[ CAS No. 31462-59-6 ] {[proInfo.proName]}

Name: 31462-59-6|Pyrimidine-4-carboxylic acid|97%
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Quality Control of [ 31462-59-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 31462-59-6 ]

CAS No. :	31462-59-6	MDL No. :	MFCD00129737
Formula :	C₅H₄N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YPOXGDJGKBXRFP-UHFFFAOYSA-N
M.W :	124.10	Pubchem ID :	169306
Synonyms :

Calculated chemistry of [ 31462-59-6 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	28.99
TPSA :	63.08 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.08 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.53
Log Po/w (XLOGP3) :	-0.03
Log Po/w (WLOGP) :	0.17
Log Po/w (MLOGP) :	-0.85
Log Po/w (SILICOS-IT) :	0.32
Consensus Log Po/w :	0.03

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-1.02
Solubility :	11.9 mg/ml ; 0.096 mol/l
Class :	Very soluble
Log S (Ali) :	-0.84
Solubility :	17.7 mg/ml ; 0.143 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.98
Solubility :	12.9 mg/ml ; 0.104 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.26

Safety of [ 31462-59-6 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P305+P351+P338	UN#:	N/A
Hazard Statements:	H319	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 31462-59-6 ]

* 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 [ 31462-59-6 ]
Downstream synthetic route of [ 31462-59-6 ]

[ 31462-59-6 ] Synthesis Path-Upstream 1~17

1
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[ 31462-59-6 ]

Yield	Reaction Conditions	Operation in experiment
80.5%	With selenium(IV) oxide In pyridine at 20 - 80℃; for 5.5 h;	To 4-Methyl pyrimidine (5.0 g, 0.053 mol) in pyridine (55ML) was added selenium dioxide (8.82 g, 0.079 mol) at RT with stirring. The reaction mixture was stirred at 55 °C for 2 h and at 80 °C for 3.5 hr. After cooling to RT and stirring over night, the reaction mixture was filtered and the residue was washed with pyridine. The combined pyridine solution was concentrated and the carboxylic acid obtained was washed with water to remove traces of selenium dioxide. Yield : 5.3 g, 80.5 percent. [00157] To Pyrimidine-4-carboxylic acid (5.0 g, 0.04 mol) in methanol (170 ml) was added conc. HCI (2 ML) at RT. After refluxing overnight, the reaction mixture was cooled to RT and neutralized with 10 percent sodium bicarbonate solution and concentrated. The ester was extracted with diethyl ether, dried over NA2SO4 AND concentrated to get the methyl ester as a yellow solid, yield : 3.3 g, 57.55 percent. [00158] TRIMETHYL ACETYLCHLORIDE (11.30 g, 0.093 mol) was added to a benzene (500 ML) solution of triethylamine (15.75 g, 0.155 mol) and 4- CHLOROANILINE (10.0 g, 0.078 mol) at 0°C. The reaction mixture was warmed to RT and stirred for 3h. The reaction mixture was then quenched with water, extracted with ethyl acetate, washed with water, brine solution and dried over NA2SO4. The solid product obtained was crystallized from pet ether. Yield : 14.0 g, 84. 43 percent. [00159] To N- (4-chlorophenyl)-2, 2-dimethyl propanamide (3.5 g, 0.0165 mol) in THF (50 MI) at 0 °C was added n-butyl lithium in hexane (2.64 g, 1.2 M, 0. 041 MOL). Stirring was continued at 0 °C for 2 h, the reaction then cooled to-70 °C, pyrimidine-4-methyl carboxylate (3.18 g, 0.023 mol) in THF (25 ML) was then added slowly and the solution was warmed to RT and stirred overnight. Diethyl ether (50 ml) and water (50 ml) were added and the organic layer was separated. The aqueous layer was further extracted with ether. The combined ether layers were washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography. Yield : 1.7 g, 32.69 percent. [00160] The protected amino ketone (1.7 g, 0.0054 mol) in sulfuric acid (10 ML, 70 percent) was heated at 95 °C over night. The reaction mixture was cooled to RT and basified with 10percent NAOH, extracted with DCM, washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography using basic alumina to yield title compound (0.20g, 16percent).
78%	at 20 - 85℃; for 41.5 h;	Preparation 2: 2-Chloro-1-methyl-1H-[4,4^l]bipyrimidinyl-6-oneStep A: Preparation of Pyrimidine-4-carboxylic acid: To a solution of 4-methyl pyrimidine (Aldrich) (10 g, 0.10 mmol) in pyridine (100 ml) was added SeO₂ (17.8 g, 0.16 mmol). The mixture was heated to 55°C for 2 hr., then 85⁰C for 3.5 hr. The reaction was allowed to cool to RT and stirred for 36 hr. The solids were filtered through diatomaceous earth. The solvent was evaporated and the residue diluted in 100 ml MeOH. The precipitate was collected to give the title compound as a brown solid (9.7 g, 78percent). ¹H-NMR(DMSO-Qf₆): δ ppm 13.4-14.0(broad, 1 H), 9.34 (s, 1 H), 9.04 (d, J=4.98 Hz, 1 H) and 8.02((d, J=4.98 Hz, 1H). Mass: (M+1) 125 calculated for C₅H₄N₂O₂.
67%	With potassium permanganate; potassium hydroxide In water at 75℃; for 1.5 h;	(i) To a suspension of4-methylpyrimidine (5.0 g, 0.053 mol) in water (300 mL), KMNO4 (21 g, 0.132 mol) and KOH(20.8 g, 0.372 mol) were added and heated the mixture at 75°C for 1.5 hours. Cooled to roomtemperature and ethanol (300 mL) was added drop wise. Filtered off the solids over Celite andconcentrated the filtrate. The resulting crude was diluted with water (50 mL) and acidified withconc. HCl. Precipitate was collected and dried under vacuum to obtain pyrimidine-4-carboxylicacid (4.5 g, 67percent yield), as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 13.93 (brs, 1H),9.37 (d, J = 1.2HZ, 1H), 9.06 (d, J = 4.8 Hz, 1H), 8.01 (dd, J = 4.8, 1.2 Hz, 1H).

58%	With potassium hydroxide; potassium permanganate In water at 75℃; for 1.5 h;	Intermediate A; Preparation of pyrimidine 4-carboxylic acid; 4-Methylpyrimidine (1.00 g, 10.6 mmol) was diluted in water (90 ml_). Potassium permanganate (4.20 g, 26.5 mmol) and potassium hydroxide (4.20 g, 74.8 mmol) were added, and the mixture was heated at 75 ⁰C for 1.5 h. Ethanol was added dropwise, and the precipitate was removed by filtration through Celite. The filtrate was concentrated under reduced pressure, diluted in water, and treated with a concentrated HCI solution until acidic. The title compound precipitated as a fine powder, which was collected by vacuum filtration and dried in a vacuum oven (770 mg, 58percent): ¹H NMR (DMSO-cfe) δ: 13.92 (1 H, br s), 9.35 (1H, d), 9.05 (1 H₁ d), 7.99 (1H, dd).
58%	With SeO₂ In pyridine	To a solution of 4-methylpyrimidine (4 g, 46.5 mmol) in pyridine (20 mL) was added SeO₂ (8.7 g, 79.06 mmol) at room temperature. The reaction mixture was then heated to 60° C. for 2 h, and then stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (50 mL) and filtered to remove selenium waste. The filtrate was concentrated to give a residue that was stirred with H₂O (20 mL), the precipitated solid was filtered and washed with acetone (2*20 mL) and dried to provide (BB12) (3.1 g, 58percent) as a brown solid. R_f: 0.2 (40percent MeOH/CHCl₃). ¹H NMR (400 MHz, DMSO-d₆): δ 13.8 (1H, br s), 9.37 (1H, s), 9.07 (1H, d, J=5.2 Hz), 8.01 (1H, d, J=4 Hz); m/z 123 (M-H)^-.

Reference： [1] Patent: WO2004/46092, 2004, A2, . Location in patent: Page 52-53
[2] Patent: WO2008/23239, 2008, A1, . Location in patent: Page/Page column 21
[3] Heterocycles, 2003, vol. 60, # 4, p. 953 - 957
[4] PLoS ONE, 2016, vol. 11, # 5,
[5] Patent: WO2008/70150, 2008, A1, . Location in patent: Page/Page column 59
[6] Patent: US2012/322722, 2012, A1,
[7] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1991, vol. 27, # 7, p. 768 - 771[8] Khimiya Geterotsiklicheskikh Soedinenii, 1991, # 7, p. 959 - 962
[9] Journal of Medicinal Chemistry, 2017, vol. 60, # 16, p. 6942 - 6990
[10] Chemische Berichte, 1899, vol. 32, p. 1533,2930, 2934
[11] Patent: WO2004/14881, 2004, A2, . Location in patent: Page 135
[12] Patent: WO2010/83384, 2010, A2, . Location in patent: Page/Page column 61
[13] Journal of Organic Chemistry, 2015, vol. 80, # 5, p. 2676 - 2699
[14] Inorganic Chemistry, 2018, vol. 57, # 11, p. 6266 - 6282

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Reference： [1] Tetrahedron, 2001, vol. 57, # 51, p. 10111 - 10117

3
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[ 31462-59-6 ]
[ 2435-50-9 ]

Reference： [1] Chemistry - A European Journal, 2008, vol. 14, # 8, p. 2340 - 2348

4
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[ 1029598-59-1 ]
[ 1029598-57-9 ]

Reference： [1] Chemistry - A European Journal, 2008, vol. 14, # 8, p. 2340 - 2348

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[ 17758-54-2 ]
[ 33342-83-5 ]
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Reference： [1] Chemistry - A European Journal, 2008, vol. 14, # 8, p. 2340 - 2348

