40004-69-1|2-Methyl-5-thiazolecarboxylic acid| Ambeed

Structure of 40004-69-1

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Quality Control of [ 40004-69-1 ] Purity: 98% SDS Specification

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Product Details of [ 40004-69-1 ]

CAS No. :	40004-69-1
Formula :	C₅H₅NO₂S
M.W :	143.16
SMILES Code :	C1=C(SC(=N1)C)C(=O)O
MDL No. :	MFCD01760300
InChI Key :	QCXCIYPOMMIBHO-UHFFFAOYSA-N
Pubchem ID :	98845

Safety of [ 40004-69-1 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 40004-69-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	9
Num. arom. heavy atoms	5
Fraction Csp3	0.2
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	34.04
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	78.43 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.11
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.21
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.15
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	-0.36
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.9
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.0

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.84
Solubility	2.09 mg/ml ; 0.0146 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.45
Solubility	0.503 mg/ml ; 0.00352 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-1.03
Solubility	13.3 mg/ml ; 0.0931 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.31 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.56

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.24

Application In Synthesis of [ 40004-69-1 ]

* 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.

Downstream synthetic route of [ 40004-69-1 ]

[ 40004-69-1 ] Synthesis Path-Downstream 1~35

1
[ 79836-78-5 ]
[ 40004-69-1 ]

Yield	Reaction Conditions	Operation in experiment
70%		b) 2-Methyl-thiazole-5-carboxylic acid To a stirred solution of <strong>[79836-78-5]2-methyl-thiazole-5-carboxylic acid ethyl ester</strong> (1.3 g, 8.0 mmol) in dioxane (12 mL) at room temperature was added NaOH (2N, 12 mL). After 1 h the reaction mixture was neutralized with HCl (IN, 12 mL), then filtered and the collected solid dried in vacuo to give the title compound (758 mg, 70percent) as an off white solid. MS: m/e = 142.0 [M-H]".
41%	With lithium hydroxide monohydrate; water; In tetrahydrofuran; at 20℃; for 16h;	To a stirred solution of compound 97 (41 g, 239.76 mmol) in THF: H2O (7: 1, 400 mL) was added lithium hydroxide monohydrate (29.49 g, 719.29 mmol) at room temperature and stirred for 16 h. The reaction was monitored by TLC. After completion of the reaction, the volatiles were removed in vacuo. The residue was diluted with water and acidified with 2 N HCl to pH~2 and extracted using EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford compound 98 (14 g, 41percent) as an off-white solid. TLC: 20percent EtOAc/ hexanes (Rf: 0.1); 1H NMR (DMSO-d6, 400 MHz): delta 13.29 (br.s, 1H), 8.16 (s, 1H), 2.69 (s, 3H); LCMS Calculated for C5H5NO2S: 143.00; Observed: 144.1 (M+1)+.
		Ethyl 2-methyl-1,3-thiazole-5-carboxylate [e.g. available from Interchim S.A.] (61 mg) in ethanol (1 ml) was treated with aqueous sodium hydroxide (2M, 0.706 ml). The clear solution was stirred at room temperature for 18 h and then treated with aqueous hydrochloric acid (2M, 0.54 ml). The solution was blown down to dryness and the residual solid dried under vacuum over phosphorus pentoxide. The solid was then suspended in dry dichloromethane (1 ml) and treated at 20° C. with oxalyl chloride (0.032 ml) and DMF (1 drop). The mixture was stirred at room temperature for 30 mins and was then added dropwise to a solution of Intermediate 16 (98 mg) in anhydrous acetonitrile (2 ml). DIPEA (0.064 ml) was added and the solution stirred at room temperature for 20 h. The mixture was diluted with dichloromethane (15 ml), washed with dilute aqueous sodium chloride (2.x.15 ml) and blown down to dryness. The residue was purified by mass directed autoprep HPLC to give a film which was further purified using an SPE cartridge (2 g, aminopropyl) which had been pre-washed with methanol. Elution with methanol gave Example 311 as a white solid (87 mg). LCMS showed MH+=429; TRET=1.94 min.

