro-5-(trifluoromethyl)pyrimidin-4-amine 133 can also be isolated.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2018/37594, 2018, A1 Location in patent: Paragraph 0471-0474
[2]Current Patent Assignee: BAYER AG - US2010/167934, 2010, A1 Location in patent: Page/Page column 25
[3]Current Patent Assignee: BAYER AG - US2010/167935, 2010, A1 Location in patent: Page/Page column 24-25
[4]Current Patent Assignee: INFINITY PHARMACEUTICALS INC - WO2015/168079, 2015, A1 Location in patent: Paragraph 00610; 00611
[5]Current Patent Assignee: FMC CORP - WO2020/160202, 2020, A1 Location in patent: Page/Page column 41; 42
[6]Current Patent Assignee: FMC CORP - WO2021/183980, 2021, A1 Location in patent: Page/Page column 58
[7]Current Patent Assignee: INFINITY PHARMACEUTICALS INC - WO2011/146882, 2011, A1 Location in patent: Page/Page column 112
[8]Current Patent Assignee: INFINITY PHARMACEUTICALS INC - US2012/122838, 2012, A1 Location in patent: Page/Page column 118

19
[ 3932-97-6 ]
[ 147123-47-5 ]
(1S,2S,3R,4R)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide [ No CAS ]
[ 1258557-76-4 ]

Yield	Reaction Conditions	Operation in experiment
		Example 150 3-({2-[(1-methyl-1H-pyrazol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)thiophene-2-carboxamide The title compound was prepared as described in Example 1, substituting <strong>[147123-47-5]3-aminothiophene-2-carboxamide</strong> for (+/-)-(1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide and 2,4-dichloro-5-(trifluoromethyl)pyrimidine for 2,4-dichloro-5-fluoropyrimidine in Example 1A. 1H NMR (400 MHz, DMSO-d6) ppm 3.80 (s, 3H) 7.30 (s, 2H) 7.46 (s, 1H) 7.66 (d, J=5.49 Hz, 1H) 7.77 (s, 1H) 8.26 (s, 1H) 8.34 (s, 1H) 9.36 (s, 1H) 11.40 (s, 1H); MS (ESI(+)) m/e 384 (M+H)+.

Reference： [1]Patent: US2010/317680,2010,A1

20
[ 14080-51-4 ]
[ 3932-97-6 ]
(1S,2S,3R,4R)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide [ No CAS ]
[ 1258557-79-7 ]

Yield	Reaction Conditions	Operation in experiment
		Example 152 2-({2-[(1-methyl-1H-pyrazol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)thiophene-3-carboxamide The title compound was prepared as described in Example 1, substituting <strong>[14080-51-4]2-aminothiophene-3-carboxamide</strong> for (+/-)-(1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide and 2,4-dichloro-5-(trifluoromethyl)pyrimidine for 2,4-dichloro-5-fluoropyrimidine in Example 1A. 1H NMR (400 MHz, DMSO-d6) ppm 3.82 (s, 3H) 6.93 (d, J=5.80 Hz, 1H) 7.42 (d, J=5.80 Hz, 3H) 7.53 (s, 1H) 7.83 (s, 1H) 8.39 (s, 1H) 9.26 (s, 1H) 12.79 (s, 1H); MS (ESI(+)) m/e 384 (M+H)+.

Reference： [1]Patent: US2010/317680,2010,A1

21
[ 3920-40-9 ]
[ 3932-97-6 ]
(1S,2S,3R,4R)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide [ No CAS ]
[ 1258557-80-0 ]

Yield	Reaction Conditions	Operation in experiment
		Example 153 1-methyl-4-({2-[(1-methyl-1H-pyrazol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}amino)-1H-pyrazole-3-carboxamide The title compound was prepared as described in Example 1, substituting <strong>[3920-40-9]4-amino-1-methyl-1H-pyrazole-3-carboxamide</strong> for (+/-)-(1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide and 2,4-dichloro-5-(trifluoromethyl)pyrimidine for 2,4-dichloro-5-fluoropyrimidine in Example 1A. 1H NMR (400 MHz, DMSO-d6) ppm 3.84 (s, 3H) 3.88 (s, 3H) 7.23 (s, 2H) 7.49 (s, 1H) 7.81 (s, 1H) 8.29 (s, 1H) 8.40 (s, 1H) 9.21 (s, 1H) 9.99 (s, 1H); MS (ESI(+)) m/e 382 (M+H)+.

Reference： [1]Patent: US2010/317680,2010,A1

22
[ 6291-01-6 ]
[ 3932-97-6 ]
[ 1187590-86-8 ]

Yield	Reaction Conditions	Operation in experiment
41%	With potassium carbonate; In acetonitrile; at 50℃; for 2h;	2-Chloro-N-cyclobutyl-5-trifluoromethylpyrimidin-4-amineA mixture of 8.07 g (37.2 mmol) of 2,4-dichloro-5-trifluoromethylpyrimidine and 12.8 g (92.9 mmol) of potassium carbonate in 150 ml of acetonitrile is warmed to 50 C. 4.00 g (37.2 mmol) of cyclobutylamine hydrochloride are then added, and the mixture is stirred for 2 h. After cooling, the reaction mixture is stirred into 500 ml of ice-water and extracted with ethyl acetate (3×200 ml). The combined organic phases are separated off, washed with water (2×250 ml), dried over MgSO4 and freed from the solvent under reduced pressure. The crude product is purified by column chromatography on silica gel (cyclohexane/ethyl acetate). This gives 4.00 g (41%) of 2-chloro-N-cyclobutyl-5-trifluoromethylpyrimidin-4-amine (V-4). logP (pH 2.3): 3.201H NMR (400 MHz, MeCN-d) delta=8.27 (s, 1H), 6.19 (br. s, 1H), 4.64-4.56 (m, 1H), 2.40-2.32 (m, 2H), 2.14-2.04 (m, 2H), 1.82-1.74 (m, 2H).
41%	With potassium carbonate; In acetonitrile; at 50℃; for 2h;	2-Chloro-N-cyclobutyl-5-trifluoromethylpyrimidin-4-amine (V-20)A mixture of 8.07 g (37.2 mmol) of 2,4-dichloro-5-trifluoropyrimidine and 12.8 g (92.9 mmol) of potassium carbonate in 150 ml of acetonitrile is warmed to 50 C. Then, 4.00 g (37.2 mmol) of cyclobutylamine hydrochloroide are added and stirring is continued for 2 h. When cold, the reaction mixture is stirred into 500 ml of ice-water and extracted with ethyl acetate (3×200 ml). The combined organic phases are separated, washed with water (2×250 ml), dried over MgSO4 and freed from solvent under reduced pressure. The crude product is purified by column chromatography over silica gel (cyclohexane/ethyl acetate). This gives 4.00 g (41%) of 2-chloro-N-cyclobutyl-5-trifluoromethylpyrimidin-4-amine. logP (pH2.3): 3.20; 1H NMR (400 MHz, MeCN-d) delta=8.27 (s, 1H), 6.19 (br. s, 1H), 4.64-4.56 (m, 1H), 2.40-2.32 (m, 2H), 2.14-2.04 (m, 2H), 1.82-1.74 (m, 2H).

Reference： [1]Patent: US2011/245249,2011,A1 .Location in patent: Page/Page column 31
[2]Patent: US2011/245284,2011,A1 .Location in patent: Page/Page column 30

23
[ 4984-22-9 ]
[ 3932-97-6 ]
[ 1224197-35-6 ]

Yield	Reaction Conditions	Operation in experiment
24%	With sodium hydride; In diethyl ether; acetonitrile; mineral oil; at 0 - 20℃;	2-Chloro-4-((R)-2-methoxy-1-methylethoxy)-5-trifluoro-methylpyrimidine A solution of 2.00 g (9.2 mmol) of 2,4-dichloro-5-trifluoromethylpyrimidine and 1.08 g (12.0 mmol) of <strong>[4984-22-9](R)-1-methoxypropan-2-ol</strong> in 24.4 ml of diethyl ether and 24.4 ml of acetonitrile were admixed at 0 C. with stirring in portions with 0.48 g of sodium hydride (55%). The mixture was slowly warmed to room temperature in an ice bath. After 3.5 hours, the mixture was admixed with ice and dilute sodium chloride solution. Extraction was carried out with ethyl acetate (2*). The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. The resulting residue was purified chromatographically (hexane/ethyl acetate 7:3). This gave 0.59 g (2.2 mmol; yield: 24%) of the product. 1H NMR (400 MHz, DMSO): delta=8.83 (s, 1H), 5.50 (m, 1H), 3.50 (d, 2H), 3.24 (s, 3H), 1.26 (d, 3H).