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Reference： [1] Chemistry - A European Journal, 2008, vol. 14, # 8, p. 2340 - 2348

7
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Reference： [1] Journal of the Chemical Society, 1953, p. 3129

8
[ 5424-21-5 ]
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Reference： [1] Chemische Berichte, 1899, vol. 32, p. 1533,2930, 2934

9
[ 626-48-2 ]
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Reference： [1] Chemische Berichte, 1899, vol. 32, p. 1533,2930, 2934

10
[ 31462-59-6 ]
[ 28648-86-4 ]

Reference： [1] Bulletin des Societes Chimiques Belges, 1957, vol. 66, p. 276,289
[2] Journal of Organic Chemistry, 2015, vol. 80, # 5, p. 2676 - 2699

11
[ 31462-59-6 ]
[ 39513-54-7 ]

Reference： [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 16, p. 6942 - 6990
[2] Inorganic Chemistry, 2018, vol. 57, # 11, p. 6266 - 6282

12
[ 31462-59-6 ]
[ 64-17-5 ]
[ 62846-82-6 ]

Yield	Reaction Conditions	Operation in experiment
77%	Stage #1: for 14 h; Reflux Stage #2: With sodium hydrogencarbonate In water at 20℃;	General Procedure 8Intermediate 23; [0245] Thionyl chloride (3.55mL, 48.4 mmol, 3 eq) was added drop-wise to a solution of pyrimidine-4-carboxylic acid (2 g, 16.1 mmol) in EtOH (15 mL) and the resulting mixture was heated to reflux for 14 h. The mixture was then cooled to RT and made alkaline with saturated aqueous NaHC0₃ to pH 8. The basic solution was then extracted with EtOAc (4 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over Na₂S0₄, filtered and concentrated in vacuo to afford Intermediate 23 (1.7g, 77percent). ¹H NMR: (DMSO- d₆) 5 9.40 (d, J= 1.0 Hz, 1H), 9.10 (d, J= 5.1 Hz, 1H), 8.05 (dd, J= 5.1, 1.3 Hz, 1H), 4.39 (q, J= 7.1 Hz, 2H), 1.35 (t, J= 7.1 Hz, 3H); MS: 153 [M + H]⁺; TLC: 40percent hexane in EtOAc: R_f: 0.40.
77%	for 14 h; Reflux	General Procedure 13 was followed in the preparation of Intermediate 19. 2129 General Procedure 13 2131 Intermediate 19 2132 [0243] Thionyl chloride (3.55mL, 48.4 mmol, 3 eq) was added dropwise to a solution of 2133 pyrimidine-4-carboxylic acid (2 g, 16.1 mmol) in EtOH (15 mL) and the resulting mixture 2134 was heated to reflux for 14 h. The mixture was then cooled to RT and made alkaline with 2135 saturated aqueous NaHC0₃ to pH 8. The basic solution was then extracted with EtOAc (4 x 2136 50 mL). The combined organic layers were washed with brine (30 mL), dried over Na₂S0₄, 2137 filtered and concentrated in vacuo to afford Intermediate 19 (1.7g, 77percent). 1H NMR: (DMSO- 2138 d₆) 5 9.40 (d, J= 1.0 Hz, 1H), 9.10 (d, J= 5.1 Hz, 1H), 8.05 (dd, J= 5.1, 1.3 Hz, 1H), 4.39 2139 (q, J= 7.1 Hz, 2H), 1.35 (t, J= 7.1 Hz, 3H); MS: 153 [M + H]⁺; TLC: 40percent hexane in EtOAc: 2140 R_f: 0.40
77%	for 14 h; Reflux	General Procedure 8 Thionyl chloride (3.55 mL, 48.4 mmol, 3 eq) was added drop-wise to a solution of pyrimidine-4-carboxylic acid (2 g, 16.1 mmol) in EtOH (15 mL) and the resulting mixture was heated to reflux for 14 h. The mixture was then cooled to RT and made alkaline with saturated aqueous NaHCO₃to pH 8. The basic solution was then extracted with EtOAc (450 mL). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to afford Intermediate 23 (1.7g, 77percent). ¹H NMR: (DMSO-d₆) δ 9.40 (d, J=1.0 Hz, 1H), 9.10 (d,J=5.1Hz, 1H), 8.05 (dd, J=5.1, 1.3 Hz, 1H), 4.39 (q, J=7.1Hz, 2H), 1.35 (t, J=7.1Hz, 3H); MS: 153 [M+H]⁺; TLC: 40percent hexane in EtOAc: R_f: 0.40.

Reference： [1] Journal of Organic Chemistry, 2015, vol. 80, # 5, p. 2676 - 2699
[2] Patent: WO2011/126903, 2011, A2, . Location in patent: Page/Page column 92
[3] Patent: WO2014/145986, 2014, A1, . Location in patent: Paragraph 0242; 0243
[4] Patent: US2017/326125, 2017, A1, . Location in patent: Paragraph 0359-0361
[5] Bulletin des Societes Chimiques Belges, 1957, vol. 66, p. 276,289
[6] Gazzetta Chimica Italiana, 1952, vol. 82, p. 652,655, 660
[7] Inorganic Chemistry, 2018, vol. 57, # 11, p. 6266 - 6282

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Reference： [1] Zhurnal Obshchei Khimii, 1955, vol. 25, p. 2313,2314, 2315; engl. Ausg. S. 2285, 2286

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[ 39870-05-8 ]

Reference： [1] PLoS ONE, 2016, vol. 11, # 5,

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[ 49689-16-9 ]
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[ 2435-50-9 ]

Reference： [1] Tetrahedron, 2001, vol. 57, # 51, p. 10111 - 10117

16
[ 3438-46-8 ]
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[ 2435-50-9 ]

Reference： [1] Chemistry - A European Journal, 2008, vol. 14, # 8, p. 2340 - 2348

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[ 17758-54-2 ]
[ 33342-83-5 ]
[ 31462-59-6 ]
[ 1029598-59-1 ]
[ 1029598-57-9 ]
[ 2435-50-9 ]

Reference： [1] Chemistry - A European Journal, 2008, vol. 14, # 8, p. 2340 - 2348

[ 31462-59-6 ] Synthesis Path-Downstream 1~88

1
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[ 31462-59-6 ]

Yield	Reaction Conditions	Operation in experiment
80.5%	With selenium(IV) oxide; In pyridine; at 20 - 80℃; for 5.5h;	To 4-Methyl pyrimidine (5.0 g, 0.053 mol) in pyridine (55ML) was added selenium dioxide (8.82 g, 0.079 mol) at RT with stirring. The reaction mixture was stirred at 55 C for 2 h and at 80 C for 3.5 hr. After cooling to RT and stirring over night, the reaction mixture was filtered and the residue was washed with pyridine. The combined pyridine solution was concentrated and the carboxylic acid obtained was washed with water to remove traces of selenium dioxide. Yield : 5.3 g, 80.5 %. [00157] To Pyrimidine-4-carboxylic acid (5.0 g, 0.04 mol) in methanol (170 ml) was added conc. HCI (2 ML) at RT. After refluxing overnight, the reaction mixture was cooled to RT and neutralized with 10 % sodium bicarbonate solution and concentrated. The ester was extracted with diethyl ether, dried over NA2SO4 AND concentrated to get the methyl ester as a yellow solid, yield : 3.3 g, 57.55 %. [00158] TRIMETHYL ACETYLCHLORIDE (11.30 g, 0.093 mol) was added to a benzene (500 ML) solution of triethylamine (15.75 g, 0.155 mol) and 4- CHLOROANILINE (10.0 g, 0.078 mol) at 0C. The reaction mixture was warmed to RT and stirred for 3h. The reaction mixture was then quenched with water, extracted with ethyl acetate, washed with water, brine solution and dried over NA2SO4. The solid product obtained was crystallized from pet ether. Yield : 14.0 g, 84. 43 %. [00159] To N- (4-chlorophenyl)-2, 2-dimethyl propanamide (3.5 g, 0.0165 mol) in THF (50 MI) at 0 C was added n-butyl lithium in hexane (2.64 g, 1.2 M, 0. 041 MOL). Stirring was continued at 0 C for 2 h, the reaction then cooled to-70 C, pyrimidine-4-methyl carboxylate (3.18 g, 0.023 mol) in THF (25 ML) was then added slowly and the solution was warmed to RT and stirred overnight. Diethyl ether (50 ml) and water (50 ml) were added and the organic layer was separated. The aqueous layer was further extracted with ether. The combined ether layers were washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography. Yield : 1.7 g, 32.69 %. [00160] The protected amino ketone (1.7 g, 0.0054 mol) in sulfuric acid (10 ML, 70 %) was heated at 95 C over night. The reaction mixture was cooled to RT and basified with 10% NAOH, extracted with DCM, washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography using basic alumina to yield title compound (0.20g, 16%).
78%	With pyridine; selenium(IV) oxide; at 20 - 85℃; for 41.5h;	Preparation 2: 2-Chloro-1-methyl-1H-[4,4l]bipyrimidinyl-6-oneStep A: Preparation of Pyrimidine-4-carboxylic acid: To a solution of 4-methyl pyrimidine (Aldrich) (10 g, 0.10 mmol) in pyridine (100 ml) was added SeO2 (17.8 g, 0.16 mmol). The mixture was heated to 55C for 2 hr., then 850C for 3.5 hr. The reaction was allowed to cool to RT and stirred for 36 hr. The solids were filtered through diatomaceous earth. The solvent was evaporated and the residue diluted in 100 ml MeOH. The precipitate was collected to give the title compound as a brown solid (9.7 g, 78%). 1H-NMR(DMSO-Qf6): delta ppm 13.4-14.0(broad, 1 H), 9.34 (s, 1 H), 9.04 (d, J=4.98 Hz, 1 H) and 8.02((d, J=4.98 Hz, 1H). Mass: (M+1) 125 calculated for C5H4N2O2.
67%	With potassium permanganate; potassium hydroxide; In water; at 75℃; for 1.5h;	(i) To a suspension of4-methylpyrimidine (5.0 g, 0.053 mol) in water (300 mL), KMNO4 (21 g, 0.132 mol) and KOH(20.8 g, 0.372 mol) were added and heated the mixture at 75C for 1.5 hours. Cooled to roomtemperature and ethanol (300 mL) was added drop wise. Filtered off the solids over Celite andconcentrated the filtrate. The resulting crude was diluted with water (50 mL) and acidified withconc. HCl. Precipitate was collected and dried under vacuum to obtain pyrimidine-4-carboxylicacid (4.5 g, 67% yield), as a white solid. 1H NMR (400 MHz, DMSO-d6): delta 13.93 (brs, 1H),9.37 (d, J = 1.2HZ, 1H), 9.06 (d, J = 4.8 Hz, 1H), 8.01 (dd, J = 4.8, 1.2 Hz, 1H).