		Synthesis of (E) To a 0° C. solution of <strong>[79836-78-5]ethyl 2-methyl-thiazole-5-carboxylate</strong> (15 g, 88 mmol) in tetrahydrofuran (50 mL) was added aqueous sodium hydroxide solution (5 N, 50 mL) over 10 minutes, and the resulting solution was stirred at room temperature for another 2 hours. It was then acidified with hydrochloric acid (2 N) to pH=1 and extracted with tetrahydrofuran (3*100 mL). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. Most of the solvents were removed under reduced pressure and the residue was lyophilized to afford Compound (E) (14 g).
		Example 311 N-[1,6-diethyI-4-(tetrahydro-2H-pyran-4-yIamino)-1H- pyrazoIo[3,4-b]pyridin-5-yl]methyl}-2-methyI-1,3-thiazole-5-carboxamideEthyl 2-methyl-1 ,3-thiazole-5-carboxylate [e.g. available from lnterchim S.A.] (61 mg) in ethanol (1ml) was treated with aqueous sodium hydroxide (2M, 0.706ml). The clear solution was stirred at room temperature for 18h and then treated with aqueous hydrochloric acid (2M, 0.54ml). The solution was blown down to dryness and the residual solid dried under vacuum over phosphorus pentoxide. The solid was then suspended in dry dichloromethane (1ml) and treated at 20°C with oxalyl chloride (0.032ml) and DMF (1 drop). The mixture was stirred at room temperature for 30mins and was then added dropwise to a solution of Intermediate 16 (98mg) in anhydrous acetonitrile (2ml). DIPEA (0.064ml) was added and the solution stirred at room temperature for 2Oh. The mixture was diluted with dichloromethane (15ml), washed with dilute aqueous sodium chloride (2 x 15ml) and blown down to dryness. The residue was purified by mass directed autoprep HPLC to give a film which was further purified using an SPE cartridge (2g, aminopropyl) which had been pre-washed with methanol. Elution with methanol gave Example 311 as a white solid (87mg). LCMS showed MH+ =
14 g	With water; sodium hydroxide; In tetrahydrofuran; at 0 - 20℃; for 2.16h;	To a 0° C. solution of <strong>[79836-78-5]ethyl 2-methyl-thiazole-5-carboxylate</strong> (15 g, 88 mmol) in tetrahydrofuran (50 mL) was added aqueous sodium hydroxide solution (5 N, 50 mL) over 10 minutes, and the resulting solution was stirred at room temperature for another 2 hours. It was then acidified with hydrochloric acid (2 N) to pH=1 and extracted with tetrahydrofuran (3*100 mL). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. Most of the solvents were removed under reduced pressure and the residue was lyophilized to afford Compound (E) (14 g).
14 g	With water; sodium hydroxide; In tetrahydrofuran; water; at 0 - 20℃; for 2.16667h;	To a 0°C. solution of <strong>[79836-78-5]ethyl 2-methyl-thiazole-5-carboxylate</strong> (15 g, 88 mmol) in tetrahydrofuran (50 ml) was added aqueous sodium hydroxide solution (5 N, 50ml) over 10 minutes, and the resulting solution was stirred at room temperature for another 2 hours. It was then acidified with hydrochloric acid (2 N) to pH=1 and extracted with tetrahydrofuran (3x100 ml). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. Most of the solvents were removed under reduced pressure and the residue was lyophilized to afford Compound (E) (14g).
14 g	With water; sodium hydroxide; In tetrahydrofuran; at 0℃; for 2.16667h;	To a 0° C. solution of <strong>[79836-78-5]ethyl 2-methyl-thiazole-5-carboxylate</strong> (15 g, 88 mmol) in tetrahydrofuran (50 mL) was added aqueous sodium hydroxide solution (5 N, 50 mL) over 10 minutes, and the resulting solution was stirred at room temperature for another 2 hours. It was then acidified with hydrochloric acid (2 N) to pH=1 and extracted with tetrahydrofuran (3×100 mL). The combined organic layers were washed with brine (30 mL) and dried over sodium sulfate. Most of the solvents were removed under reduced pressure and the residue was lyophilized to afford Compound (E) (14 g).