Reference： [1]Patent: US2011/251222,2011,A1 .Location in patent: Page/Page column 15

24
[ 3932-97-6 ]
[ 74-89-5 ]
[ 515824-43-8 ]

Yield	Reaction Conditions	Operation in experiment
45%	With triethylamine In methanol at -10 - 20℃;	7 To a cooled (-10 °C) solution of 2,4-dichloro-5-trifluoromethylpyrimidine (20 g, 0.089 mol) in methanol (100 mL) was added triethylamine (12.5 mL, 0.089 mol) and a 2 M solution of methylamine in methanol (45 mL). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated and re-dissolved in ethyl acetate. The solution was washed with sat. NaHCC , brine, dried over MgS04, filtered and concentrated. The crude product was purified by column chromatography (5-25% EtOAc in heptane) to give 2- chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (8.6 g, 45%). 1H- MR (DMSO): δ 8.37 (s, 1H), 7.90 (s, 1H), 2.90 (s, 3H).
45%	With triethylamine In methanol at -10 - 20℃;	3 Intermediate 3 2-Chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine To a cooled (-10 °C) solution of 2,4-dichloro-5-trifluoromethylpyrimidine (20 g, 0.089 mol) in methanol (100 mL) was added triethylamine (12.5 mL, 0.089 mol) and a 2 M solution of methylamine in methanol (45 mL). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated and re -dissolved in ethyl acetate. The solution was washed with sat. NaHC03, brine, dried over MgS04, filtered and concentrated. The crude product was purified by column chromatography (5-25% EtOAc in heptane) to give 2- chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (8.6 g, 45%). 'lI-NMR (DMSO): δ 8.37 (s, 1H), 7.90 (s, 1H), 2.90 (s, 3H).
45%	With triethylamine In methanol at -10 - 20℃;	Intermediate 1 : 2-Chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine To a cooled (-10 °C) solution of 2,4-dichloro-5-trifluoromethylpyrimidine (20 g, 0.089 mol) in methanol (100 mL) was added triethylamine (12.5 mL, 0.089 mol) and a 2 M solution of methylamine in methanol (45 mL). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated and re -dissolved in ethyl acetate. The solution was washed with sat. NaHC03, brine, dried over MgSC^, filtered and concentrated. The crude product was purified by column chromatography (5-25% EtOAc in heptane) to give 2- chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (8.6 g, 45%). 'FI-NMR (DMSO): δ 8.37 (s, 1H), 7.90 (s, 1H), 2.90 (s, 3H).

40%	With triethylamine In methanol at 0 - 20℃; for 12h;
30%	In ethanol at -50℃; for 1h;
18.5%	With triethylamine In tetrahydrofuran; methanol at 20℃; for 16h;	15.1 Step 1: 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine To a cooled solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (6.7 g, 30.8 mmol) in MeOH (150 mL) was added TEA (4.3 mL, 30.8 mmol) and methanamine (15.6 mL, 2.0 M in THF, 31.1 mmol) at rt. The mixture was stirred at room temperature for 16 hrs. The mixture was concentrated and the residue was purified by silica gel chromatography (PE /EA= 10/1 to 5/1) to afford 2- chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (1.2 g, 18.5%) as a white solid. [M+H] Calc’d for C6H5CIF3N3, 212; Found, 212.
	In methanol; ethanol at 20℃;

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2012/62783, 2012, A1 Location in patent: Page/Page column 68
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2013/164321, 2013, A1 Location in patent: Page/Page column 36
[3]Current Patent Assignee: ROCHE HOLDING AG - WO2013/164323, 2013, A1 Location in patent: Page/Page column 43
[4]Chen, Zhen; Shao, Tuo; Gao, Wei; Fu, Hualong; Collier, Thomas Lee; Rong, Jian; Deng, Xiaoyun; Yu, Qingzhen; Zhang, Xiaofei; Davenport, April T.; Daunais, James B.; Wey, Hsiao-Ying; Shao, Yihan; Josephson, Lee; Qiu, Wen-Wei; Liang, Steven [ChemMedChem, 2019, vol. 14, # 17, p. 1580 - 1585]
[5]Liang, Xuewu; Zang, Jie; Li, Xiaoyang; Tang, Shuai; Huang, Min; Geng, Meiyu; Chou, C. James; Li, Chunpu; Cao, Yichun; Xu, Wenfang; Liu, Hong; Zhang, Yingjie [Journal of Medicinal Chemistry, 2019, vol. 62, # 8, p. 3898 - 3923]
[6]Current Patent Assignee: KINNATE BIOPHARMA INC - WO2021/11796, 2021, A1 Location in patent: Paragraph 00220
[7]Location in patent: experimental part Chen, Huifen; Chan, Bryan K.; Drummond, Jason; Estrada, Anthony A.; Gunzner-Toste, Janet; Liu, Xingrong; Liu, Yichin; Moffat, John; Shore, Daniel; Sweeney, Zachary K.; Tran, Thuy; Wang, Shumei; Zhao, Guiling; Zhu, Haitao; Burdick, Daniel J. [Journal of Medicinal Chemistry, 2012, vol. 55, # 11, p. 5536 - 5545]

25
[ 3932-97-6 ]
[ 5188-07-8 ]
[ 919116-36-2 ]

Yield	Reaction Conditions	Operation in experiment
94.91%		To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (10 g, 46.09 mmol, 1 eq) in THF (200 mL) was added dropwise ZnCh (1 M, 59.91 mL, 1.3 eq) at 0C. After addition, the mixture was stirred at this temperature for 2 h, and then NaSMe (3.88 g, 55.31 mmol, 3.52 mL, 1.2 eq) was added dropwise at 0 C. The resulting mixture was stirred at 15 C for 14 h. The mixture was quenched with aq. HC1 (150 mL, 1M), and then extracted with EtOAc (60 mL x 3), dried over Na2S04 and concentrated. The residue was purified by column chromatography (S1O2, (0290) PE/DCM=l:0 to 50:1) to afford the title compound (10 g, 43.74 mmol, 94.91% yield) as a colorless oil.
82%		To a solution of the 2,4-dichloro-5-(trifluoromethyl)pyrimidine (2.50 g, 11 .5 mmol) inTHF (50 mL) in an ice bath under nitrogen was added zinc(ll) chloride (1.0 M in ether, 13.8 mL, 3.8 mmol) dropwise. The mixture was stirred in the ice bath for two hours, then sodium methanethiolate (0.888 g, 12.7 mmol) was added. The mixture was stirred overnight, allowing the reaction to slowly come to room temperature. After 18 hours the reaction was quenched with 2 M HCI (15 mL), and the organics removed by evaporation under reduced pressure. The aqueous residue was diluted with brine (15 mL), and extracted with DCM (3x30 mL). The combined organic phases were dried (phase separator) and carefully evaporated to give a pale yellow oil.Chromatography (Biotage Isolera, 2x40g silica cartridge, 0-20% DCM/n-hexane) followed by carefully evaporation of solvent (40C(at)400 mmHg then roomtemperature(at)200 mmHg) gave the title compound (113) (2.149 g, 82% yield) as a colourless oil; 1H NMR (600 MHz, CDCl3) 5 8.66 (s, 1 H), 2.61 (s, 3H). LCMS Method C: rt: 7.95 min, m/z 229.1 (M+H]+.
82%		To a solution of the 2,4-dichloro-5-(trifiuoromethyl)pyrimidine (2.50 g, 11.5 mmol) in THF (50 mL) in an ice bath under nitrogen was added zinc(li) chloride (1.0 M in ether, 13.8 mL, 13.8 mmol) dropwise. The mixture was stirred in the ice bath for two hours, then sodium methanethioiate (0.888 g, 12.7 mmol) was added. The mixture was stirred overnight, allowing the reaction to slowly come to room temperature. After 18 hours the reaction was quenched with 2 M HCI ( 5 mL), and the organics removed by evaporation under reduced pressure. The aqueous residue was diluted with brine (15 mL), and extracted with DCM (3x30 mL). The combined organic phases were dried (phase separator) and carefully evaporated to give a pale yellow oil. Chromatography (Biotage isoiera, 2x40g silica cartridge, 0-20% DCM/n-hexane) followed by carefully evaporation of solvent (40C400 mmHg then room temperature200 mmHg) gave the title compound (113) (2.149 g, 82% yield) as a colourless oil; 1 H NMR (600 MHz, CDCI3) delta 8.66 (s, 1 H), 2.61 (s, 3H). LCMS Method C: rt: 7.95 min; m z 229.1 [M+H]+. Note: 113 s volatile.

		Step 1: To a solution of 60_1 (2.00 g, 9.22 mmol, 1.00 eq) in THF (40 mL) was added ZnCi2-Et20 (1 M, 11.06 mL, 1.20 eq) at 0C under nitrogen protection. The mixture was stirred for 2 hours at 0C. Methylsulfanylsodium (646.23 mg, 9.22 mmol, 02429524H5-01 - TO SS?.48 muL·, 1.00 eq) was added. The resulting mixture was stirred at 20C for 16 hours. TLC (pure PE) showed reactant 1 (Rf=0.5) consumed and product (Rf=0.3) formed. The mixture was quenched with 1M HC1 (20 mL) and concentrated. The aqueous layer was extracted with DCM (20 mL*3). The combined organic layer was concentrated and purified by silica gel column (PE: EA=1 :0~50: 1) to give 60_2 (1.00 g, 1.97 mmol, 21.4% yield, 45.1% purity) as colorless oil. LCMS: RT = 0.794 min, mlz 228.9 [M+H]+ NMR (CDC13, 400 MHz) delta 8.67 (s, 1H), 2.62 (s, 3H).
		To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (10 g, 46.09 mmol, 1 eq) in THF (200 mL) was added dropwise ZnCL (1 M, 59.91 mL, 1.3 eq) at 0C. After addition, the mixture was stirred at this temperature for 2 h, and then NaSMe (3.88 g, 55.31 mmol, 3.52 mL, 1.2 eq) was added dropwise at 0 C. The resulting mixture was stirred at 15 C for 14 h. The mixture was quenched with aqueous HC1 (150 mL, 1M), and then extracted with EtOAc (60 mL x 3), dried over Na2S04and concentrated. The residue was purified by column chromatography (SiC PE/DCM=l:0 to 50:1) to afford the title compound (10 g, 43.74 mmol, 94.91% yield) as a colorless oil.