58%	With potassium hydroxide; potassium permanganate; In water; at 75℃; for 1.5h;	Intermediate A; Preparation of pyrimidine 4-carboxylic acid; 4-Methylpyrimidine (1.00 g, 10.6 mmol) was diluted in water (90 ml_). Potassium permanganate (4.20 g, 26.5 mmol) and potassium hydroxide (4.20 g, 74.8 mmol) were added, and the mixture was heated at 75 0C for 1.5 h. Ethanol was added dropwise, and the precipitate was removed by filtration through Celite. The filtrate was concentrated under reduced pressure, diluted in water, and treated with a concentrated HCI solution until acidic. The title compound precipitated as a fine powder, which was collected by vacuum filtration and dried in a vacuum oven (770 mg, 58%): 1H NMR (DMSO-cfe) delta: 13.92 (1 H, br s), 9.35 (1H, d), 9.05 (1 H1 d), 7.99 (1H, dd).
58%	With SeO2; In pyridine;	To a solution of 4-methylpyrimidine (4 g, 46.5 mmol) in pyridine (20 mL) was added SeO2 (8.7 g, 79.06 mmol) at room temperature. The reaction mixture was then heated to 60 C. for 2 h, and then stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (50 mL) and filtered to remove selenium waste. The filtrate was concentrated to give a residue that was stirred with H2O (20 mL), the precipitated solid was filtered and washed with acetone (2*20 mL) and dried to provide (BB12) (3.1 g, 58%) as a brown solid. Rf: 0.2 (40% MeOH/CHCl3). 1H NMR (400 MHz, DMSO-d6): delta 13.8 (1H, br s), 9.37 (1H, s), 9.07 (1H, d, J=5.2 Hz), 8.01 (1H, d, J=4 Hz); m/z 123 (M-H)-.
		3-Methyl-pyrimidine [(9. 41] g, 100 mmol), potassium permanganate (26.9 g) and sodium carbonate (10.6 g) was refluxed in water (100 ml) for 72 h followed by filtration through celite. The filtrate was washed with several portions of DCM and EtOAc before acidification with conc. HC1. The formed precipitate was collected and washed with water to yield 1.37 g of the title compound as a white solid. 1H NMR (DMSO-d6) d (ppm): 13.94 (br. s, 1H), 9.37 (d, 1H), 9.07 (d, 1H), 8.01 (dd, 1H).

Reference： [1]Patent: WO2004/46092,2004,A2 .Location in patent: Page 52-53
[2]Patent: WO2008/23239,2008,A1 .Location in patent: Page/Page column 21
[3]Heterocycles,2003,vol. 60,p. 953 - 957
[4]PLoS ONE,2016,vol. 11
[5]Patent: WO2008/70150,2008,A1 .Location in patent: Page/Page column 59
[6]Patent: US2012/322722,2012,A1
[7]Chemistry of Heterocyclic Compounds,1991,vol. 27,p. 768 - 771
Khimiya Geterotsiklicheskikh Soedinenii,1991,p. 959 - 962
[8]Journal of Medicinal Chemistry,2017,vol. 60,p. 6942 - 6990
[9]Chemische Berichte,1899,vol. 32,p. 1533,2930, 2934
[10]Patent: WO2004/14881,2004,A2 .Location in patent: Page 135
[11]Patent: WO2010/83384,2010,A2 .Location in patent: Page/Page column 61
[12]Journal of Organic Chemistry,2015,vol. 80,p. 2676 - 2699
[13]Inorganic Chemistry,2018,vol. 57,p. 6266 - 6282

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[ 1450-14-2 ]
[ 120809-59-8 ]

Reference： [1]Tetrahedron,1988,vol. 44,p. 3281 - 3288

3
[ 31462-59-6 ]
[ 952754-43-7 ]
pyrimidine-4-carboxylic acid (2-phenylaminobenzothiazol-4-yl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With benzotriazol-1-ol; diisopropyl-carbodiimide; In N,N-dimethyl-formamide; at 20℃;	To a flask was added N2-phenyl-benzothiazole-2,4-diamine Compound 2b (3 mg, 0.012 mmol), <strong>[31462-59-6]pyrimidine-4-carboxylic acid</strong> (1.5 mg, 0.012 mmol), HOBt (1.7 mg, 0.012 mmol), DIC (1.6 mg, 0.012 mmol) and DMF (2 mL). The mixture was stirred at rt overnight, then poured into H2O and extracted with EtOAc. The organic layer was dried over MgSO4, then concentrated and the residue was purified by flash chromatography (silica gel, CH2Cl2 :EtO Ac/5: 5) to afford 3.5 mg (82%) of pyrimidine- 4-carboxylic acid (2-phenylamino-benzothiazol-4-yl)-amide Compound 15. 1H NMR (400 MHz, DMSO) delta 10.95 (s, 1 H), 10.65 (s, 1 H), 9.35 (s, 1 H), 9.02 (m, 1 H), 8.90 <n="51"/>(s, 1 H), 8.35 (d, J= 7.1 Hz, 1 H), 7.88 (d, J= 7.2 Hz, 2 H), 7.58 (d, J= 7.2 Hz, 1 H), 7.45 (t, J= 7.2 Hz, 2 H), 7.22 (t, J= 7.2 Hz, 1 H), 7.12 (t, J= 7.2 Hz, 1 H). MS (ESI) m/z: 348 (M+H)+.

Reference： [1]Patent: WO2007/121154,2007,A2 .Location in patent: Page/Page column 49-50

4
[ 67-56-1 ]
[ 31462-59-6 ]
[ 2450-08-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sulfuric acid; for 16h;Heating / reflux;	Step B: Preparation of Pyrimidine-4-carboxylic acid methyl ester: A solution of the product of Preparation 2, Step A (6.17 g, 49.7 mmol), in MeOH (60 ml) was added to sulfuric acid (0.3 ml) and heated to refluxed for 16 hr. Excess solvent was removed under vacuum to obtain a residue, which was dissolved in 10% MeOH/CHCI3 (100 ml) and adsorbed onto silica gel. The crude material was purified by column chromatography over silica gel eluting with CHCl3 then 10% MeOH/CHCI3 to obtain the title compound as a yellow solid (5.8 g, 85%). 1H-NMR(DMSO): delta 9.4(s, 1 H), 9.0(d, J=4.9 Hz, 1H), 8.0(d, J=4.9 Hz, 1 H) and 4.0(s,3H). Mass: (M+H) 140 calculated for C6H7N2O2.

Reference： [1]Patent: WO2008/23239,2008,A1 .Location in patent: Page/Page column 21
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 6942 - 6990

5
[ 31462-59-6 ]
C₂₁H₂₀F₆N₂O [ No CAS ]
C₂₆H₂₂F₆N₄O₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5310 - 5315

6
[ 31462-59-6 ]
[ 120809-68-9 ]

Reference： [1]Tetrahedron,1988,vol. 44,p. 3281 - 3288

7
[ 31462-59-6 ]
[ 28648-86-4 ]

Reference： [1]Bulletin des Societes Chimiques Belges,1957,vol. 66,p. 276,289
[2]Journal of Organic Chemistry,2015,vol. 80,p. 2676 - 2699

8
[ 5424-21-5 ]
[ 31462-59-6 ]

Reference： [1]Chemische Berichte,1899,vol. 32,p. 1533,2930, 2934

9
[ 626-48-2 ]
[ 31462-59-6 ]

Reference： [1]Chemische Berichte,1899,vol. 32,p. 1533,2930, 2934

10
[ 31462-59-6 ]
[ 2450-08-0 ]