References: [1]Journal of the American Chemical Society,2016,vol. 138,p. 14639 - 14649.
[2]Patent: WO2010/127974,2010,A1 .Location in patent: Page/Page column 43; 44.
[3]Patent: WO2018/160878,2018,A1 .Location in patent: Page/Page column 279.
[4]Chemische Berichte,1940,vol. 73,p. 1240,1252.
[5]Australian Journal of Chemistry,2004,vol. 57,p. 599 - 604.
[6]Patent: US2009/131431,2009,A1 .Location in patent: Page/Page column 142.
[7]Patent: US2010/240903,2010,A1 .Location in patent: Page/Page column 14.
[8]Patent: WO2007/36733,2007,A1 .Location in patent: Page/Page column 212.
[9]Journal of Chemical Research,2011,vol. 35,p. 313 - 316.
[10]Patent: US2014/113855,2014,A1 .Location in patent: Paragraph 0279; 0288; 0289.
[11]Patent: US2018/78532,2018,A1 .Location in patent: Paragraph 0233; 0238.
[12]Patent: US2018/161279,2018,A1 .Location in patent: Paragraph 0474-0475.

2
[ 40004-69-1 ]
[ 62-53-3 ]
[ 91137-85-8 ]

References: [1]Journal of general chemistry of the USSR,1961,vol. 31,p. 2444 - 2448.
Zhurnal Obshchei Khimii,1961,vol. 31,p. 2618 - 2623.

3
[ 40004-69-1 ]
[ 62-53-3 ]
[ 95074-54-7 ]

References: [1]Journal of general chemistry of the USSR,1961,vol. 31,p. 2444 - 2448.
Zhurnal Obshchei Khimii,1961,vol. 31,p. 2618 - 2623.

4
[ 3581-87-1 ]
[ 124-38-9 ]
[ 40004-69-1 ]

References: [1]Bulletin de la Societe Chimique de France,1967,p. 4134 - 4143.

Yield	Reaction Conditions	Operation in experiment
86%		(194-2) To a solution of the compound of Example 194-1 (5.74 g) in THF (100 mL)-MeOH (100 mL) was added a 6N NaOH solution (27 mL), and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure, and thereto was added a 6N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate, and dried over MgSO4. The solvent was evaporated under reduced pressure to give 2-methyl-1,3-thiazole-5-carboxylic acid (4.02 g, 86percent). 1H NMR (DMSO-d6, 400 MHz) delta 13.31 (brs, 1H), 8.17 (s, 1H), 2.70 (s, 3H).
86%		(194-2) To a solution of the compound of Example 194-1 (5.74 g) in THF (100 mL)-MeOH (100 mL) was added a 6N NaOH solution (27 mL), and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure, and thereto was added a 6N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate, and dried over MgSO4. The solvent was evaporated under reduced pressure to give 2-methyl-1,3-thiazole-5-carboxylic acid (4.02 g, 86 percent). 1H NMR (DMSO-d6, 400MHz) delta 13.31 (brs, 1H), 8.17 (s, 1H), 2.70 (s, 3H).
		EXAMPLE 93 1-(2-Methylthiazole-5-carbonyl)-2-cyanoaziridine. 1.6 g. 2-Methylthiazole-5-carboxylic acid (m.p. 209° C.) and 0.76 g.

6
[ 280-57-9 ]
[ 40004-69-1 ]
[ 60971-72-4 ]

Yield	Reaction Conditions	Operation in experiment
96.0% and 92.8%	In 5,5-dimethyl-1,3-cyclohexadiene;	EXAMPLE 14 In a similar apparatus to Example 1, 10.0 g (0.07 mole) of <strong>[40004-69-1]2-methylthiazole-5-carboxylic acid</strong> were suspended in 100 ml of xylene, followed by the addition of 0.03 g of triethylenediamine. Under heating and reflux, phosgene was blown at a rate of 930 ml/hr for 6 hours (0.25 mole). After completion of the blowing, stirring was continued for additional 2 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 10.5 g of <strong>[40004-69-1]2-methylthiazole-5-carboxylic acid</strong> chloride. Its purity and yield were 96.0percent and 92.8percent, respectively.

References: [1]Patent: US5136042,1992,A .