Reference： [1]Patent: WO2019/143719,2019,A1 .Location in patent: Paragraph 134
[2]Patent: WO2012/110773,2012,A1 .Location in patent: Page/Page column 58; 59
[3]Patent: WO2014/27199,2014,A1 .Location in patent: Page/Page column 61
[4]Patent: WO2017/21969,2017,A1 .Location in patent: Page/Page column 69-70
[5]Patent: WO2019/143730,2019,A1 .Location in patent: Paragraph 159; 167

26
[ 3932-97-6 ]
[ 304897-49-2 ]
[ 1393901-46-6 ]

Yield	Reaction Conditions	Operation in experiment
90%		2,4-Dichloro-5-(trifluoromethyl)pyrimidine (0.546 g, 2.52 mmol) in 1 :1 dichloroethane: ferf-butanol was cooled to 0 C under nitrogen. A 1.0 M solution of zinc(ll) chloride in diethyl ether (3.43 mL, 3.34 mmol) was added, and the mixture stirred for one hour at 0 "C. ferf'Butyl 4-(4-aminobenzyl)piperazine-1 -carboxylate (193) (0.667 g, 2.29 mmol) in 1 : 1 dichloroethane: ferf-butanol (20 mL) was added dropwise over thirty minutes, followed by triethylamine (0.351 mL, 2.52 mmol) in 1 :1 dichloroethane: ferf-butanol ( 0 mL). The mixture was stirred overnight, allowing the ice bath to come to room temperature over this time. The mixture was concentrated onto silica gel and chromatographed (40 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40- 60 C) to give a residue which was triturated with petroleum benzine 40-60 C to give the title compound (194) (0.976 g, 90%) as an off white solid; H NMR (400 MHz, d4- MeOD) delta 8.68 (d, J = 0.6 Hz, 1 H), 7.85 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 4.30 (s, 2H), 3.27 - 3.00 (br, overlaps with solvent), 1.47 (s, 9H). LCMS Method C: 5.08 min; m/z 472.1 [M+H]+; m/z 470.1 [M-H]
90%		2,4-Dichloro-5-(trifluoromethyl)pyrimidine (0.546 g, 2.52 mmol) in 1 : 1 dichioroethane: fe/f-butanol was cooled to 0 C under nitrogen. A 1.0 M solution of zinc(ll) chloride in diethyl ether (3.43 mL, 3.34 mmol) was added, and the mixture stirred for one hour at 0 C. iert-Butyl 4-(4-aminobenzyi)piperazine-1-carboxylate (193) (0.667 g, 2.29 mmol) in 1 : 1 dichioroethane: ferf-butanol (20 mL) vv'as added dropwise over thirty minutes, followed by triethyiamine (0.351 mL, 2.52 mmol) in 1 :1 dichioroethane: ferf-butanol (10 mL). The mixture was stirred overnight, allowing the ice bath to come to room temperature over this time. The mixture was concentrated onto silica gel and chromatographed (40 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40- 60 C) to give a residue which was triturated with petroleum benzine 40-60 C to give the title compound {194) (0.976 g, 90%) as an off white solid; 1H NMR (400 MHz, dr MeOD) delta 8.68 (d, J = 0.6 Hz, 1 H), 7.85 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 4.30 (s, 2H), 3.27 - 3,00 (br, overlaps with solvent), 1.47 (s, 9H). LCMS Method C: 5.08 min; m/z 472.1 [M+H]+; m/z 470.1 [M-H]

Reference： [1]Patent: WO2012/110773,2012,A1 .Location in patent: Page/Page column 120; 121
[2]Patent: WO2014/27199,2014,A1 .Location in patent: Page/Page column 123

27
[ 170011-57-1 ]
[ 3932-97-6 ]
[ 1383682-52-7 ]

Yield	Reaction Conditions	Operation in experiment
98%		Key intermediate 3: tert-Butyl 4-(4-((4-chloro-5-(trifl uoromethyl)pyri m idi n-2-yI)amino)phenyl)piperidine-1 -carboxylate (K3)2,4-Dichloro-5-(trifluoromethyl)pyrimidine (4.122 g, 19.00 mmol) was stirred in a 1:1mixture (400 mL) at room temperature. A 1.0 M ZnCI2 solution in Et20 (21.71 mL, 21.71 mmol) was added cautiously and the resulting mixture was stirredfor 10 minutes. 1-Boc-4-(4-aminophenyl)piperidine (5.00 g, 18.1 mmol) was added followed by Et3N (6.052 mL, 43.42 mmol) and stirring continued at room temperature overnight. The volatiles were evaporated to dryness and the resulting residue was suspended in water (500 mL). After sonication for 30 minutes the suspension was filtered and the filter cake was washed with water (2 x 100 mL) and dried under ahigh vacuum to yield the title compound K3 as a tan solid (8.11 g, 98%); 1H NMR (400 MHz, d6-DMSO) O 10.61 (5, 1H), 8.78 (5, 1H), 7.59 (d, J= 8.4 Hz, 2H), 7.23 (d, J= 8.5 Hz, 2H), 4.07 (d, J= 11.1 Hz, 2H), 2.80 (5, 2H), 2.65 (t, J= 12.0 Hz, 1H), 1.74 (d, J= 12.3 Hz, 2H), 1.42 (5, 11H). LCMS-A: rt6.834 mm; m/z457 [M+H].
88%		Zinc chloride (1.0 M in Et20) (1 .97 mL, 1.97 mmol) was added to a solution of 2,4- dichloro-5-(trifluoromethyl)pyrimidine (0.384 g, 1.77 mmol) in 1 :1 DCE/f-BuOH (10 mL) at 0 C under a stream of N2 gas. The mixture was stirred for 1 hour at 0 C and then tert-butyl 4-(4-aminophenyl)piperidine- 1-carboxylate (144) (0.453 g, 1 .64 mmol) in 1 : 1 DCE//BuOH (7 mL) was added. A solution of NEt3 (0.251 mL, 1.80 mmol) in 1 :1 DCE/f-BuOH (8 mL) was next added dropwise at 0 C. The reaction mixture was vigorously stirred for a further 30 minutes at 0 C after the final addition and then at room temperature for 24 hours. The solvent was removed in vacuo to afford a brown oily residue which was purified by column chromatography on silica gel (0-20% EtOAc in petroleum benzine 40-60 C) to yield a pale yellow solid. The solid was suspended in MeOH (10 mL) and water (10 mL). The resulting precipitate was filtered to afford the title compound (145) (0.658 g, 88%) as a white solid; 1H NM (400 MHz, oVDMSO) delta 10.60 (s, 1 H). 8.77 (d, J = 0.5 Hz, 1 H), 7.59 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 4.13 - 3.98 (m, 2H), 2.80 (bs, 2H), 2.69 - 2.61 (m, 1 H), 1.74 (d, J = 12.4 Hz, 2H), 1.53 - 1.39 (m, 11 H). LCMS Method C: rt 6.81 min; m/z 401 [M-'Butyl+2H]+, 357 [M-Boc+2H]+.
88%		Zinc chloride (1.0 M in Et20) (1.97 mL, 1.97 mmol) was added to a solution of 2,4- dichloro-5-(trifluoromethyl)pyrimidine (0.384 g, 1.77 mmol) in 1 :1 DCE/i-BuOH (10 mL) at 0 C under a stream of N2 gas. The mixture was stirred for 1 hour at 0 C and then feri-butyl 4-(4-aminophenyl)piperidine-1 -carboxylate (144) (0.453 g, 1.64 mmol) in 1 :1 DCE/fBuOH (7 mL) was added. A solution of NEt3 (0.251 mL, 1.80 mmol) in 1 : 1 DCE/f-BuOH (8 mL) was next added dropwise at 0 C. The reaction mixture was vigorously stirred for a further 30 minutes at 0 C after the final addition and then at room temperature for 24 hours. The solvent was removed in vacuo to afford a brown oily residue which was purified by column chromatography on silica gel (0-20% EtOAc in petroleum benzine 40-60 C) to yield a pale yellow solid. The solid was suspended in MeOH (10 mL) and water (10 mL). The resulting precipitate was filtered to afford the title compound (145) (0.658 g, 88%) as a white solid; 1H N (400 MHz, afe-DMSO) delta 10.60 (s, 1 H), 8.77 (d, J = 0.5 Hz, 1 H), 7.59 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 4.13 - 3.98 (m, 2H), 2.80 (bs, 2H), 2.69 - 2.61 (m, 1 H), 1.74 (d, J = 12.4 Hz, 2H), 1.53 - 1.39 (m, 11 H). LCMS Method C: rt 8.81 min; m/z 401 [M-iButyl+2H]?, 357 [M-Boc+2H]+.

Reference： [1]Patent: WO2014/26243,2014,A1 .Location in patent: Page/Page column 87
[2]Patent: WO2014/26242,2014,A1 .Location in patent: Page/Page column 78; 79
[3]Patent: WO2012/110773,2012,A1 .Location in patent: Page/Page column 82; 84
[4]Patent: WO2014/27199,2014,A1 .Location in patent: Page/Page column 86

28
[ 101251-09-6 ]
[ 3932-97-6 ]
N-(4-{2-[(4-morpholin-4-ylphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl}phenyl)acetamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 7653 - 7658

29
[ 101251-09-6 ]
[ 3932-97-6 ]
[ 1415666-10-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 7653 - 7658

30
[ 3932-97-6 ]
[ 1374640-70-6 ]

Reference： [1]Patent: WO2013/138495,2013,A1
[2]Patent: WO2013/138502,2013,A1
[3]Patent: WO2014/182593,2014,A1

31
[ 916421-36-8 ]
[ 3932-97-6 ]
[ 1566543-57-4 ]

Yield	Reaction Conditions	Operation in experiment
56%		(C) tert-Butyl 3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yI) amino) phenyl)azetidine1-carboxylate (K4)Zinc chloride (1.0 M in Et20) (4.83 mL, 4.83 mmol) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (0.769 g, 3.54 mmol) in 1:1 dichloroethane/teitbutanol (64 mL) at room temperature under nitrogen. After stirring for 10 minutes, teit-butyl 3-(4-am inophenyl)azetidine- 1 -carboxylate (17) (0.800 g, 3.22 m mol) was added followed by Et3N (1.08 mL, 7.73 mmol). The resulting mixture was stirred at room temperature for 20 hours then the volatiles removed in vacuo. Water wasadded to the solid residue and the resulting suspension sonicatated for 2 minutes.The suspension was filtered, and the filter cake dried then adsorbed onto silica geland purified using column chromatography (CombiFlash Rf, 40 g Si02 Cartridge, 10-40% EtOAc in cyclohexane) to give a white solid. The solid was suspended in MeOH(7 mL) and sonicated for 30 seconds. The resulting suspension was filtered and thefilter cake was washed with MeOH (3 mL) then dried to give the title compound K4 asa white solid (0.777 g, 56%); 1H NMR (300 MHz, d6-DMSO) 0 10.6 (5, 1H), 8.79 (5, 1H), 7.66 (d, J= 8.4 Hz, 2H), 7.33 (d, J= 8.4 Hz, 2H), 4.23 (t, J= 7.6 Hz, 2H), 3.80 (5, 3H), 1.40 (5, 9H). LCMS-B: rt 8.810 mm; m/z 429 [M+H].