Yield	Reaction Conditions	Operation in experiment
57.55%	With hydrogenchloride; methanol; In water; at 20℃;Heating / reflux;	To 4-Methyl pyrimidine (5.0 g, 0.053 mol) in pyridine (55ML) was added selenium dioxide (8.82 g, 0.079 mol) at RT with stirring. The reaction mixture was stirred at 55 C for 2 h and at 80 C for 3.5 hr. After cooling to RT and stirring over night, the reaction mixture was filtered and the residue was washed with pyridine. The combined pyridine solution was concentrated and the carboxylic acid obtained was washed with water to remove traces of selenium dioxide. Yield : 5.3 g, 80.5 %. [00157] To Pyrimidine-4-carboxylic acid (5.0 g, 0.04 mol) in methanol (170 ml) was added conc. HCI (2 ML) at RT. After refluxing overnight, the reaction mixture was cooled to RT and neutralized with 10 % sodium bicarbonate solution and concentrated. The ester was extracted with diethyl ether, dried over NA2SO4 AND concentrated to get the methyl ester as a yellow solid, yield : 3.3 g, 57.55 %. [00158] TRIMETHYL ACETYLCHLORIDE (11.30 g, 0.093 mol) was added to a benzene (500 ML) solution of triethylamine (15.75 g, 0.155 mol) and 4- CHLOROANILINE (10.0 g, 0.078 mol) at 0C. The reaction mixture was warmed to RT and stirred for 3h. The reaction mixture was then quenched with water, extracted with ethyl acetate, washed with water, brine solution and dried over NA2SO4. The solid product obtained was crystallized from pet ether. Yield : 14.0 g, 84. 43 %. [00159] To N- (4-chlorophenyl)-2, 2-dimethyl propanamide (3.5 g, 0.0165 mol) in THF (50 MI) at 0 C was added n-butyl lithium in hexane (2.64 g, 1.2 M, 0. 041 MOL). Stirring was continued at 0 C for 2 h, the reaction then cooled to-70 C, pyrimidine-4-methyl carboxylate (3.18 g, 0.023 mol) in THF (25 ML) was then added slowly and the solution was warmed to RT and stirred overnight. Diethyl ether (50 ml) and water (50 ml) were added and the organic layer was separated. The aqueous layer was further extracted with ether. The combined ether layers were washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography. Yield : 1.7 g, 32.69 %. [00160] The protected amino ketone (1.7 g, 0.0054 mol) in sulfuric acid (10 ML, 70 %) was heated at 95 C over night. The reaction mixture was cooled to RT and basified with 10% NAOH, extracted with DCM, washed with water, brine and dried over NA2SO4. The product obtained upon concentration was purified by column chromatography using basic alumina to yield title compound (0.20g, 16%).

Reference： [1]Patent: WO2004/46092,2004,A2 .Location in patent: Page 52-53

Yield	Reaction Conditions	Operation in experiment
70%		EXAMPLE 7 Phenylacetamido desacetoxycephalosporanic acid Following Example 3, but replacing the isonicotinic acid hydrobromide by 2.19 g (1.07 cmoles) of 4-pyrimidine carboxylic acid hydrobromide, the product of the title was obtained with a 72% yield. 4-pyrimidine carboxylic acid was recovered with a 70% yield.

12
[ 31462-59-6 ]
[ 929301-65-5 ]
3-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)methyl]-9-(pyrimidin-4-ylcarbonyl)-3,9-diazaspiro[5.5]undecane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With triethylamine; HATU; In dichloromethane; at 20℃; for 1.5h;	Example 73-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)methyl]-9-(pyrimidin-4-ylcarbonyl)-3,9-diazaspiro[5.5]undecane EPO <DP n="101"/>A mixture of Intermediate A (14 mg, 0.44 mmol), HATU (17 mg, 0.44 mmol), pyridimine- 4-carboxylic acid (7 mg, 0.53 mmol), triethylamine (11 mul, 0.78 mmol) and dichloromethane (1 mL) was stirred at room temperature for 1.5 h. The reaction mixture was diluted with EtOAc and washed with sodium hydrogen carbonate solution. The organic layer was isolated, evaporated to dryness and the residue was purified by preparative HPLC (RP-18) to give the product as a white solid (6 mg, 32%).1H NMR (399.99 MHz, CD3OD) delta 9.25-9.18 (m, IH), 8.99-8.90 (m, IH), 7.68-7.62 (m, IH), 7.32-7.25 (m, IH), 7.24-7.16 (m, IH), 6.98-6.88 (m, IH), 4.32-4.21 (m, 2H), 3.83- 3.72 (m, 2H), 3.48-3.35 (m, 4H), 3.28-3.08 (m, 4H), 2.11-1.99 (m, 2H), 1.85-1.56 (m, 6H), 1.54-1.45 (m, 6HAPCI-MS m/z: 421.2 [MH+]HPLC (Method A) Retention time: 5.97 minHPLC (Method B) Retention time: 7.70 min

Reference： [1]Patent: WO2007/30061,2007,A1 .Location in patent: Page/Page column 99-100

13
[ 31462-59-6 ]
[ 184951-32-4 ]

Yield	Reaction Conditions	Operation in experiment
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 27℃; for 2.16667h;	General procedure: Typical procedure for the preparation of intermediates via pyrimidine ring formation from heteroaryl carboxylic acids as exemplified by the preparation of Intermediate 8, 6-chloro-4,4'-bipyrimidine4-Pyrimidinecarboxylic acid (Intermediate 9, 3.0 g, 24.2 mmol) in DMF (0.01 mL) and CH2CI2(60 mL) was cooled to 0 C before the dropwise addition over 10 min of oxalyl chloride (2.7 mL, 31.5 mmol). After stirring at rt for 2 h the reaction mixture was concentrated in vacuo and the resulting crude acid chloride redissolved in THF (10 mL). Separately, EtOAc (8.3 mL, 84.6 mmol) was dissolved in THF (30 mL) and cooled to -78 C before the dropwise addition of LDA (36.0 mL of a 2 M solution in THF, 72.0 mmol). After stirring at -78 C for 1 h the THF solution of the crude acid chloride was added and the mixture stirred at -78 C for 3 h. Aqueous HCl (IN, 25 mL) was added, followed by H20 (100 mL) and EtOAc (100 mL), and the phases were separated. The aqueous phase was extracted with EtOAc (3 x 100 mL) and the combined organic phases were dried (Na2S04) and concentrated in vacuo. Purification by gradient flash chromatography, eluting with 0-8% EtOAc in hexane yielded ethyl 3-oxo-3-(pyrimidin-4-yl)propanoate (0.40 g, 2.06 mmol) as a white solid.TLC: Rf 0.6, Hexane / Ethyl acetate 4: 1Ethyl 3-oxo-3-(pyrimidin-4-yl)propanoate (1.2 g, 6.18 mmol), sodium methoxide (1.33 g, 24.6 mmol) and formamidine hydrochloride (1.0 g, 12.4 mmol) were dissolved in MeOH (20 mL) and stirred at room temperature for 24 h before concentration in vacuo. H20 (50 mL) and EtOAc (50 mL) were added and the phases were separated. The aqueous phase was extracted with EtOAc (3 x 50 mL) and the combined organic phases were dried (Na2S04), and concentrated in vacuo to yield crude [4,4'-bipyrimidin]-6-ol (200 mg) which was used in the next step without further purification.TLC: Rf 0.1, Ethyl acetateCrude [4,4'-Bipyrimidin]-6-ol (120 mg, 0.69 mmol) was dissolved in phosphorus(V) oxychloride (4.0 mL, 42.9 mmol) and stirred at rt for 14 h. The mixture was neutralized to approximately pH 7 with saturated aqueous NaHC03solution (30 mL) at 0 C and stirred for 15 min before the addition of EtOAc (300 mL) and H20 (100 mL). The phases were separated, the aqueous phase was extracted with EtOAc (300 mL), and the combined organic phases were dried (Na2S04) and concentrated in vacuo. Purification by gradient flash chromatography, eluting with 0-9% EtOAc in hexane yielded the title compound (42 mg, 0.22 mmol) as a white solid.Data in table 1.
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere;	General procedure: 2-(Benzyloxy)-3,5-dibromobenzamide (1.0 g, 2.58 mmol) was dissolved in BH3THF (13.24 mL, 13.24 mmol) under N2 and the mixture was heated to reflux. The reaction stirred for 48 h at 75 C and was monitored by TLC (10 mL additional BH3THF was added at 30 h). Methanol (10 mL*2) was added dropwise to quench the reaction, and then the solvent was removed in vacuo. The product was used crude in the subsequent step without purification. 1H NMR (400 MHz, DMSO-d6) delta 7.95 (d, J = 2.5 Hz, 1H), 7.91 (s, 1H), 7.74 (s, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.48-7.42 (m, 2H), 7.40-7.29 (m, 3H), 4.95 (s, 2H), 4.36 (t, 2H). 13C NMR (101 MHz, DMSO-d6) delta 151.79, 136.32, 136.20, 134.68, 131.19, 128.40, 128.39, 119.03, 116.67, 60.79, 29.25. 2-Nitrobenzonic acid (534.8 mg, 3.20 mmol) was dissolved in CH2Cl2 and the solution was cooled to 0 C under N2. Oxalyl chloride (0.550 mL, 6.40 mmol) was added dropwise, followed by DMF (1 drop). The reaction was allowed to warm to room temperature as it stirred for 2 h. Solvent and excess oxalyl chloride was removed in vacuo and then the residue was resuspended in CH2Cl2. This acid chloride was added dropwise to a solution of (2-(benzyloxy)-3,5-dibromophenyl)methanamine (655 mg, 1.60 mmol) in CH2Cl2 (32 mL, 0.1 M). Triethylamine (1.56 mL, 11.2 mmol) was added, followed by DMAP (cat.) and the mixture stirred overnight at room temperature. After quenching the reaction with water (25 mL), more CH2Cl2 was added (50 mL) and the organic layer was washed with HCl (50 mL, 1 M), sat. NaHCO3 (50 mL) and then brine (50 mL), and then was dried over Na2SO4. Purification via silica-gel column chromatography (product elutes around 30% EtOAc) afforded 354 mg of the desired product, 42.5% yield.