7
[ 40004-69-1 ]
[ 60971-72-4 ]

Yield	Reaction Conditions	Operation in experiment
95.0% and 95.0%	In toluene;	EXAMPLE 5 In a similar apparatus to Example 1,5.7 g (0.04 mole) of <strong>[40004-69-1]2-methylthiazole-5-carboxylic acid</strong> were suspended in 100 ml of toluene. Under heating and reflux, phosgene was blown at a rate of 390 ml/hr for 10 hours (0.17 mole). After completion of the blowing, stirring was continued for additional 2 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 5.7 g of <strong>[40004-69-1]2-methylthiazole-5-carboxylic acid</strong> chloride. Its purity and yield were 95.0percent and 95.0percent, respectively. NMR (deltaCDCl 3/TMS, ppm): 2.79(3H,s).
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 0.5h;Product distribution / selectivity;	Ethyl 2-methyl-1,3-thiazole-5-carboxylate [e.g. available from Interchim S.A.] (61 mg) in ethanol (1 ml) was treated with aqueous sodium hydroxide (2M, 0.706 ml). The clear solution was stirred at room temperature for 18 h and then treated with aqueous hydrochloric acid (2M, 0.54 ml). The solution was blown down to dryness and the residual solid dried under vacuum over phosphorus pentoxide. The solid was then suspended in dry dichloromethane (1 ml) and treated at 20° C. with oxalyl chloride (0.032 ml) and DMF (1 drop). The mixture was stirred at room temperature for 30 mins and was then added dropwise to a solution of Intermediate 16 (98 mg) in anhydrous acetonitrile (2 ml). DIPEA (0.064 ml) was added and the solution stirred at room temperature for 20 h. The mixture was diluted with dichloromethane (15 ml), washed with dilute aqueous sodium chloride (2.x.15 ml) and blown down to dryness. The residue was purified by mass directed autoprep HPLC to give a film which was further purified using an SPE cartridge (2 g, aminopropyl) which had been pre-washed with methanol. Elution with methanol gave Example 311 as a white solid (87 mg). LCMS showed MH+=429; TRET=1.94 min.
	With oxalyl dichloride;N-formyldiethylamine; In dichloromethane; for 0.25h;Product distribution / selectivity;	2-Methyl-1,3-thiazole-5-carboxylic acid (0.133 g, 0.93 mmol) (e.g. which can optionally be prepared as in Example 311) was suspended in dichloromethane (3 ml) and treated at 20° C. under nitrogen with oxalyl chloride (0.24 ml, 2.75 mmol) and diethylformamide (1 drop). A vigorous reaction occurred. After 15 min, the reaction mixture was evaporated to dryness to give a dark yellow oil which was presumed to be 2-methyl-1,3-thiazole-5-carbonyl chloride.

With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 0.5h;

Example 311 N-[1,6-diethyI-4-(tetrahydro-2H-pyran-4-yIamino)-1H- pyrazoIo[3,4-b]pyridin-5-yl]methyl}-2-methyI-1,3-thiazole-5-carboxamideEthyl 2-methyl-1 ,3-thiazole-5-carboxylate [e.g. available from lnterchim S.A.] (61 mg) in ethanol (1ml) was treated with aqueous sodium hydroxide (2M, 0.706ml). The clear solution was stirred at room temperature for 18h and then treated with aqueous hydrochloric acid (2M, 0.54ml). The solution was blown down to dryness and the residual solid dried under vacuum over phosphorus pentoxide. The solid was then suspended in dry dichloromethane (1ml) and treated at 20°C with oxalyl chloride (0.032ml) and DMF (1 drop). The mixture was stirred at room temperature for 30mins and was then added dropwise to a solution of Intermediate 16 (98mg) in anhydrous acetonitrile (2ml). DIPEA (0.064ml) was added and the solution stirred at room temperature for 2Oh. The mixture was diluted with dichloromethane (15ml), washed with dilute aqueous sodium chloride (2 x 15ml) and blown down to dryness. The residue was purified by mass directed autoprep HPLC to give a film which was further purified using an SPE cartridge (2g, aminopropyl) which had been pre-washed with methanol. Elution with methanol gave Example 311 as a white solid (87mg). LCMS showed MH+ =

References: [1]Patent: US5136042,1992,A .
[2]Patent: US2009/131431,2009,A1 .Location in patent: Page/Page column 142.
[3]Patent: US2009/131431,2009,A1 .Location in patent: Page/Page column 151.
[4]Patent: WO2007/36733,2007,A1 .Location in patent: Page/Page column 212.
[5]Journal of Chemical Research,2011,vol. 35,p. 313 - 316.