Reference： [1]Patent: WO2014/26243,2014,A1 .Location in patent: Page/Page column 89
[2]Patent: WO2014/26242,2014,A1 .Location in patent: Page/Page column 133; 134

32
[ 1029413-55-5 ]
[ 3932-97-6 ]
[ 1566543-66-5 ]

Yield	Reaction Conditions	Operation in experiment
78%		Synthesis of Key Intermediate 8: tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yI)amino)-1 H-pyrazol-1 -yI)piperidine-1 -carboxylate (K8) A 1.0 M solution of ZnCI2 in Et20 (22.5 mL, 22.5 mmol) was added to a solution of2,4-dichloro-5-(trifluoromethyl)pyrimidine (4.48 g, 20.7 mmol) in t-BuOH (50 mL) andDOE (50 mL) and the mixture was stirred for 10 minutes. The mixture was dilutedwith t-BuOH (50 mL) and DOE (50 mL) before teit-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (5.00 g, 18.8 mmol) and Et3N (3.14 mL, 22.5 mmol) wereadded. Stirring was continued overnight and the volatiles were subsequently removed in vacuo. The resultant residue was suspended in acetone (50 mL) then water (500 mL) and sonicated for 15 minutes before the solid was removed by vacuum filtration and the filter cake washed with water (100 mL). The solid wassuspended in acetone (25 mL), filtered and the filter cake was washed with petroleum benzine 40-60O (200 mL) to give the title compound K8 as a light pink solid (6.57 g, 78%). LOMS-D: rt 3.618 mm; m/z 445.1 [M-H].

Reference： [1]Patent: WO2014/26243,2014,A1 .Location in patent: Page/Page column 95; 96
[2]Patent: WO2014/26242,2014,A1 .Location in patent: Page/Page column 170

33
[ 1018446-95-1 ]
[ 3932-97-6 ]
[ 1566544-26-0 ]

Yield	Reaction Conditions	Operation in experiment
14%		(a) tert-Butyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yI)amino)- 1H-pyrazole- 1- carboxylate (A61)A 1.0 M solution of zinc chloride in Et20 (4.0 mL, 4.0 mmol) was added to 2,4- dichloro-5-trifluoromethylpyrimidine (0.49 mL, 3.6 mmol) in a 1:1 mixture of DCEItBuOH (40 mL) at 0 00 under a nitrogen atmosphere. The mixture was stirred for 1 hour before teit-butyl 4-amino-i H-pyrazole-1-carboxylate (0.606 g, 3.31 mmol) and triethylamine (0.51 mL, 3.7 mmol) in a 1:1 mixture of DCE/t-BuOH (30 mL) wasadded. The mixture was allowed to warm to room temperature and stirred for 20 hours before concentrating in vacuo and adding gradually to 100 mLwater. The resulting precipitate was removed by vacuum filtration and washed with DCM. The filtrate was purified using silica gel column chromatography (0-30% EtOAc in DCM) to give the title compound A61 (0.170 g, 14%). LCMS-D: rt 3.622 mm; m/z 362.1 [M20 H].

Reference： [1]Patent: WO2014/26243,2014,A1 .Location in patent: Page/Page column 163

34
[ 51460-32-3 ]
[ 3932-97-6 ]
[ 1610025-90-5 ]

Yield	Reaction Conditions	Operation in experiment
23%	Stage #1: 1-(5-aminopyridin-2-yl)ethan-1-one With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: 2,4-dichloro-5-trifluoromethylpyrimidine In N,N-dimethyl-formamide at 60℃; for 2.08333h; Inert atmosphere;

Reference： [1]Current Patent Assignee: CANCER THERAPEUTICS CRC PTY LTD - WO2014/26242, 2014, A1 Location in patent: Page/Page column 177

35
[ 350684-49-0 ]
[ 3932-97-6 ]
[ 1566584-48-2 ]

Yield	Reaction Conditions	Operation in experiment
46%		To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine(0.46 mL,3.4 mmol) in DCE (12 mL) and tBuOH (12 mL) was added 4mL ZnCl2 solution (1M in diethyl ether). The mixture was stirredunder ice bath for 1 h. Then the mixture was added compound21(1.04 g, 3.4 mmol in 3mL DCE: tBuOH 1:1) and stirred foranother 1.5 h under ice bath. Then the mixture was added Et3N(0.52 mL, 3.7 mmol) dropwise. The mixture was concentrated undervacuum and extracted with dichloromethane (20 mL x 3). Theorganic phase was washed with brine (15mL x 3) and dried overanhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography to get compound 12 as white solid (0.76 g, 46%). Mp: 182-183 C. 1H NMR (400 MHz,DMSO-d6) delta 10.90 (s, 1H), 8.85 (s, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.45 (d,J = 8.4 Hz, 2H), 3.40 (s, 8H), 1.42 (s, 9H).13C NMR (100 MHz,DMSO-d6) delta 168.96, 160.37, 158.08 (d, J = 5.0 Hz),157.73, 153.81,139.80, 130.26, 128.07, 119.55, 112.32-111.32 (m), 79.14, 43.49, 42.90, 27.99.

Reference： [1]Patent: WO2014/26242,2014,A1 .Location in patent: Page/Page column 95; 96
[2]European Journal of Medicinal Chemistry,2019,vol. 177,p. 32 - 46

36
[ 188975-15-7 ]
[ 3932-97-6 ]
[ 1566584-53-9 ]

Reference： [1]Patent: WO2014/26242,2014,A1 .Location in patent: Page/Page column 98; 99

37
[ 62020-09-1 ]
[ 3932-97-6 ]
[ 1616974-44-7 ]

Yield	Reaction Conditions	Operation in experiment
36%		General procedure: Methyl 2-(methylsulfonyl)acetate (8.58 g, 56.39 mmol) was dissolved in DMF (100 ml),to this was added NaH (4.92 g, 102.53 mmol) and the reaction was stirred for 5min. before the addition of 4,6-dichloro-2-(methylthio)pyrimidine (10g, 51.26 mmol). The reaction was stirredfor 24 hours quenched with 2M HCl (100 ml), extracted with Et2O (3 x100 ml), the organic layer was dried over MgSO4, filtered andevaporated to afford a yellow gum. The crude product was purified by flashsilica chromatography, elution gradient 100% Et2O. Fractions wereevaporated to dryness to afford a yellow gum.The gum was triturated with Et2O to give a solid which was collected by filtration anddried under vacuum to give methyl2-(6-chloro-2-(methylthio)pyrimidin-4-yl)-2-(methylsulfonyl)acetate (9.30 g,58.4 %) as a white solid. 1H NMR (400 MHz, CDCl3)delta 7.36 (s,1H), 5.03 (s, 1H), 3.86 (s, 3H), 3.19 (s, 3H) and 2.55 (s, 3H); m/z (ES+) (M+H)+ = 311

Reference： [1]Tetrahedron Letters,2014,vol. 55,p. 3851 - 3855

38
[ 3932-97-6 ]
[ 625471-18-3 ]
[ 1622003-20-6 ]

Yield	Reaction Conditions	Operation in experiment
57%	With triethylamine; zinc(II) chloride; In 1,2-dichloro-ethane; tert-butyl alcohol; at 20℃; for 1h;pH <= 7;	Step 1: (S)-tert-butyl 3-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (Intermediate 1) To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (5 g, 23 mmol) in dichloroethane: t-butanol (50 ml, 1:1) was added dry zinc chloride (3.7 g, 27 mmol) and triethylamine (2.52 g, 25 mmol), and the mixture was stirred at rt for 1 h (pH should not be >7). To this mixture, (S)-tert-butyl 3-aminopiperidine-1-carboxylate (4.9 g, 25 mmol) was added and stirring continued at rt for 16 h. TLC showed formation of the major compound (0.2 Rf) and a minor other isomer (0.25 Rf) and ?10% starting material in 15% EtOAc: hexane solvent system. Solvents were evaporated, and crude was diluted with ice cold water (50 mL) and stirred for 5 min at rt to get a pale yellow gummy mass. The crude pale yellow gummy mass (6 g) was taken in 60 mL hexane and stirred for 10 min at rt to get a solid which was immediately filtered to get the pure desired compound (5 g, 57%). MS m/z: 381.1 (ES+, M+H).