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 1803 - 1808
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 9589 - 9606
[3]Organic Letters,2013,vol. 15,p. 1922 - 1925
[4]Patent: WO2015/8073,2015,A1 .Location in patent: Page/Page column 32; 33
[5]Journal of Organic Chemistry,2015,vol. 80,p. 2676 - 2699
[6]Journal of Medicinal Chemistry,2015,vol. 58,p. 6653 - 6664
[7]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 153 - 165
[8]Journal of Medicinal Chemistry,2017,vol. 60,p. 6622 - 6637
[9]Journal of the American Chemical Society,2018,vol. 140,p. 11487 - 11494

14
[ 31462-59-6 ]
nickel(II) chloride hexahydrate [ No CAS ]
trans-nickel(II) diaqua-bis(pyrimidine-4-carboxylate) dihydrate [ No CAS ]

Reference： [1]Inorganica Chimica Acta,2006,vol. 359,p. 1255 - 1262

15
[ 31462-59-6 ]
[ 7732-18-5 ]
zinc dibromide [ No CAS ]
trans-zinc(II) diaqua-bis(pyrimidine-4-carboxylate) dihydrate [ No CAS ]

Reference： [1]Inorganica Chimica Acta,2006,vol. 359,p. 1255 - 1262

16
[ 31462-59-6 ]
{H₂O(NH₃)5Ru}⁽²⁺⁾*2CF₃COO^(1-)={H₂O(NH₃)5Ru}(CF₃COO)2 [ No CAS ]
sodium perchlorate [ No CAS ]
Ru(NH₃)5(C₄H₃N₂COOH)⁽³⁺⁾*3ClO₄^(1-)*4H₂O=Ru(NH₃)5(C₄H₃N₂COOH)(ClO₄)3*4H₂O [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1984,vol. 106,p. 5532 - 5537

17
[ 31462-59-6 ]
copper(ll) sulfate pentahydrate [ No CAS ]
trans-copper(II) diaqua-bis(pyrimidine-4-carboxylate) dihydrate [ No CAS ]

Reference： [1]Inorganica Chimica Acta,2006,vol. 359,p. 1255 - 1262

18
[ 31462-59-6 ]
methyl 5-(4-aminophenyl)-3-[[(trans-4-methylcyclohexyl)carbonyl](1-methylethyl)amino]-2-thiophenecarboxylate [ No CAS ]
methyl 3-[[(trans-4-methylcyclohexyl)carbonyl](1-methylethyl)amino]-5-{4-[(4-pyrimidinylcarbonyl)amino]phenyl}-2-thiophenecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of <strong>[31462-59-6]4-pyrimidinecarboxylic acid</strong> (66 mg), HATU (220 mg) and DIPEA (248 mg) were dissolved in DMF (5 ml.) and the reaction was stirred at room temperature for 1 h. Methyl 5- (4-aminophenyl)-3-[[(frans-4-methylcyclohexyl)carbonyl](1-methylethyl)amino]-2- thiophenecarboxylate (200 mg, a synthesis of which is described as Intermediate 9) was added and the reaction was stirred at room temperature for 18 h, then at 5O0C over a weekend. HATU (220 mg), DIPEA (248 mg) and <strong>[31462-59-6]4-pyrimidinecarboxylic acid</strong> (66 mg) were added and the reaction was stirred at 5O0C for 4 h. The reaction was evaporated in vacuo and partitioned between DCM and sodium bicarbonate solution. The organic phases were separated, dried using a hydrophobic frit and evaporated in vacuo. The crude material was <n="53"/>purified by ISCO Companion silica chromatography, eluting with a gradient 5-100% EtOAc in cyclohexane to give the title compound. MS calcd for (C28H32N4O4S + H)+: 521 MS found (electrospray): (M+H)+ = 521

Reference： [1]Patent: WO2008/59042,2008,A1 .Location in patent: Page/Page column 51-52

19
[ 3438-46-8 ]
[ 17758-54-2 ]
[ 33342-83-5 ]
[ 31462-59-6 ]
[ 1029598-59-1 ]
[ 1029598-57-9 ]

Reference： [1]Chemistry - A European Journal,2008,vol. 14,p. 2340 - 2348

20
[ 3438-46-8 ]
[ 31462-59-6 ]
[ 1029598-59-1 ]
[ 1029598-57-9 ]

Reference： [1]Chemistry - A European Journal,2008,vol. 14,p. 2340 - 2348

21
[ 31462-59-6 ]
[ 95-76-1 ]
[ 1161205-01-1 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 4115 - 4118

22
[ 31462-59-6 ]
[ 912536-37-9 ]
[ 1179356-26-3 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 7706 - 7723

23
[ 31462-59-6 ]
[ 912536-41-5 ]
[ 1179356-31-0 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 7706 - 7723

24
[ 31462-59-6 ]
[ 912463-61-7 ]
[ 1179356-24-1 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 7706 - 7723

25
[ 31462-59-6 ]
3-(2-isobutoxybenzyl)-3,9-diazaspiro[5.5]undecane [ No CAS ]
3-(2-isobutoxybenzyl)-9-(pyrimidin-4-ylcarbonyl)-3,9-diazaspiro[5.5]undecane [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 7706 - 7723

26
[ 31462-59-6 ]
[ 912536-38-0 ]
[ 1179356-28-5 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 7706 - 7723

27
[ 31462-59-6 ]
C₂₁H₃₂N₂O [ No CAS ]
[ 1179356-34-3 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 7706 - 7723

28
[ 31462-59-6 ]
tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate [ No CAS ]
C₁₉H₂₈N₄O₃ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 7706 - 7723

29
[ 31462-59-6 ]
[ 1227193-49-8 ]
[ 1227191-12-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 5039 - 5043

30
[ 31462-59-6 ]
[ 298201-68-0 ]
[ 1120368-21-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 401 - 410

31
[ 31462-59-6 ]
[ 436089-18-8 ]
[ 1266338-05-9 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 1106 - 1110

32
[ 31462-59-6 ]
4-phenyldecahydroquinolin-4-ol [ No CAS ]
C₂₀H₂₃N₃O₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2359 - 2364

33
[ 31462-59-6 ]
[ 1332336-55-6 ]
[ 1332336-41-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4891 - 4899

34
[ 31462-59-6 ]
[ 1338358-68-1 ]

Reference： [1]Patent: WO2011/126903,2011,A2
[2]Patent: WO2014/145986,2014,A1
[3]Patent: US2017/326125,2017,A1

35
[ 31462-59-6 ]
[ 1350608-07-9 ]
[ 1350605-63-8 ]

Yield	Reaction Conditions	Operation in experiment
66%	With dmap; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; at 20℃;	To a solution of 2-(azetidin-3-yloxy)-3-(3,6-dihydro-2H-pyran-4-yl)pyridine hydrochloride (see PREPARATION P26.1; 100 mg,0.45 mmol), <strong>[31462-59-6]pyrimidine-4-carboxylic acid</strong> (55 mg, 0.45 mmol) and triethylamine (96.13 mg, 0.95 mmol) in CH2CI2 (10 mL) was added 4- Dimethylaminopyridine (DMAP) (55 mg, 0.47 mmol) and propyl phosphonic anhydride (500 mg, 0.9 mmol). The reaction mixture was stirred at room temperature for overnight. Then the reaction mixture was concentrated and the crude product was purified by silica gel column chromatography to give the desired compound (48 mg, 0.16 mmol, yield 66%). [M+l]: 339. IC50 (uM): 0.99.

Reference： [1]Patent: WO2011/143495,2011,A1 .Location in patent: Page/Page column 259

36
[ 31462-59-6 ]
[ 1239013-81-0 ]
[ 1239013-53-6 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 7639 - 7647

37
[ 31462-59-6 ]
[ 1365607-11-9 ]
[ 1365609-21-7 ]

Yield	Reaction Conditions	Operation in experiment
		Example 25: l-[l-(9-MethyI-8-pyrimidin-4-yl-9H-purin-6-yI)piperidin-4-yl]-l,3- dihydro-2H-benzimidazol-2-one (Compound 298)l-ri-(9-MethYl-8-Pyrimidin-4-vI-9H-purin-6-yl)piperidin-4-yl1-1.3-dihvdro-2H- benzimidazol-2-one [00229] To a solution of 1 -( 1 -(5-amino-6-(methylamino)pyrimidin-4-yl)piperidin-4-yl)- lH-benzo[d]imidazol-2(3H)-one (50 mg, 0.14 mmol) in anhydrous DMA (5 mL) and diisopropylethylamine (0.5 mL) were added HATU (150 mg, 0.39 mmol), and pyrimidine-4- carbox lic acid (100 mg, 0.8 mmol). The reaction mixture was stirred for 1 h, and concentrated under reduced pressure. The resulting oil was dissolved in 10 mL of dichloromethane, and the solution was washed with 5 mL of water. The organic layer was dried over MgS04, concentrated under reduced pressure, and the residue was dissolved in Acetic acid (2 mL). The reaction mixture was heated in a microwave reactor to 150 C for 20 min, and concentrated under reduced pressure. The product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 3 mg of the title compound. NMR (400MHz, DMSO-d6): delta 10.85 (s, IH), 9.34 (s, IH), 8.96 (d, IH), 8.36 (s, IH), 8.27 (d, IH), 7.21 - 7.14 (m, IH), 6.93 (d, 3H), 4.64 - 4.52 (m, lH), 4.18 (s, 3H), 2.37 (dd, 2H), 1.85 (t, 2H); MS (El) for C23H21N90: 428.4 (MH+).