8
[ 40004-69-1 ]
[ 4205-90-7 ]
1-(2-methyl-thiazol-5-oyl)-2-(2',6'-dichlorophenylamino)-2-imidazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1,1'-carbonyldiimidazole; In tetrahydrofuran; dimethyl sulfoxide;	EXAMPLE 30 3.15 g (22.0 millimoles) of <strong>[40004-69-1]2-methyl-thiazole-5-carboxylic acid</strong> are dissolved in 500 ml of absolute tetrahydrofuran and 50 ml of absolute dimethylsulfoxide, 3.6 g (22.2 millimoles) of N,N'-carbonyldiimidazole are added and the mixture is stirred for 45 minutes at room temperature. A solution of 5.0 g (21.7 millimoles) of 2-(2',6'-dichlorophenylamino)-2-imidazoline in 100 ml of absolute tetrahydrofuran is then added dropwise and the mixture is stirred overnight at room temperature. The solvents are stripped off under reduced pressure on a rotary evaporator and the residue is stirred thoroughly with 100 ml of 0.5 percent strength sodium bicarbonate solution, whereupon crystallization occurs. The crystals are filtered off, washed with water and dried under reduced pressure, over a phosphorus pentoxide desiccant. 5.6 g of crude 1-(2-methylthiazol-5-oyl)-2-(2',6'-dichlorophenylamino)-2-imidazoline are obtained and are recrystallized from isopropanol, giving 2.7 g of pure product, of melting point 183°-185° C. The following compounds were also obtained by the method described in Example 30:

References: [1]Patent: US4389403,1983,A .

9
[ 40004-69-1 ]
[ 1148157-32-7 ]
[ 1148157-33-8 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0℃;pH 8.5;	Synthesis of (F); To a 0° C. solution of Compound (D) (41 mmol) and <strong>[40004-69-1]2-methyl-thiazole-5-carboxylic acid</strong> (E) (6.0 g, 42 mmol), HOBT (7.9 g, 50 mmol) and HBTU (18.0 g, 50 mmol) in tetrahydrofuran (800 mL) was added a solution of N,N-diethylisopropylamine (50 g) in tetrahydrofuran (200 mL) over 5 minutes until its pH reached approximately 8.5. The resulting mixture was stirred at same temperature overnight. It was then quenched with saturated aqueous sodium bicarbonate solution (200 mL), and most of the solvents were removed under reduced pressure. The residual mixture was extracted with ethyl acetate (3.x.400 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (200 mL) and brine (100 mL), dried over sodium sulfate and filtered through Celite-545. The solvents were removed under reduced pressure and residue was purified by flash chromatography (silica gel, ethyl acetate with 2percent methanol). Compound (F) (17.1 g) was isolated and characterized by LC/MS (LRMS (MH) m/z: 436.15).
17.1 g	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0℃;pH 8.5;	To a 0° C. solution of Compound (D) (41 mmol) and <strong>[40004-69-1]2-methyl-thiazole-5-carboxylic acid</strong> (E) (6.0 g, 42 mmol), HOBT (7.9 g, 50 mmol) and HBTU (18.0 g, 50 mmol) in tetrahydrofuran (800 mL) was added a solution of N,N-diethylisopropylamine (50 g) in tetrahydrofuran (200 mL) over 5 minutes until its pH reached approximately 8.5. The resulting mixture was stirred at same temperature overnight. It was then quenched with saturated aqueous sodium bicarbonate solution (200 mL), and most of the solvents were removed under reduced pressure. The residual mixture was extracted with ethyl acetate (3×400 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (200 mL) and brine (100 mL), dried over sodium sulfate and filtered through Celite-545. The solvents were removed under reduced pressure and residue was purified by flash chromatography (silica gel, ethyl acetate with 2percent methanol). Compound (F) (17.1 g) was isolated and characterized by LC/MS (LRMS (MH) m/z: 436.15).

References: [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 3028 - 3038.
[2]Patent: US2010/240903,2010,A1 .Location in patent: Page/Page column 14.
[3]Patent: US2018/161279,2018,A1 .Location in patent: Paragraph 0476-0477.

10
[ 40004-69-1 ]
[ 1148157-34-9 ]
[ 935888-69-0 ]

References: [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 3028 - 3038.