Reference： [1]Patent: US2014/228322,2014,A1 .Location in patent: Paragraph 0380

39
[ 76697-50-2 ]
[ 3932-97-6 ]
2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2%		2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyrimidin-4-amine (0437) To a solution of 1-Amino-2-(isopropylsulphonyl)benzene (350 mg, 1.6 mmol) in 4 mL of N,N-Dimethyl formamide at 0 degree, was added Sodium hydride (100 mg) and the reaction mixture was allowed to stirred at 0 degree for 20 minutes. 2,4-Dichloro-5-(trifluoromethyl) pyrimidine (350 mg, 1.6 mmol) was added in one portion and the reaction mixture was warmed to room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with Ethyl acetate. The combined Ethyl acetate layers were dried over Sodium Sulfate and solvent was removed under reduced pressure. The residue was purified by Prep-HPLC to yield the desired product as a white solid (10 mg, 2percent yield).

Reference： [1]Patent: US2015/225436,2015,A1 .Location in patent: Paragraph 0437

40
[ 3932-97-6 ]
[ 115619-01-7 ]
4-chloro-N-[4-(4-ethylpiperazin-1-yl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine [ No CAS ]

Reference： [1]Patent: WO2015/117547,2015,A1 .Location in patent: Page/Page column 21; 22

41
[ 100960-07-4 ]
[ 3932-97-6 ]
[ 74-89-5 ]
N⁴-methyl-N²-(1 H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine [ No CAS ]
N²-methyl-N⁴-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20 mg; 11 mg		Example 182: Preparation of N4-methyl-N2-(lH-pyrrolo[2,3-b]pyridin-5-yl)-5- (trifluoromethyl)pyrimidine-2,4-diamine and N2-methyl-N4-(lH-pyrrolo[2,3-b]pyridin-5- yl)- -(trifluoromethyl)pyrimidine-2,4-diamineN-(4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)-lH-pyrrolo[2,3-b]pyridin-5-amine (0.100 g, 0.319 mmol, contains 30% of the regioisomer) and methanamine (0.1 19 ml, 0.956 mmol) were mixed in DMF (2 mL). The mixture was microwaved at 100 C for 20 minutes and then concentrated. 20 mg of N4-methyl-N2-(lH-pyrrolo[2,3-b]pyridin-5-yl)-5- (trifluoromethyl)pyrimidine-2,4-diamine and 1 1 mg of N2-methyl-N4-(lH-pyrrolo[2,3-b]pyridin- 5-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine were recovered after automated reverse phase chromatography (water- eCN eluent). MS calcd for [CuHuFsNe+H]"1": 309.1 1 , found 308.95

Reference： [1]Patent: WO2016/33100,2016,A1 .Location in patent: Page/Page column 180; 181

42
[ 1862-88-0 ]
[ 3932-97-6 ]
C₁₃H₉ClF₃N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 100℃; for 0.166667h;Microwave irradiation;	Example 99: Preparation of N-meth l-2- 2-(phenylamino)-5-(trifluoromethyl)pyrimidin-4-yI)oxy)benzamideA solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (100 mg, 0.461 mmol, 1 .0 equiv), <strong>[1862-88-0]2-hydroxy-N-methylbenzamide</strong> (69 mg, 0.461 mmol, 1.0 equiv) and N,N-diisopropyl ethylamine (0.08 mL, 0.461 mmol, 1.0 equiv) in acetonitrile (3 mL) was microwaved at 100 C for 10 min. The mixture was concentrated in vacuo, then aniline (0.042 mL, 0.461 mmol, 1.0 equiv) and acetic acid (2 mL) were added. This mixture was microwaved at 120 C for 10 min, then concentrated in vacuo. A fraction of the crude product was purified by reverse phase HPLC to yield the product (13 mg). MS calcd for [C19Hi5F3N402+H]+: 389.12, found 389.32.

Reference： [1]Patent: WO2016/33100,2016,A1 .Location in patent: Page/Page column 146

43
[ 22246-13-5 ]
[ 22236-04-0 ]
[ 3932-97-6 ]
6-((4-((2-(difluoromethoxy)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroquinolin-2(1H)-one [ No CAS ]
N<SUP>2</SUP>,N<SUP>4</SUP>-bis(2-(difluoromethoxy)phenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine [ No CAS ]
6,6'-((5-(trifluoromethyl)pyrimidine-2,4-diyl)bis(azanediyl))bis(3,4-dihydroquinolin-2(1H)-one) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 27 mg 2: 9 mg 3: 14 mg	Stage #1: 2-(difluoromethoxy)aniline; 2,4-dichloro-5-trifluoromethylpyrimidine With N-ethyl-N,N-diisopropylamine In acetonitrile at 100℃; for 0.166667h; Microwave irradiation; Stage #2: 6-amino-3,4-dihydro-1H-quinolin-2-one With acetic acid at 120℃; for 0.166667h; Microwave irradiation;	120 Example 99: Preparation of N-meth l-2- 2-(phenylamino)-5-(trifluoromethyl)pyrimidin-4-yI)oxy)benzamide General procedure: Example 99: Preparation of N-meth l-2- 2-(phenylamino)-5-(trifluoromethyl)pyrimidin-4-yI)oxy)benzamideA solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (100 mg, 0.461 mmol, 1 .0 equiv), 2-hydroxy-N-methylbenzamide (69 mg, 0.461 mmol, 1.0 equiv) and N,N-diisopropyl ethylamine (0.08 mL, 0.461 mmol, 1.0 equiv) in acetonitrile (3 mL) was microwaved at 100 °C for 10 min. The mixture was concentrated in vacuo, then aniline (0.042 mL, 0.461 mmol, 1.0 equiv) and acetic acid (2 mL) were added. This mixture was microwaved at 120 °C for 10 min, then concentrated in vacuo. A fraction of the crude product was purified by reverse phase HPLC to yield the product (13 mg). MS calcd for [C19Hi5F3N402+H]+: 389.12, found 389.32.

Reference： [1]Current Patent Assignee: SALK INSTITUTE FOR BIOLOGICAL STUDIES; SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE; YALE UNIVERSITY - WO2016/33100, 2016, A1 Location in patent: Page/Page column 153; 154

44
[ 100960-07-4 ]
[ 3932-97-6 ]
[ 62-53-3 ]
N⁴-phenyl-N²-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine [ No CAS ]
N⁴-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19 mg; 15 mg		Example 181: Preparation of N4-phenyl-N2-(lH-pyrrolo[2,3-b]pyridin-5-yl)-5- (trifluoromethyl)pyrimidine-2,4-diamine and N4-(lH-pyrrolo[2,3-b]pyridin-5-yl)-5- (trifluoromethyl)pyrimidine-2,4-diamineN-(4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)-lH-pyrrolo[2,3-b]pyridin-5-amine (0.1 00 g, 0.31 9 mmol, contains 30% of the regioisomer), aniline (0.029 ml, 0.319 mmol) and N-ethyl-N- isopropylpropan-2-amine (0.1 1 1 ml, 0.638 mmol) were mixed in Acetonitrile (2 ml). The mixture was microwaved at 130 C for 20 minutes and then concentrated. In order to degrade the unreacted minor starting material regioisomer, ammonia (455 mL, 7M in MeOH), was added and the mixture was microwaved at 120 C for 20 minutes. 19 mg of N4-phenyl-N2-(l H-pyrrolo[2,3- b]pyridin-5-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine and 15 mg of N4-(l H-pyrrolo[2,3- b]pyridin-5-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine were recovered after automated reverse phase chromatography (water-MeCN eluent). MS calcd for [CigH] 3F3N6+H]+: 371 .13, found 371.10. MS calcd for [Ci2H9F3N6+H]+: 295.09, found 294.85.

Reference： [1]Patent: WO2016/33100,2016,A1 .Location in patent: Page/Page column 180

45
[ 100960-07-4 ]
[ 3932-97-6 ]
[ 4141-08-6 ]
2-((2-((1H-pyrrolo[2,3-b]pyridin-5-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34 mg		Example 201: Preparation of 2-((2-((lH-pyrrolo[2,3-b]pyridin-5-yl)amino)-5-(trifluoro methyl) pyrimidin-4-yl)amino)-N-methylbenzamide2,4-Dichloro-5-(trifluoromethyl)pyrimidine (0.085 g, 0.392 mmol), 2-amino-N- methylbenzamide (0.059 g, 0.392 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.068 ml, 0.392 mmol) were mixed in Acetonitrile (1 ml). The mixture was microwaved at 90 C for 10 minutes and then concentrated. lH-pyrrolo[2,3-b]pyridin-5-amine (0.052 g, 0.392 mmol) and acetic acid (0.024 g, 0.392 mmol) were added. The mixture was microwaved at 1 10 C for 1 0 minutes and then concentrated. Added methanol and filtered the solid, then washed with THF. 34 mg of product was isolated. MS calcd for [C2oHi6F3N70+H]+: 428.15, found 428.15.

Reference： [1]Patent: WO2016/33100,2016,A1 .Location in patent: Page/Page column 188; 189

46
[ 100960-07-4 ]
[ 3932-97-6 ]
N-(4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-amine [ No CAS ]
N-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; zinc(II) chloride; In dichloromethane; tert-butyl alcohol; at -10 - 21℃; for 1h;Inert atmosphere;	Example 176: Preparation of N-(4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)-lH- pyrrolo[2,3-b]pyridin-5-amine and N-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-lH- pyrrolo[2,3-b ridin-5-amineTo 2,4-dichloro-5-(trifluoromethyl)pyrimidine (0.4 g, 1 .844 mmol) in Dichloromethane (5 ml) and t-Butanol (5.00 ml) at - 10 C under nitrogen was added zinc(II) chloride (0.502 g, 3.69 mmol). Kept at - 10 to 0 C for 1 h. lH-pyrrolo[2,3-b]pyridin-5-amine (0.245 g, 1 .844 mmol) and triethylamine (0.283 ml, 2.028 mmol) were then added. Let the cold bath warm to 21 C.Concentrated to remove DCM, then filtered solid and washed with water. 620 mg of a 70:30 mix of isomers (N-(4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)-l H-pyrrolo[2,3-b]pyridin-5-amine major) was isolated. MS calcd for [C12H7C1F3N5+H]+: 314.04, found 313.80.