Reference： [1]Patent: WO2012/37226,2012,A1 .Location in patent: Page/Page column 178-179

38
[ 31462-59-6 ]
[ 1380672-05-8 ]

Reference： [1]Patent: WO2012/76898,2012,A1

39
[ 31462-59-6 ]
[ 1312919-50-8 ]

Reference： [1]Patent: WO2012/76898,2012,A1

40
[ 31462-59-6 ]
[ 95-51-2 ]
[ 1312904-06-5 ]

Yield	Reaction Conditions	Operation in experiment
87%		Method a): (0199) To a solution of acid (1.0 equiv.) and DIPEA (1.2 equiv.) in dried DMF (0.2-0.5 M) was added HATU (1.1 equiv.) under an inert atmosphere. The reaction was stirred for 1 h before the amine (1.1 equiv.) was added. The stirring was continued for 2 to 24 hours and then evaporated to dryness. The residue was either first extracted (treated with a diluted aqueous sodium bicarbonate and DCM) or directly purified by flash column chromatography on silica gel (gradient of ethyl acetate in heptane, usually 10 to 100%) to afford the target amides.
68%	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 14h;	To a flask charged with <strong>[31462-59-6]pyrimidine-4-carboxylic acid</strong> (1.4 g, 11.28 mmol) were added DCM (50 ml), DIPEA (5.89 ml, 33.84 mmol), HATU (4.75 g, 12.4 mmol) and 2-chloro benzenamine (1.18 ml, 11.28 mmol). The resulting mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the organic layer was separated using a separating funnel. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, and subjected to column chromatography on silica gel using a cyclohexane and ethyl acetate gradient as eluent to afford N-(2-chlorophenyl)pyrimidine-4- carboxamide as a solid. Yield 1.79 g (68%). MS (ESI) m/z for C11H8ClN3O = 234.04 (calcd) 234.1 ([M + H]+, found)
30%		(a) Preparation of N-(2-chlorophenyl)pyrimidine-4-carboxamide 3:To a suspension of <strong>[31462-59-6]pyrimidine-4-carboxylic acid</strong> 1 (0.5 g, 4 mmol) in 30 mL of dichloromethane was added thionyl chloride (3 mL). The mixture was stirred at ambient temperature for 18 h. After removal of all solvent, the residue was suspended in 50 mL of dichloromethane and added to 1.0 g (8 mmol) of o-chloroaniline. The mixture was stirred at ambient temperature for 16 h. After removal of solvent, the residue was purified by column (2: 1 of hexane/ethyl acetate) to give N-(2-chlorophenyl)pyrimidine-4-carboxamide 3 as a solid. Yield: 0.28 g, 30%.'HNMR (CDCI3) delta (ppm): 10.60 (s, 1 H); 9.35 (d, 1 H); 9.10 (d, 1 H); 8.65(d, 1 H); 8.45 (d, 1 H); 7.50-7.10 (m, 3 H).

Reference： [1]Patent: WO2019/243822,2019,A1 .Location in patent: Page/Page column 49; 53
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 10013 - 10025
[3]Patent: WO2018/118868,2018,A1 .Location in patent: Page/Page column 27
[4]Patent: WO2012/76898,2012,A1 .Location in patent: Page/Page column 61-62

41
[ 31462-59-6 ]
[ 1233497-85-2 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 19 (2R,6S,13aS,14aR,16aS,Z)-2-(benzo[c][1,8]naphthyridin-6-yloxy)-N-(cyclopropylsulfonyl)-5,16-dioxo-6-(pyrimidine-4-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide Example 19 is prepared according to the procedure utilized for the preparation of Example 12, replacing 2-pyrazinecarboxylic acid with <strong>[31462-59-6]pyrimidine-4-carboxylic acid</strong>.

Reference： [1]Patent: US8232246,2012,B2

42
[ 31462-59-6 ]
[ 1233497-99-8 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 30 (2R,6S,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-5,16-dioxo-6-(pyrimidine-4-carboxamido)-2-(pyrimido[4,5-c]isoquinolin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide Example 30 is prepared according to the procedure utilized for the preparation of Example 23, replacing 2-pyrazinecarboxylic acid with <strong>[31462-59-6]pyrimidine-4-carboxylic acid</strong>.

Reference： [1]Patent: US8232246,2012,B2

43
[ 31462-59-6 ]
[ 1379224-56-2 ]

Reference： [1]Patent: WO2012/110986,2012,A1

44
[ 31462-59-6 ]
[ 39687-95-1 ]
[ 1394161-93-3 ]

Yield	Reaction Conditions	Operation in experiment
		5-(pyrimidin-4-yl)oxazole-4-carboxylic acidStep 1 : To a solution of <strong>[31462-59-6]pyrimidine-4-carboxylic acid</strong> (261 mg, 2.00 mmol) and DIPEA (0.52 mL, 2.96 mmol) in DMF (8 mL) was added methyl isocyanoacetate (0.28 mL, 2.93 mmol) at rt. The resulting yellow solution was stirred at rt for 5 min and cooled to 0 C. DPPA (0.54 mL, 2.43 mmol) was then added and the resulting solution was stirred at 0 C for 1 h and at rt for 30 min. Aq. sat. NaHC03-solution was added and the mixture extracted with EtOAc (4x). The combined organic extracts were dried (Na2S04), filtered and concentrated in vacuo. Purification by FC (hept/ EtOAc 9:1 to 100% EtOAc) yielded methyl 5-(pyrimidin-4- yl)oxazole-4-carboxylate. LC-MS conditions A: tR = 0.68 min, [M+H]+ = 206.43.

Reference： [1]Patent: WO2012/110986,2012,A1 .Location in patent: Page/Page column 39

45
[ 31462-59-6 ]
[ 63463-07-0 ]
C₃₀H₃₀N₆O₅ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10118 - 10129

46
[ 31462-59-6 ]
pyrimidine-4-carbonyl azide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 9589 - 9606

47
[ 31462-59-6 ]
[ 326023-07-8 ]
C₁₇H₁₄ClN₅O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;	4. METHOD Da. iV-(2-CHLOROPHENYL)-2-(PYRIMIDIN-4-YL)-lH-BENZO[D]lMIDAZOLE-5- SULFONAMIDETo a stirred solution of 3,4 diamino-N-(2-chlorophenyl)benzenesulfonamide (0.100 g, 0.336 mmol), HOBt (0.045 g, 0.336 mmol), EDCI (0.084 g, 0.436 mmol), 4- pyrimidine carboxylic acid (0.042 g, 0.336 mmol) in DMF (2.0 mL) was added diisopropylethylamine (0.23 mL, 1.31 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (2 x 10 mL). The organic extracts were combined and concentrated. The residue was purified by column chromatography eluting with ethyl acetate/hexanes 0 to 70% to give the intermediate amide (0.06 g). Amide (0.06 g, mmol) was dissolved in 10% acetic acid in ethanol (3 mL) and heated in a microwave at 160 0C for min. The reaction mixture was diluted with water and the precipitate was filtered and dried under vacuum at 50 0C to give product. LCMS: >98% (at) 214 nm, tR = 2.66 min; m/z 386.1 [M+H]+.

Reference： [1]Patent: WO2011/11722,2011,A1 .Location in patent: Page/Page column 87

48
[ 31462-59-6 ]
[ 1429044-32-5 ]

Reference： [1]Organic Letters,2013,vol. 15,p. 1922 - 1925

49
[ 31462-59-6 ]
1-benzyl-1'-((trifluoromethyl)sulfonyl)-4,5-dihydro-1H,1'H-spiro[cyclopenta[b]pyrrole-3,4'-pyrimidin]-2(3aH)-one [ No CAS ]

Reference： [1]Organic Letters,2013,vol. 15,p. 1922 - 1925

50
[ 31462-59-6 ]
methyl 1-benzyl-2-oxo-2,3a,4,5-tetrahydro-1H,1'H-spiro[cyclopenta[b]pyrrole-3,4'-pyrimidine]-1'-carboxylate [ No CAS ]

Reference： [1]Organic Letters,2013,vol. 15,p. 1922 - 1925

51
[ 886852-47-7 ]
[ 31462-59-6 ]
[ 1448225-44-2 ]

Reference： [1]Organic Letters,2013,vol. 15,p. 3974 - 3977

52
[ 886852-47-7 ]
[ 31462-59-6 ]
[ 1448225-85-1 ]
[ 1448225-86-2 ]

Reference： [1]Organic Letters,2013,vol. 15,p. 3974 - 3977

53
[ 31462-59-6 ]
(-)-2-((3,4-trans)-4-methylpyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one [ No CAS ]
(-)-2-((3,4-trans)-4-methyl-1-(pyrimidine-4-carbonyl)pyrrolidin-3-yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃;Inert atmosphere;	124. f-)-2-f(3.,4-trans)-4-methyl-l-fpyrimi(iine-4-carbonyl)pyrroli(iin-3-yl)- 7-ftetrahvdro-2H-pyran-4-yl)imidazo[5,l- 1 [l,2,41triazin-4f3H -one [1083] To a stirred solution of (-)-2-((3,4-trans)-4-methylpyrrolidin-3-yl)-7- (tetrahydro-2H-pyran-4-yl)imidazo[5,l- J[l,2,4]triazin-4(3H)-one (100 mg, 0.33 mmol) in DMF (7 mL) were added EDCI (95 mg, 0.49 mmol), HOBt (67 mg, 0.49 mmol), DIPEA (0.2 mL, 0.99 mmol) and <strong>[31462-59-6]pyrimidine-4-carboxylic acid</strong> (62 mg, 0.49 mmol) at 0 C under argon atmosphere. The resulting reaction mixture was allowed to warm to room temperature and stirred for 8 h. The reaction mass was diluted with water (100 mL) and extracted with DCM (4 x 50 mL). Combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified by silica gel column chromatography to afford (-)-2-((3,4-trans)-4-methyl-l-(pyrimidine-4-carbonyl)pyrrolidin-3-yl)-7- (tetrahydro-2H-pyran-4-yl)imidazo[5,l: ][l,2,4]triazin-4(3H)-one (25 mg, 18%) as an off-white solid.1H-NMR (DMSO d6, 500 MHz): delta 11.94 (bs, 1H), 9.27 (s, 1H), 9.04 (d, 1H), 7.94-7.91 (m, 1H), 7.65 (d, 1H), 4.12-3.91 (m, 5H), 3.44-3.39 (m, 3H), 3.26- 3.21 (m, 1H), 3.09-3.02 (m, 1H), 2.72-2.68 (m, 1H), 1.87-1.82 (m, 4H), 1.09 (d, 3H); Mass (ESI): 408 [M-1]; LC-MS: 99.22%; 410.3 (M++l); (column; X-bridge C-18, (50x3.0 mm, 3.5mu); RT 1.85 min. 0.05% TFA in water: ACN; 0.8 ml/min); UPLC (purity): 98.39%; (column; Acquity BEH C-18, (50x2.1 mm, 1.7mu); RT 1.32 min. 0.025% TFA (Aq): ACN; 0.50 ml/min; Chiral HPLC: 100%, R, = 6.46 min (Chiralpak IA, 250 x 4.6mm, 5mu; mobile phase (A) 0.1% DEA in n-Hexane (B) DCM:MeOH (80:20) (A: B : 60:40); flow Rate: 1.00 mL/min); Optical rotation [a]D2: -11.85 (c = 0.25, DCM). TLC: 10% MeOH/DCM (Rf: 0.5).