11
[ 40004-69-1 ]
[ 18718-83-7 ]
[ 1254969-89-5 ]

Yield	Reaction Conditions	Operation in experiment
61%		) 2- [2-(5-Methyl-3 -phenyl- isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acidTo a stirred solution of <strong>[40004-69-1]2-methyl-thiazole-5-carboxylic acid</strong> (100 mg, 0.7 mmol) in THF (5 mL) at -72°C and under argon was added LDA (0.7 mL of a 2M solution in THF, 1.40 mmol) dropwise. After 1.5 h a solution of 4-chloromethyl-5-methyl-3 -phenyl- isoxazo Ie (145 mg, 0.7 mmol) in THF (5 mL) was added dropwise. After 1 h the reaction mixture was quenched with HCl (IN, 10 mL) then warmed to room temperature and extracted with ethyl acetate. The combined extracts were dried, filtered and concentrated then triturated with diisopropyl ether to give the title compound (135 mg, 61percent) as a light brown solid which was used directly in the next reaction.

References: [1]Patent: WO2010/127974,2010,A1 .Location in patent: Page/Page column 44.

12
[ 40004-69-1 ]
[ 1239465-22-5 ]
C₁₄H₁₈N₂O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 1242-[(E)-2-(3-Butyl-5-methyl-isoxazol-4-yl)-vinyl]-thiazole-5-carboxylic acid isoprop- ylamidea) 2-[2-(3-Butyl-5-methyl-isoxazol-4-yl)-2-hydroxy-ethyl]-thiazole-5-carboxylic acid methyl esterTo a stirred solution of <strong>[40004-69-1]2-methyl-thiazole-5-carboxylic acid</strong> (215 mg, 1.50 mmol) in THF (10 mL) at -78°C and under argon was added n-butyllithium (1.88 mL of a 1.60M solution in hexane, 3.0 mmol) dropwise. After 1 h, a solution of 3 -butyl-5 -methyl- isoxazole-4-carbaldehyde (251 mg, 1.50 mmol) in THF (10 mL) was added dropwise. After 2 h the reaction mixture was quenched with 10percent aqueous citric acid (10 mL) then warmed to room temperature. The reaction mixture was extracted with ethyl acetate then the combined extracts were dried, filtered and concentrated. The resultant oil was redissolved in methanol (15 mL) and ether (7 mL) then (trimethylsilyl)diazomethane (2.25 mL of a 2M solution in ether, 4.5 mmol) was added dropwise. After 30 min, further (trimethylsilyl)diazomethane (2.25 mL of a 2M solution in ether, 4.5 mmol) was added. After 30 min, the reaction mixture was quenched with acetic acid (3 drops) then was concentrated and the residue redissolved in ethyl acetate and washed with NaOH (2 N). The organic phase was dried, filtered and concentrated then purified by chromatography (silica, 0 to 4percent methanol in dichloromethane) to give the title compound (49 mg, 10percent) as a brown oil. MS: m/e = 307.3 [M+H]+.

References: [1]Patent: WO2010/127974,2010,A1 .Location in patent: Page/Page column 116; 117.

13
[ 40004-69-1 ]
[ 1254962-92-9 ]
C₁₄H₁₈N₂O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 572-[2-(3-Butyl-5-methyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid isopropylamidea) 2-[2-(3-Butyl-5-methyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid methyl esterTo a stirred solution of <strong>[40004-69-1]2-methyl-thiazole-5-carboxylic acid</strong> (286 mg, 2.0 mmol) in THF (14 mL) at -72°C and under argon was added n-butyllithium (2.50 mL of a 1.6M solution in hexane, 4.0 mmol) dropwise. After 2 h, a solution of 3-butyl-4-chloromethyl-5-methyl-isoxazole (375 mg, 2.0 mmol) in THF (6 mL) was added dropwise. After 2.5 h the reaction mixture was quenched with 10 percent aqueous citric acid (10 mL) then warmed to room temperature. The reaction mixture was extracted with ethyl acetate then the combined extracts were dried, filtered and concentrated. The resultant oil was dissolved in methanol (15 mL) and ether (7 mL) then (trimethylsilyl)diazomethane (3 mL of a 2M solution in ether, 6.0 mmol) was added dropwise. After 30 min, further (trimethylsilyl)diazomethane (3 mL of a 2M solution in ether, 6.0 mmol) was added. After 15 h, the reaction mixture was quenched with acetic acid (3 drops) then was concentrated and purified by chromatography (silica, 0 to 75percent ethyl acetate in heptane) to give the title compound (360 mg, 58 percent) was a light brown oil. MS: m/e = 309.2 [M+H]+.