Reference： [1]Patent: WO2016/33100,2016,A1 .Location in patent: Page/Page column 177; 178

47
[ 100960-07-4 ]
[ 3932-97-6 ]
N²-(1H-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9 mg		Example 217: Preparation of N2-(lH-pyrrolo[2,3-b]pyridin-5-yl)-5-(trifluoromethyl) pyrimidine-2, -diamine2,4-Dichloro-5-(trifluoromethyl)pyrimidine (0.060 g, 0.277 mmol), 2,2- difluorocyclopropan-l -amine-HCl (0.036 g, 0.277 mmol) and N-ethyl-N-isopropylpropan-2- amine (0.096 ml, 0.553 mmol) were mixed in Acetonitrile (I ml). The mixture was microwaved at 70 C for 10 minutes and then concentrated. lH-pyrrolo[2,3-b]pyridin-5-amine (0.037 g, 0.277 mmol) and acetic acid (0.016 ml, 0.277 mmol) were added. The mixture was microwaved at 120 C for 20 minutes and then concentrated. 9 mg of side product was recovered after automated reverse phase chromatography (water- MeCN eluent). MS calcd for [C]2H9F3N6+H]+: 295.09, found 294.90.

Reference： [1]Patent: WO2016/33100,2016,A1 .Location in patent: Page/Page column 195

48
[ 3932-97-6 ]
[ 934-22-5 ]
[ 326827-21-8 ]
N²-(1H-benzo[d]imidazol-6-yl)-N⁴-(5-cyclobutyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14 mg		Example 297: Preparation of N2-(lH-benzo[d]imidazol-6-yl)-N4-(5-cyclobutyl-lH-pyrazol- 3-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine2,4-Dichloro-5-(trifluoromethyl)pyrimidine (0.087 g, 0.401 mmol), 5-cyclobutyl-lH- pyrazol-3-amine (0.055 g, 0.401 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.077 ml,0.441 mmol) were mixed in acetonitrile (2 ml). The mixture was microwaved at 80 C for 20 min and then concentrated. lH-benzo[d]imidazol-6-amine (0.053 g, 0.401 mmol) and acetic acid (0.024 g, 0.401 mmol) were added. The mixture was microwaved at 110 C for 20 min and then concentrated. 14 mg of product was recovered after automated reverse phase chromatography (water-MeCN). MS calcd for [Ci9Hi7F3N8+H]+: 415.16, found 415.20.

Reference： [1]Patent: WO2016/33100,2016,A1 .Location in patent: Page/Page column 227

49
[ 3932-97-6 ]
[ 24101-09-5 ]

Yield	Reaction Conditions	Operation in experiment
50%	With ammonia In neat (no solvent) at 20℃; for 1h; Inert atmosphere;	4 Example 4 Synthesis of compound 4 Ammonia in methanol (7N solution, lOOmL) was added dropwise to stirred neat 2,4-dichloro-5-(trifluoromethyl) pyrimidine (20.98g, 96.69mmol) under argon and the resulting mixture was stirred at rt for 1 hour. The reaction mixture was quenched with water(200mL) and then extracted with DCM (300mL). The combined organic layers were washed with brine (lOOmL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel to afford the compound 4a as a white solid (9.52g, 50%). MS: 198(M+H).
47%	With ammonia In tetrahydrofuran; methanol at -5℃; for 4h;	46.1 Step 1: 2-chloro-5 -(trifluoromethyl)pyrimidin-4-amine [01293] A solution of 2, 4-dichloro-5-(trifluoromethyl)pyrimidine (4.7 g, 21.66 mmol, 1.00 equiv) and ammonia (25% in methanol, 3 mL) in tetrahydrofuran (50 mL) was stirred for 4 hours at -5°C. The reaction solution was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in the title compound (2 g, 47%) as a white solid. LCMS [M+H] 198.
38%	With ammonia In methanol at 20℃; for 2.5h;

Reference： [1]Current Patent Assignee: JACOBIO PHARMACEUTICALS GROUP CO LTD - WO2018/19252, 2018, A1 Location in patent: Page/Page column 34; 35
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2016/128529, 2016, A1 Location in patent: Paragraph 01291; 01292; 01293
[3]Choi, Min Jung; Roh, Eun Joo; Hur, Wooyoung; Lee, So Ha; Sim, Taebo; Oh, Chang-Hyun; Lee, Sun-Hwa; Kim, Jong Seung; Yoo, Kyung Ho [Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 23-24, p. 3761 - 3765]

50
[ 76697-50-2 ]
[ 3932-97-6 ]
4-chloro-N-(2-(isopropylsulfonyl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5%	With trifluoroacetic acid; In tetrahydrofuran; at 60℃; for 1.5h;	2- (isopropylsulfonyl) aniline (1.99 g, 10 mmol),2,4-dichloro-5- (trifluoromethyl) pyrimidine (2.6 g, 12 mmol)And a catalytic amount of trifluoroacetic acid (80 mg) were added to tetrahydrofuran (30 mL)And heated at 60 ° C for 1.5 hours.The solvent was spin-dried and ethyl acetate (50 mL) was added,, Washed with saturated sodium bicarbonate (50 mL)The organic phase was dried, concentrated, and column chromatographed (petroleum ether: ethyl acetate = 10: 1-5: 1) to give the product (188 mg, 5percent yield).

Reference： [1]Patent: CN105884695,2016,A .Location in patent: Paragraph 0274; 0275; 0276

51
[ 1220696-34-3 ]
[ 3932-97-6 ]
5-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In acetonitrile; at 80℃; for 4h;Inert atmosphere;	Step 1 5-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine (Compound 22-2) 2,4-dichloro-5-trifluoromethyl pyrimidine (1.0 g, 6.5 mmol), PdCl2 (dppf) (0.5 g, 0.65 mmol) and 6.5 ml of 2.0 mol/L sodium carbonate solution were added to a solution of compound <strong>[1220696-34-3]1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine</strong> (4.3 g, 6.5 mmol) in 25 ml of acetonitrile, and vigorously stirred under N2 atmosphere at 80 C. for 4 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with EA/water system, washed with water for three times, and dried, and the organic layer was concentrated under reduced pressure to give the crude product which was purified by Combi-flash column chromatography [PE:EA=100:0-20:80] to give compound 22-2 (0.6 g, 36%). MS m/z (ESI): 313.0[M+H]+.

Reference： [1]Patent: US2017/8889,2017,A1 .Location in patent: Paragraph 0268; 0269

52
[ 3932-97-6 ]
[ 5188-07-8 ]
[ 919116-35-1 ]
[ 919116-36-2 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at -25 - 25℃; for 16h;Inert atmosphere;	To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1-6, 1 g, 4.61 mmol) in THF (10 mL) was added a solution of NaSMe (2.42 g, 6,92 mmol, 2.20 mL) dropwise at -25 C under N2. The reaction mixture was then stirred at -25 C for 1 hour followed by stirred at 25 C for 15 h. The reaction mixture was diluted with CH2CI2 (20 mL) and washed with 1 N HC1 (3 chi 10 mL). The organic phase was dried over anhydrous Nu8(>4, filtered and concentrated to afford a mixture of 2- chloro-4-methylsulfanyl-5-(trifluoromethyl)pyrimidine and 4-chloro-2-methylsulfanyl-5- (trifluoromethyl)pyrimidine as yellow oil.

Reference： [1]Patent: WO2017/87905,2017,A1 .Location in patent: Page/Page column 211

53
[ 3189-13-7 ]
[ 3932-97-6 ]
3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-methoxy-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	With aluminum (III) chloride In 1,2-dimethoxyethane at 70℃; Inert atmosphere;	143.1 Step 1: preparation of 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-methoxy-1H-indole 6-methoxy-1H-indole (5 g, 33.97 mmol), 2,4-dichloro-5-(trifluoromethyl)pyrimidine (8.1 g, 37.36 mmol) and aluminum trichloride (6.79 g, 50.95 mmol) were dissolved in DME (50 mL), and the reaction was stirred overnight at 70 °C. After the reaction was completed, the reaction solution was poured into ice water and extracted three times with methyl tert-butyl ether. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated to dry to obtain a crude product which was further purified by flash silica gel column chromatography to obtain 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-methoxy-1H-indole (4.3 g, 39%).

Reference： [1]Current Patent Assignee: HANSOH PHARMACEUTICAL GROUP CO LTD - EP3205650, 2017, A1 Location in patent: Paragraph 0106; 0725; 0726

54
[ 3932-97-6 ]
[ 66607-26-9 ]
1-(2-chloro-5-trifluoromethylpyrimidin-4-yl)-3-fluoro-1H-indazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of 3-fluoroindazole (680.5 mg, 5.0 mmol) in dry DMF (15 mL) cooled to 0 C is treated with NaH (200 mg, 5.0 mmol, 60% in mineral oil). After stirring at 25 C for 2 h the mixture is cooled to 0 C and 2,4-dichloro-5-trifluoromethylpyrimidine (1.085 g, 5.0 mmol) is added. After stirring for 4 h the mixture is quenched with water (50 mL) and extracted with ethyl acetate (3 x 25 mL), washed with water (2 x 25 mL) and saturated brine (25 mL), and dried over MgSO4. The solvent is removed under reduced pressure, and the residue is purified by column chromatography (Pet/EtOAc 20/1) to afford the 1-(2-chloro-5-trifluoromethylpyrimidin-4-yl)-<strong>[66607-26-9]3-fluoro-1H-indazole</strong> as a white solid.