Reference： [1]Patent: WO2013/142269,2013,A1 .Location in patent: Paragraph 1083

54
[ 31462-59-6 ]
(2'R,4S,4a'R₉a'S)-7'-isopropyl-1',2',3',4',4a',9a'-hexahydro-5H-spiro[1,3-oxazole-4,9'-xanthene]-2,2'-diamine [ No CAS ]
N,N'-((4S,4a'R,9a'S)-7-isopropyl-1',2',3',4',4a',9a'-hexahydro-5H-spiro[1,3-oxazole-4,9'-xanthene]-2,2'-diyl)bis(pyrimidine-4-carboxamide) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
200 mg	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;	[00242] Step A: EDCI (184 mg, 0.96 mmol), HOBT (130 mg, 0.96 mmol) and DIPEA (206 mg, 1.6 mmol) were added at 0C to a mixture of (4S,4a'i?,9a'5)-7'-isopropyl- l,,2',3,,4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diamine (100 mg, 0.32 mmol) and <strong>[31462-59-6]pyrimidine-4-carboxylic acid</strong> (134 mg, 0.79 mmol) in DCM (8 mL). The mixture was stirred at room temperature overnight. Saturated NaHC03 was added, and the mixture was extracted with EtOAc. The organic layer was concentrated to give N,N'-((4S',4a'i?,9a'5)-7'-isopropyl- r,2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2'-diyl)bis(pyrimidine-4- carboxamide) (200 mg crude) that was used without further purification.

Reference： [1]Patent: WO2013/148851,2013,A1 .Location in patent: Paragraph 00242

55
[ 31462-59-6 ]
[ 59578-12-0 ]
2,2',3,3',4,4'-hexa(trimethylsilyl)-6,6'-bis(pyrazine-2-carbonyl)-α,α-D-trehalose [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%		General procedure: To a stirred solution of 2,6-dichlorobenzoic acid (210mg, 1.1mmol) in anhydrous CH2Cl2 (10ml) was added DCC (227 mg, 1.1mmol) and DMAP (135 mg, 1.1mmol). The mixture was stirred for 15 min. 2,2',3,3',4,4'-hexa(trimethylsilyl)-alpha,alpha-D-trehalose (5, 388mg, 0.5mmol) was added. After stirring for 24 h, the reaction mixture was filtered. The filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate: 20/1) to give 3

Reference： [1]Journal of Antibiotics,2013,vol. 66,p. 531 - 537

56
[ 31462-59-6 ]
[ 59578-12-0 ]
6,6'-bis(pyrazine-2-carbonyl)-α,α-D-trehalose [ No CAS ]

Reference： [1]Journal of Antibiotics,2013,vol. 66,p. 531 - 537

57
[ 31462-59-6 ]
[ 503860-57-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6933 - 6937

58
[ 31462-59-6 ]
C₂₀H₁₈N₆O₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6933 - 6937

59
[ 31462-59-6 ]
C₂₀H₂₁N₅O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6933 - 6937

60
[ 31462-59-6 ]
C₂₀H₂₁N₅O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6933 - 6937

61
[ 31462-59-6 ]
C₁₉H₁₈FN₅O₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6933 - 6937

62
[ 31462-59-6 ]
C₂₀H₂₁N₅O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6933 - 6937

63
[ 31462-59-6 ]
C₂₀H₂₀FN₅O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6933 - 6937

64
[ 31462-59-6 ]
C₂₁H₂₃N₅O₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6933 - 6937

65
[ 31462-59-6 ]
C₂₀H₁₇FN₆O₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6933 - 6937

66
[ 31462-59-6 ]
C₁₉H₁₇ClFN₅O₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6933 - 6937

67
[ 31462-59-6 ]
[ 503860-53-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6933 - 6937
[2]Patent: WO2008/23239,2008,A1

68
[ 31462-59-6 ]
[ 503860-54-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6933 - 6937
[2]Patent: WO2008/23239,2008,A1

69
[ 31462-59-6 ]
[ 6148-64-7 ]
[ 64210-67-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 6933 - 6937

70
[ 31462-59-6 ]
[ 1940-11-0 ]
[ 1609959-24-1 ]

Reference： [1]MedChemComm,2014,vol. 5,p. 165 - 170

71
[ 31462-59-6 ]
[ 62-53-3 ]
[ 99973-06-5 ]

Yield	Reaction Conditions	Operation in experiment
		Pyrimidine-4-carboxylic acid (1 g, 8.06 mmol) was slurried in N,N- Dimethylformamide (dry) (10 ml), DIPEA (1.684 ml, 9.67 mmol) was added followed by HATU (3.37 g, 8.86 mmol). After 15 mins aniline (0.808 ml, 8.86 mmol) was added to the brown suspension and the resulting reaction mixture stirred further at room temperature for 20 hours. The reaction mixture was evaporated to half its volume. This mixture was added to a cold water/ sat. sodium bicarbonate mixture (2:1, 20 ml), washed with cold H2O and dried on air to give a purple/brown solid. The solid was triturated in MeOH for 2 hours and the mixture was filtered. The residue was placed in a vacuum oven at 40 degrees for 24 hours. Used as such.

Reference： [1]Journal of the American Chemical Society,2018,vol. 140,p. 11487 - 11494
[2]Organic Letters,2014,vol. 16,p. 1764 - 1767
[3]Patent: WO2018/118868,2018,A1 .Location in patent: Page/Page column 65

72
[ 31462-59-6 ]
[ 62-53-3 ]
[ 1575753-24-0 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 1764 - 1767

73
[ 31462-59-6 ]
[ 1416231-32-7 ]
[ 1416233-08-3 ]

Yield	Reaction Conditions	Operation in experiment
32%		A solution isonicotinic acid (0.26 g, 2.1 mmol) in anhydrous methylene chloride (20 ml) and dimethylformamide (10 ml) was stirred together with EDCI (0.45 g, 2.3 mmol) and HOBt (0.25 g, 1.8 mmol) for 10 min at room temperature, and then together with 9b-amino-4b-hydroxy-7-isopropyl-1-nitro-4bH-benzo[d]indeno[1,2-b]furan-10(9bH)-one (0.46 g, 1.56 mmol) for 24 hrs at room temperature. The reaction mixture was diluted in methylene chloride, and washed many times with water, and the organic layer was dried and filtered. Purification by column chromatography (ethylacetate:hexane=1:4) afforded the title compound. 0.20 g (32%). [0806] 1H-NMR (300 MHz, CD3OD) delta 1.20 (d, J=6.9 Hz, 6H, CH3) 2.81-2.90 (m, 1H, CH) 6.70 (brs, 1H, ArH) 6.91-6.93 (m, 1H, ArH) 7.42-7.47 (m, 1H, ArH) 7.72-7.82 (m, 6H) 8.66-8.68 (m, 2H, ArH).

Reference： [1]Patent: US2014/114068,2014,A1 .Location in patent: Paragraph 0805-0806

74
[ 31462-59-6 ]
[ 1071-46-1 ]
[ 64210-67-9 ]

Reference： [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 6060 - 6082

75
[ 31462-59-6 ]
aminohexane geldanamycin [ No CAS ]
17-(6-(pyrimidine-4-carboxamido)hexylamino)-17-demethoxygeldanamycin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1-hydroxy-pyrrolidine-2,5-dione; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 24h;	General procedure: Compound 6 was dissolved in 10 mL of dimethyl formamide and treated with EDC*HCl (1.2 equiv.), NHS (1.2 equiv.) and substitutional carboxylic acid (1.2 equiv.). The reaction mixture was stirred overnight at room temperature. TLC was used to monitor the progress of the reaction. After the reaction complete, the mixture was poured into 40 mL of water and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed by brine (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by flash column chromatography (silica gel, ethyl acetate/petroleum ether 1:1) to afford 7a as a purple solid.