References: [1]Patent: WO2010/127974,2010,A1 .Location in patent: Page/Page column 76.

14
[ 40004-69-1 ]
[ 1254969-97-5 ]
[ 1254970-00-7 ]

Yield	Reaction Conditions	Operation in experiment
		Example 402-{2-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-thiazole-5-carboxylic acid (tetrahydro-pyran-4-yl)-amidea) 2- {2-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl} -thiazole-5-carboxylic acid methyl esterTo a stirred solution of <strong>[40004-69-1]2-methyl-thiazole-5-carboxylic acid</strong> (1.37 g, 9.58 mmol) in THF (80 mL) at -700C and under argon was added BuLi (1.6M in hexanes, 12 mL, 19.15 mmol) dropwise. After 2 h at -75°C a solution of 2-(4-chloromethyl-5-methyl-isoxazol-3-yl)-5-fluoro- pyridine (2.17 g, 9.58 mmol) in THF (30 mL) was added dropwise. After 4 h the reaction mixture was quenched with citric acid solution (5percent, 60 mL) then warmed to room temperature and extracted with ethyl acetate. The combined extracts were dried, filtered and concentrated to give the intermediate acid compound (4.12 g) as a yellow solid. To a solution of intermediate acid (4.12 g) in MeOH (72 mL) and diethylether (40 mL) was added trimethylsilyldiazo methane (2M in diethylether, 3 x 9.6 mL, 57.48 mmol) under ice cooling. Then the reaction mixture was quenched by addition of acetic acid (cone, 0.7 mL), evaporated and extracted with with ethyl acetate. The combined extracts were washed with NaOH (1 N, 100 mL), water, dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, heptane:ethyl acetate 1 :0 to 0:1) afforded the title compound (1.37 g, 41percent) as a yellow solid. MS: m/e = 348.1 [M+H]+.

References: [1]Patent: WO2010/127974,2010,A1 .Location in patent: Page/Page column 66.

15
[ 40004-69-1 ]
[ 1254966-73-8 ]
[ 1254970-08-5 ]

Yield	Reaction Conditions	Operation in experiment
66%		Example 772-{(E)-2-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5- carboxylic acid (tetrahydro-pyran-4-yl)-amidea) 2- {2-[3-(5-Fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-2-hydroxy-ethyl} -thiazole-5- carboxylic acidTo a stirred solution of <strong>[40004-69-1]2-methyl-thiazole-5-carboxylic acid</strong> (1.15 g, 8.05 mmol) in THF(67 mL) at -700C and under argon was added BuLi (1.6M in hexanes, 10.06 mL, 16.1 mmol) dropwise. After 2 h a solution of 3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazole-4-carbaldehyde(1.66 g, 8.05 mmol) in THF (24 mL) was added dropwise. After 3h the reaction mixture was quenched with citric acid solution (5percent, 50 mL) then warmed to room temperature and extracted with ethyl acetate. The combined extracts were washed with brine, water, dried over sodium sulfate, filtered and concentrated. Purification by trituration (ethyl acetate) afforded the title compound (1.85 g, 66percent) as a light yellow solid. MS: m/e = 348.2 [M-H]".

References: [1]Patent: WO2010/127974,2010,A1 .Location in patent: Page/Page column 89; 90.

16
[ 40004-69-1 ]
[ 1254969-90-8 ]
[ 1254969-96-4 ]

Yield	Reaction Conditions	Operation in experiment
		Example 212- [2-(5-Methyl-3-pyridin-2-yl-isoxazol-4-yl)-ethyl] -thiazole-5-carboxylic acid methyl esterTo a stirred solution of <strong>[40004-69-1]2-methyl-thiazole-5-carboxylic acid</strong> (1.03 g, 7.0 mmol) in THF (61 mL) at -700C and under argon was added BuLi (1.6M in hexanes, 8.99 mL, 14.0 mmol) dropwise. After 2 h a solution of 2-(4-chloromethyl-5 -methyl- isoxazo 1-3 -yl)-pyridine (1.5 g, 7.0 mmol) in THF (26 mL) was added dropwise. After 3h the reaction mixture was quenched with citric acid solution (5percent, 10 mL) then warmed to room temperature and extracted with ethyl acetate. The combined extracts were dried, filtered and concentrated to give the intermediate acid compound (2.43 g) as a light brown solid. To a solution of intermediate acid (2.43 g) in MeOH (54 mL) and diethylether (30 mL) was added trimethylsilyldiazomethane (2M in diethylether, 21.6 mL, 4.3 mmol) in two portions under ice cooling. Then the reaction mixture was quenched by addition of acetic acid (cone, 0.7 mL), evaporated and extracted with with ethyl acetate. The combined extracts were washed with NaOH (IN), water, dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, heptane:ethyl acetate 8:2 to 2:3) afforded the title compound (915 mg, 39percent) as an orange solid. MS: m/e = 330.0 [M+H]+.