Reference： [1]Patent: WO2017/120429,2017,A1 .Location in patent: Page/Page column 320

55
[ 3932-97-6 ]
[ 57631-05-7 ]
1-(2-chloro-5-trifluoromethylpyrimidin-4-yl)-3-trifluoromethyl-1H-indazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of 3-triflouromethylindazole (931 mg, 5.0 mmol) in dry DMF (15 mL) cooled to 0 C is treated with NaH (200 mg, 5.0 mmol, 60% in mineral oil). After stirring at 25 C for 2 h the mixture is cooled to 0 C and 2,4-dichloro-5-trifluoromethylpyrimidine (1.085 g, 5.0 mmol) is added. After stirring for 4 h the mixture is quenched with water (50 mL) and extracted with ethyl acetate (3 x 25 mL), washed with water (2 x 25 mL) and saturated brine (25 mL), and dried over MgSO4. The solvent is removed under reduced pressure, and the residue is purified by column chromatography (Pet/EtOAc 20/1) to afford 1-(2-chloro-5-trifluoromethylpyrimidin-4-yl)-<strong>[57631-05-7]3-trifluoromethyl-1H-indazole</strong> as a white solid.

Reference： [1]Patent: WO2017/120429,2017,A1 .Location in patent: Page/Page column 321

56
[ 75-04-7 ]
[ 3932-97-6 ]
[ 1374829-47-6 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at 0 - 25℃; for 2h;Inert atmosphere;	To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (70 g, 322.61 mmol) in THF (1.4 L) was added a solution of ethanamine (32 g, 709.74 mmol, 46.37 mL) in THF (100 mL) dropwise at 0 C. under N2 over a period of 1 h. After addition, the mixture was stirred at 25 C. for 1 h. The mixture was filtered and concentrated under reduced pressure to afford a residue. The residue was triturated with DCM (200 mL) and filtered. The filtrate was recrystallizated with n-heptane (600 mL) and MTBE (400 mL). The precipitated phase was syrup. The liquid was discarded. The syrup residue was purified by silica gel column chromatography (PE:EtOAc=20:1) to afford 2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.22-8.27 (m, 1H), 5.40 (br s, 1H), 3.56-3.65 (m, 2H), 1.29 (t, J=7.22 Hz, 3H). HPLC: RT: 2.68 min. N4-ethyl-N2-[1-(3-isocyanocyclobutyl)-5-methylpyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine:

Reference： [1]Patent: US2017/362206,2017,A1 .Location in patent: Paragraph 0344

57
[ 92146-82-2 ]
[ 3932-97-6 ]
[ 1374507-23-9 ]

Yield	Reaction Conditions	Operation in experiment
49.6%	With N-ethyl-N,N-diisopropylamine In butan-1-ol at 0 - 20℃;	1.1 step 1:(3 - ((2-chloro-5- (trifluoromethyl) pyrimidin-4- yl) amino) phenyl) carbamateButyl ester Tert-Butyl 3-aminobenzoate (4.8 g, 23 mmol) was dissolved in n-butanol (45 mL)Then cooled to 0 oC. 2,4-Dichloro-5- (trifluoromethyl) -pyrimidine (5.0 g, 23 mmol) and DIPEA were sequentially added dropwise to the above solution.The resulting mixture was stirred at 0-5 o C for one hour and then warmed to room temperature until the reaction was complete.The reaction was beaten with PE (45 mL) and then filtered.The filter cake was washed with PE, collected and dried under vacuum to give tert-butyl (3 - ((2-chloro-5- (trifluoromethyl) pyrimidin- 4-yl) amino) phenyl) carbamate (4.434 g, Rate: 49.6%).

Reference： [1]Current Patent Assignee: PHARMARESOURCES SHANGHAI CO LTD - CN104130265, 2017, B Location in patent: Paragraph 0102; 0104; 0105; 0106

58
[ 50820-65-0 ]
[ 3932-97-6 ]
methyl 3-[2-chloro-5-(trifluoromethyl) pyrimidin-4-yl]-1H-indole-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 2, 4-dichloro -5-(trifluoromethyl)pyrimidine (24.77 g, 114.16 mmol, 2.00 eq) in DCE (200.00 mL) was added AlCl3 (15.98 g, 119.87 mmol, 6.55 mL, 2.10 eq). The mixture was stirred at 90 C for 30 min, and then <strong>[50820-65-0]methyl 1H-indole-6-carboxylate</strong> (10.00 g, 57.08 mmol, 1.00 eq) was added at 90 C. The resulting mixture was stirred at 90 C for 15.5 h. The reaction mixture was filtered. The filtrate was diluted with water (200 mL) and extracted with DCM (80 mLx3). The combined organic layers were washed with brine (200 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was washed with MeOH (50 mL) and filtered to afford the title compound (4.00 g, 10.57 mmol, 18.52% yield, 94% purity) as a yellow solid.
		To a solution of 2, 4-dichloro -5- (trifluoromethyl) pyrimidine (24.77 g, 114.16 mmol, 2.00 eq) in DCE (200.00 mL) was added AlCl3 (15.98 g, 119.87 mmol, 6.55 mL, 2.10 eq). The mixture was stirred at 90 C for 30 min, and then methyl lH-indole- 6-carboxylate (10.00 g, 57.08 mmol, 1.00 eq) was added at 90 C. The resulting mixture was stirred at 90 C for 15.5 h. The reaction mixture was filtered. The filtrate was diluted with water (200 mL) and extracted with DCM (80 mLx3). The combined organic layers were washed with brine (200 mLx2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was washed with MeOH (50 mL) and filtered to afford the title compound (4.00 g, 10.57 mmol, 18.52% yield, (0396) 94% purity) as a yellow solid.

Reference： [1]Patent: WO2018/13867,2018,A1 .Location in patent: Paragraph 350
[2]Patent: WO2019/143719,2019,A1 .Location in patent: Paragraph 167

59
[ 50609-01-3 ]
[ 3932-97-6 ]
4-chloro-5-trifluoromethyl-2-[4-{2-(pyrrolidin-1-yl)ethoxy}phenylamino]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2%		2,4-dichloro-5-trifluoromethylpyrimidine (1.0 g, 4.61 mmol) was added to a round bottom flask and was dissolved in a solution of tert-butanol and dichloroethane (1:1, 40 mL) and then stirred in zinc chloride (5.53 mL, 1 M solution in ether) at 0 C. After one hour, <strong>[50609-01-3]4-(2-(pyrrolidin-1-yl)ethoxy)aniline</strong> (0.87 mL, 4.61 mmol) and triethylamine (0.71 mL, 5.07 mmol) were added to the reaction solution. After completion of the reaction, the reaction solution was allowed to cool to room temperature and then filtered. The solvent was removed from the filtrate by distillation under reduced pressure and a saturated aqueous sodium chloride solution was added to the reaction mixture. The resulting mixture was extracted with dichloromethane and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the residue was purified by column chromatography (methanol:dichloromethane, 2:3, v/v) to obtain a compound (35 mg, 2%); 1H NMR (400 MHz, CDCl3) delta 1.81 (s, 5H), 2.65 (s, 5H), 2.92 (t, J=5.92 Hz, 2H), 3.92 (s, 1H), 4.11 (t, J=5.92 Hz, 2H), 6.92 (d, J=9.0 Hz, 2H), 7.43 (d, J=8.8 Hz, 2H), 8.50 (s, 1H); 13C NMR (400 MHz, CDCl3) (23.48, 54.72, 55.07, 67.34, 114.57, 114.83, 115.04, 121.34, 122.93, 124.54, 130.30, 156.18, 157.35, 160.91.
10.5 mg	With triethylamine; zinc(II) chloride; In diethyl ether; dichloromethane; tert-butyl alcohol; for 2h;Cooling with ice;	Diethyl ether (50 muL) was added to the reaction flask. Tert-butyl alcohol (50muL), Dichloromethane (50 muL) and Zinc Chloride (9.99 mg, 2.2 eq), Add 2,4-dichloro-5-trifluoromethylpyrimidine (7.2411^,169) under ice bath conditions. 4-(2-Pyrrolidine-1-ethoxy)aniline (7.57 mg, 1.leq) and triethylamine (6.54 mg), Reaction for 2 hours, electromagnetic stirring. Stop the reaction and extract with ethyl acetate (10mL*5). Combine the organic phases, dry over anhydrous sodium sulfate, suction filter, concentrate, and chromatograph on crude silica gel to give 2-(4-(2-pyrrolidine-1-ethoxy). ) Anilino)-4-chloro-5-trifluoromethylpyrimidine (10.5 mg).

Reference： [1]Patent: US2019/315726,2019,A1 .Location in patent: Paragraph 0207-0208
[2]Patent: CN103709172,2018,B .Location in patent: Paragraph 0100; 0103; 0104

60
[ 1196473-37-6 ]
[ 3932-97-6 ]
C₁₂H₇BClF₃N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
140 mg		Step 4: 2,4-Dichloro-5-trifluoromethylpyrimidine (2.89 g, 13.34 mmol, 1.0 eq) was dissolved in 1,2-dichloroethane (25 mL) and tert-butanol (25 mL).After cooling to 0 ° C, a solution of zinc dichloride in diethyl ether (40 mL, 40.00 mmol, 3.0 eq) was added, and the mixture was stirred at 0 ° C for 20 minutes.Intermediate 5-16 (2.00 g, 13.34 mmol, 1.0 eq) of a mixed solution of 1,2-dichloroethane (25 mL) and tert-butanol (25 mL) was slowly added dropwise.Triethylamine (4.05 g, 40.02 mmol, 3.0 eq), after completion of the addition, the cooling was stopped, and the mixture was allowed to react to room temperature for 16 hours.The reaction mixture was poured into chloroform (200 mL), washed with water (50 mL)The filtrate was purified on silica gel column, dichloromethane: methanol (20: 1) to give Intermediate 4-7 were combined and concentrated to give a total of 140mg.