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 87,p. 346 - 363

76
[ 31462-59-6 ]
(2R,3aS,5aR,5bS,9S,14R,16aS,16bR)-13-amino-9-ethyl-14-methyl-2-(((2R,3R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,3a,5b,6,9,10,11,12,13,14,16a,16b-dodecahydro-1H-as-indaceno[3,2-d][1]oxacyclododecine-7,15(2H,5aH)-dione [ No CAS ]
N-((2R,3aS,5aR,5bS,9S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxo-2-(((2R,3R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b-hexadecahydro-1H-as-indaceno[3,2-d][1]oxacyclododecin-13-yl)pyrimidine-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.92 g	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 55℃; for 1h;	Example 2 N-((2R,3aS,5aR,5bS,9S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxo -2-(((2R,3R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahvdro-2H-pyran-2-yl)oxy)-2,3,3a,5a,5 b,6,7,9,10,l l,12,13,14,15,16a,16b-hexadecahvdro-lH-as-indacenor3,2-diriloxacyclodod ecin-13-yl)pyrimidine-4-carboxamide Add dropwise a mixture of (2R,3aS,5aR,5bS,9S,14R,16aS,16bR)-13-amino-9-ethyl-14- methyl-2-(((2R,3R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,3a ,5b,6,9,10,l l,12,13,14,16a,16b-dodecahydro-lH-as-indaceno[3,2-d][l]oxacyclododecine- 7,15(2H,5aH)-dione and (2S,3aR,5aS,5bS,9S,14R,16aS,16bS)-13-amino-9-ethyl-4,14- dimethyl-2-(((2R,3R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3, 3a,5b,6,9,10,l l,12,13,14,16a,l 6b-dodecahydro- 1 H-as-indaceno[3 ,2-d] [ 1 Joxacyclododeci ne-7,15(2H,5aH)-dione (85:15,5g, 8.49 mmol) in CH2C12 (40 mL) to a mixture of <strong>[31462-59-6]pyrimidine-4-carboxylic acid</strong> (2.09 g , 17.13 mmol), HATU (6.45 g , 16.96 mmol) and DIPEA (2.75 g , 21.32 mmol) in DMF (40 mL) at ambient temperature. Then heat the mixture to 55 for 1 hour. After cooling the mixture to room temperature, filter the reaction mixture, and concentrate the filtrate under reduced pressure to give a brown solid. Purify the residue by acidic preparative HPLC first, then followed by SFC separation to afford N-((2R,3aS,5aR,5bS,9S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxo-2-(((2R, 3R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,3,3a,5a,5b,6,7,9,l 0,11, 12,13, 14,15,16a, 16b-hexadecahydro- 1 H-as-indaceno[3 ,2-d] [ 1 Joxacyclododecin- 13-y l)pyrimidine-4-carboxamide (1.92 g , yelid: 32.6%) as brown solid. MS (m/z): 718 (M+23). *H NMR (400 MHz, CDC13) delta 0.83 (t, 7=7.5 Hz, 3 H) 0.90 - 1.02 (m, 1 H) 1.17 (d, 7=6.8 Hz, 3 H) 1.26 - 1.36 (m, 6 H) 1.48 - 1.57 (m, 4 H) 1.94 (dd, 7=13.4 & 7.0 Hz, 1 H) 2.19 - 2.31 (m, 2 H) 2.47 (dd, 7=13.7 & 3.1 Hz, 1 H) 2.89 (dd, 7=11.5 & 8.8 Hz, 1 H) 3.08 (br. s., 1 H) 3.13 (t, 7=9.4 Hz, 1 H) 3.21 (dd, 7=13.7 & 5.1 Hz, 1 H) 3.39 (dd, 7=9.9 & 6.8 Hz, 1 H) 3.45 - 3.61 (m, 16 H) 4.30 - 4.35 (m, 2 H) 4.73 (d, 7=7.1 Hz, 1 H) 4.87 (d, 7=1.1 Hz, 1 H) 5.81 - 5.85 (m, 1 H) 5.89 - 5.92 (m, 1 H) 6.80 (br. s., 1 H) 7.93 (d, 7=9.9 Hz, 1 H) 8.20 (dd, 7=5.1 & 1.3 Hz, 1 H) 9.02 (d, 7=5.1 Hz, 1 H) 9.28 (d, 7=1.1 Hz, 1 H).

Reference： [1]Patent: WO2014/197703,2014,A1 .Location in patent: Page/Page column 14; 15

77
[ 31462-59-6 ]
(2R,3aS,5aR,5bS,9S,14R,16aS,16bR)-13-amino-9-ethyl-14-methyl-2-(((2R,3R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,3a,5b,6,9,10,11,12,13,14,16a,16b-dodecahydro-1H-as-indaceno[3,2-d][1]oxacyclododecine-7,15(2H,5aH)-dione [ No CAS ]
N-((2R,3aS,5aR,5bS,9S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxo-2-(((2R,3R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b-hexadecahydro-1H-as-indaceno[3,2-d][1]oxacyclododecin-13-yl)pyrimidine-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; N,N-dimethyl-formamide; at 55℃; for 1h;	Add dropwise a mixture of (2R,3aS,5aR,5bS,9S,14R,16aS,16bR)-13-amino-9-ethyl-14- methyl-2-(((2R,3R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3,3a ,5b,6,9,10,l l,12,13,14,16a,16b-dodecahydro-lH-as-indaceno[3,2-d][l]oxacyclododecine- 7,15(2H,5aH)-dione and (2S,3aR,5aS,5bS,9S,14R,16aS,16bS)-13-amino-9-ethyl-4,14- dimethyl-2-(((2R,3R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-3, 3a,5b,6,9,10,l l,12,13,14,16a,16b-dodecahydro-lH-as-indaceno[3,2-d][l]oxacyclododeci ne-7,15(2H,5aH)-dione (85: 15,5g, 8.49 mmol) in CH2C12 (40 mL) to a mixture of <strong>[31462-59-6]pyrimidine-4-carboxylic acid</strong> (2.09 g , 17.13 mmol), HATU (6.45 g , 16.96 mmol) and DIPEA (2.75 g , 21.32 mmol) in DMF (40 mL) at ambient temperature. Then heat the mixture to 55 for 1 hour. After cooling the mixture to room temperature, filter the reaction mixture, and concentrate the filtrate under reduced pressure to give a brown solid. Purify the residue by acidic preparative HPLC first, then followed by SFC separation to afford N-((2R,3aS,5aR,5bS,9S,14R,16aS,16bR)-9-ethyl-14-methyl-7,15-dioxo-2-(((2R, 3R,5S,6S)-3,4,5-trimethoxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-2,3,3a,5a,5b,6, 7,9,1 0,11, 12, 13, 14, 15, 16a, 16b-hexadecahydro- 1 H-as-indaceno [3 ,2-d] [ 1 ]oxacyclododecin- 13 -y l)pyrimidine-4-carboxamide (1.92 g , yelid: 32.6%) as brown solid. MS (m/z): 718 (M+23). 1H NMR (400 MHz, CDC13) delta 0.83 (t, J=7.5 Hz, 3 H) 0.90 - 1.02 (m, 1 H) 1.17 (d, J=6.8 Hz, 3 H) 1.26 - 1.36 (m, 6 H) 1.48 - 1.57 (m, 4 H) 1.94 (dd, J=13.4 & 7.0 Hz, 1 H) 2.19 - 2.31 (m, 2 H) 2.47 (dd, J=13.7 & 3.1 Hz, 1 H) 2.89 (dd, J=11.5 & 8.8 Hz, 1 H) 3.08 (br. s., 1 H) 3.13 (t, J=9.4 Hz, 1 H) 3.21 (dd, J=13.7 & 5.1 Hz, 1 H) 3.39 (dd, J=9.9 & 6.8 Hz, 1 H) 3.45 - 3.61 (m, 16 H) 4.30 - 4.35 (m, 2 H) 4.73 (d, J=7.1 Hz, 1 H) 4.87 (d, J=l .l Hz, 1 H) 5.81 - 5.85 (m, 1 H) 5.89 - 5.92 (m, 1 H) 6.80 (br. s., 1 H) 7.93 (d, J=9.9 Hz, 1 H) 8.20 (dd, J=5.1 & 1.3 Hz, 1 H) 9.02 (d, J=5.1 Hz, 1 H) 9.28 (d, J=l . l Hz, 1 H).

Reference： [1]Patent: WO2014/194503,2014,A1 .Location in patent: Page/Page column 14-15

78
[ 31462-59-6 ]
6-chloro-4,4'-bipyrimidine [ No CAS ]

Reference： [1]Patent: WO2015/8073,2015,A1
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 6653 - 6664

79
[ 31462-59-6 ]
[ 64210-67-9 ]

Reference： [1]Patent: WO2015/8073,2015,A1
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 6653 - 6664

80
[ 31462-59-6 ]
[4,4'-bipyrimidin]-6-ol [ No CAS ]

Reference： [1]Patent: WO2015/8073,2015,A1
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 6653 - 6664

81
[ 31462-59-6 ]
3-(4,4'-bipyrimidin-6-yl)-5-chlorobenzonitrile [ No CAS ]

Reference： [1]Patent: WO2015/8073,2015,A1
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 6653 - 6664

82
[ 31462-59-6 ]
[ 1361189-49-2 ]
[ 1361188-01-3 ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 1669 - 1690

83
[ 31462-59-6 ]
5-(2-((1E,3E)-5-((E)-1-(3-aminopropyl)-3,3-dimethylindolin-2-ylidene)penta-1,3-dien-1-yl)-3,3-dimethyl-3H-indol-1-ium-1-yl)pentanoate [ No CAS ]
C₃₈H₄₄N₅O₃⁽¹⁺⁾ [ No CAS ]

Reference： [1]Chemical Communications,2015,vol. 51,p. 7386 - 7389

84
[ 31462-59-6 ]
cobalt(II) chloride hexahydrate [ No CAS ]
[Co^II(pyrimidine-4-carboxylate)₂(H₂O)₂]*2H₂O [ No CAS ]

Reference： [1]Inorganic Chemistry,2015,vol. 54,p. 241 - 252

85
[ 31462-59-6 ]
[ 90648-34-3 ]

Reference： [1]Journal of Organic Chemistry,2015,vol. 80,p. 2676 - 2699

86
[ 31462-59-6 ]
N-ethylpyrimidine-4-carboxamide [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2015,vol. 80,p. 2676 - 2699

87
[ 31462-59-6 ]
[ 42839-04-3 ]

Reference： [1]Journal of Organic Chemistry,2015,vol. 80,p. 2676 - 2699

88
[ 31462-59-6 ]
4-(diethylcarbamoyl)-1-methylpyrimidinium trifluoromethanesulfonate [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2015,vol. 80,p. 2676 - 2699

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P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
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P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
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H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 31462-59-6 ] {[proInfo.proName]}

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[ 31462-59-6 ] Synthesis Path-Upstream 1~17

[ 31462-59-6 ] Synthesis Path-Downstream 1~88

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Carboxylic Acids

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