Reference： [1]Patent: CN108329274,2018,A .Location in patent: Paragraph 0210; 0212; 0217

61
[ 129488-10-4 ]
[ 3932-97-6 ]
C₁₇H₁₅ClF₃N₅O₂ [ No CAS ]
C₁₇H₁₅ClF₃N₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32.15%; 40.19%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 20℃;	Compound 2,4-dichloro-5-(trifluoromethyl)pyrimidine (3 g, 13.825 mmol) and N,N-diisopropylethylamine (2.14g, 16.59 mmol) were dissolved in isopropanol (100 mL), compound Reg-1-1-c (3.2 g, 13.825 mmol) was then added tothe aforementioned solution in portions. The reaction was performed at room temperature for 16 hours. LC-MS indicatedthe reaction was complete. The reaction solution was filtered, and the filter cake was rinsed once with isopropanol toafford compound Reg-1-24 (2.3 g, pink solid, yield: 40.19percent); the filtrate was washed with saturated brine, dried overanhydrous sodium sulfate, and then concentrated to dryness, to afford compound Reg-1-23 (1.84 g, dark red solid, yield:32.15percent. Characterization data of the compound are as follows:
32.15%; 40.19%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 20℃; for 16h;	Compound 2,4-dichloro-5-(trifluoromethyl)pyrimidine (3 g, 13.825 mmol) and N,N-diisopropylethylamine (2.14 g, 16.59 mmol) were dissolved in isopropanol (100 mL), compound Reg-1-1-c (3.2 g, 13.825 mmol) was then added to the aforementioned solution in portions. The reaction was performed at room temperature for 16 hours. LC-MS indicated the reaction was complete. The reaction solution was filtered, and the filter cake was rinsed once with isopropanol to afford compound Reg-1-24 (2.3 g, pink solid, yield: 40.19percent); the filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated to dryness, to afford compound Reg-1-23 (1.84 g, dark red solid, yield: 32.15percent). Characterization data of the compound are as follows

Reference： [1]Patent: EP3421465,2019,A1 .Location in patent: Page/Page column 0123; 0124
[2]Patent: EP3421464,2019,A1 .Location in patent: Paragraph 0121; 0122

62
[ 81290-20-2 ]
[ 13544-44-0 ]
[ 3932-97-6 ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium fluoride; copper(l) iodide; 1,10-Phenanthroline; Trimethyl borate; In dimethyl sulfoxide; at 60℃; for 2h;Inert atmosphere;	<strong>[13544-44-0]2,4-dichloro-5-iodopyrimidine</strong> (24.5g) and TMSCF3 (25.5g) were placed in a 500 mL three-necked flask.KF (10.4g), trimethyl borate (18.5g), CuI (1.7g), Phen (1.6g),DMSO (250 mL) was heated to 60 C under nitrogen.After reacting for 2 hours, the temperature was lowered to room temperature, and ethyl acetate (500 mL) and water (300 mL) were added and the mixture was separated.The organic phase was washed with 1N diluted hydrochloric acid (300 mL) and dried over sodium sulfate.Spin dry to obtain a crude product which was beaten with petroleum ether to give the product 15.6 g.The yield was 81%.

Reference： [1]Patent: CN109761914,2019,A .Location in patent: Paragraph 0036-0037

63
[ 3932-97-6 ]
[ 54-20-6 ]

Yield	Reaction Conditions	Operation in experiment
90.6%	With acetic acid; In water; at 110℃; for 5h;	2,4-Dichloro-5-trifluoromethylpyrimidine (15.6 g), acetic acid (30 mL), and water (15 mL) were placed in a 250 mL vial and heated to 110 C.The reaction was carried out for 5 hours, concentrated to 30 mL, added toluene (120 mL), concentrated to 100 mL, and then,Yield 90.6%

Reference： [1]Patent: CN109761914,2019,A .Location in patent: Paragraph 0038-0039

64
[ 259860-08-7 ]
[ 3932-97-6 ]
6-bromo-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-5-fluoro-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%		To a andrt solution of 2,4-dichloro-5-trifluoromethylpyrimidine (945 uL, 7.01 mmol) in anh. (anhydrous) DCE (3 mL) under nitrogen, was added aluminum trichloride (472 mg, 3.51 mmol), and the resulting mixture was stirred at 80 C for 30 min. After this time, the reaction mixture was cooled to RT, and <strong>[259860-08-7]6-bromo-5-fluoro indole</strong> (500 mg, 2.34 mmol) was added. The resulting mixture was stirred at 80 C for 3 h, where the solution became reddish overtime. The mixture was then poured into crushed ice and EtOAc. Layers were separated, and organic layer was then dried over anh. Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (C18, ACN in aq. 10 mM ammonium formate, pH 3.8, 45 to 85% gradient) to afford the title compound (431 mg, 1.09 mmol, 47% yield) as a beige solid.

Reference： [1]Patent: WO2019/143719,2019,A1 .Location in patent: Paragraph 352

65
[ 1196473-37-6 ]
[ 3932-97-6 ]
N-(3-((2-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acrylamide [ No CAS ]

Reference： [1]Bioorganic and medicinal chemistry,2019

66
[ 1036389-05-5 ]
[ 3932-97-6 ]
methyl 2-bromo-5-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	Stage #1: 2,4-dichloro-5-trifluoromethylpyrimidine With zinc(II) chloride In tetrahydrofuran; 1,2-dichloro-ethane; <i>tert</i>-butyl alcohol at 0℃; for 1h; Stage #2: 5-amino-2-bromo-3-fluorobenzoate methyl ester With triethylamine In tetrahydrofuran; 1,2-dichloro-ethane; <i>tert</i>-butyl alcohol at 30℃; for 24h;	2-3-5 To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.5 g, 6.9 mmol) in a mixture of DCE/t-BuOH ( 54 mL, v/v: 1/1) was added ZnCl2 (8.3 mL, 1N in THF) at 0 oC, the resulting mixture was stirred at 0 oC for 1 h. Then methyl 5-amino-2-bromo-3-fluorobenzoate (1.7 g, 6.9 mmol) and Et3N (766 mg, 7.6 mmol) in DCE/t-BuOH (1:1, 10 mL) were added, the reaction mixture was stirred at 30 oC for 24 h. The mixture was poured into water, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with water, brine, concentrated in vacuo to give a residue, which was purified by silica chromatography (PE/EtOAc (50/1 to 10/1)) to give methyl 2-bromo-5-((4-chloro-5-(trifluoromethyl)pyrimidin-2- yl)amino)-3-fluorobenzoate (1.4 g, yield 47%) as a yellow solid.1H NMR (300 MHz, DMSO-d6) d 11.13 (s, 1H), 8.93 (s, 1H), 8.04 (d, J = 11.2 Hz, 1H), 7.93 (s, 1H), 3.89 (s, 3H) ppm. MS (ESI+): m/z = 425.8, 427.8 (M-H)-

Reference： [1]Current Patent Assignee: BORAGEN; BORAH - WO2021/3501, 2021, A1 Location in patent: Paragraph 0775; 0780

67
[ 368-50-3 ]
[ 3932-97-6 ]
3-((2-chloro-5-trifluoromethylpyrimidin-4-yl)amino)benzenesulfonyl fluoride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; water at 45℃; for 24h;	5 Example 5 Synthesis of compound of formula 4 (3-((2-chloro-5-trifluoromethylpyrimidin-4-yl)amino)benzenesulfonyl fluoride) Add 3-aminobenzenesulfonyl fluoride (35.0mg, 0.2mmol), 2,4-dichloro-5-trifluoromethylpyrimidine (52.1mg, 1.2eq) to the reaction flask, methanol/water=1:1 ( 0.66mL), react at 45°C for 24h.

Reference： [1]Current Patent Assignee: SUN YAT-SEN UNIVERSITY (CHINA) - CN112110863, 2020, A Location in patent: Paragraph 0113-0115

68
[ 261925-02-4 ]
[ 3932-97-6 ]
4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-5-(trifluoromethyl)pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
662 mg	Stage #1: 2,4-dichloro-5-trifluoromethylpyrimidine With zinc(II) chloride In diethyl ether; 1,2-dichloro-ethane; butan-1-ol at 20℃; for 1h; Stage #2: 3-[(methylsulfonyl)methyl]aniline With triethylamine In diethyl ether; 1,2-dichloro-ethane; butan-1-ol at 20℃; for 5h;

Reference： [1]Lücking, Ulrich; Kosemund, Dirk; Böhnke, Niels; Lienau, Philip; Siemeister, Gerhard; Denner, Karsten; Bohlmann, Rolf; Briem, Hans; Terebesi, Ildiko; Bömer, Ulf; Schäfer, Martina; Ince, Stuart; Mumberg, Dominik; Scholz, Arne; Izumi, Raquel; Hwang, Stuart; Von Nussbaum, Franz [Journal of Medicinal Chemistry, 2021, vol. 64, # 15, p. 11651 - 11674]

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H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 3932-97-6 ]

Quality Control of [ 3932-97-6 ]

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Product Details of [ 3932-97-6 ]

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Physicochemical Properties

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Druglikeness

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Application In Synthesis of [ 3932-97-6 ]

[ 3932-97-6 ] Synthesis Path-Upstream 1~4

[ 3932-97-6 ] Synthesis Path-Downstream 1~68

Related Functional Groups of [ 3932-97-6 ]

Fluorinated Building Blocks

Chlorides

Trifluoromethyls

Related Parent Nucleus of [ 3932-97-6 ]

Pyrimidines

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[ 3932-97-6 ]

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[ 3932-97-6 ]