References: [1]Patent: WO2010/127974,2010,A1 .Location in patent: Page/Page column 54.

17
[ 40004-69-1 ]
[ 1332459-54-7 ]

References: [1]Journal of Chemical Research,2011,vol. 35,p. 313 - 316.

18
[ 40004-69-1 ]
[ 1541172-37-5 ]
[ 1541172-41-1 ]

Yield	Reaction Conditions	Operation in experiment
22%	With pyridine; trichlorophosphate; In dichloromethane; at 0℃; for 3h;	CS)-Benzyl 3-methoxy-2-((S)-3-methoxy-2-(2-methyl-N-((5-methyl-2-oxo-l, 3- dioxol-4-yl)methyl)thiazole-5-carboxamido)propanamido)propanoate Referring to FIG. 38, phosphorous oxychloride (323 mu, 3.46 mmol) was added dropwise to (S)-benzyl 3-methoxy-2-((S)-3-methoxy-2-(((5-methyl-2-oxo-l,3-dioxol-4- yl)methyl)amino)propanamido)propanoate (1.46 g, 3.46 mmol), 2-methylthiazole-5- carboxylic acid (248 mg, 3.46 mmol) and pyridine (1.07 mL, 10 mmol) in DCM (20ml) at 0 °C. The reaction mixture was stirred at 0 °C for 3 hours, diluted with IN HCl, and extracted with DCM. The organic layer was separated, dried (Na2S04) and evaporated. The residue was purified by flash column chromatography to give the product as a white solid (346 mg, 22percent).

References: [1]Patent: WO2014/11695,2014,A2 .Location in patent: Page/Page column 169.

19
[ 40004-69-1 ]
C₃₅H₄₇N₅O₈S*ClH [ No CAS ]
C₄₀H₅₀N₆O₉S₂ [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 1770 - 1776.

20
[ 40004-69-1 ]
[ 1010136-49-8 ]

References: [1]Patent: US2014/113855,2014,A1 .
[2]Patent: US2018/78532,2018,A1 .
[3]Patent: US2018/161279,2018,A1 .

21
[ 40004-69-1 ]
[ 935888-69-0 ]

References: [1]Patent: US2014/113855,2014,A1 .
[2]Patent: US2018/78532,2018,A1 .
[3]Patent: US2018/161279,2018,A1 .

22
[ 40004-69-1 ]
(x)C₂HF₃O₂*C₁₅H₂₂N₂O₅ [ No CAS ]
[ 1148157-33-8 ]

Yield	Reaction Conditions	Operation in experiment
17.1 g	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0℃;pH 8.5;	To a 0°C. solution of Compound (D) (41 mmol) and<strong>[40004-69-1]2-methyl-thiazole-5-carboxylic acid</strong> (E) (6.0 g, 42 mmol), HOST (7.9 g, 50 mmol) and HH11J (18.0 g, 50 mmol) in tetrahydroffiran (800 mE) was added a solution of N,N-diethylisopropylamine (.?50 g) in tetrahydroffiran (200 mE) over 5 minutes until its pH reached approximately 8.5. The resulting mixture was stirred at same temperature overnight. It was then quenched with saturated aqueous sodium bicarbonate solution (200 mE), and most of the solvents were removed under reduced pressure. The residual mixture was extracted with ethyl acetate (3x400 ml). The combined organic layers were washed with saturated aqueous sodium bicarbonate (200 mE) and brine (100 ml), dried over sodium sulfate and filtered through Celite-545. The solvents were removed under reduced pressure and residue was purified by flash chromatography (silica gel, ethyl acetate with 2percent methanol). Compound (F) (17.1 g) was isolated and characterized by LC/MS (LRMS (MH)m/z: 436.15).
	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at -5℃; for 4h;	P) To a -5 °C mixture of TFA salt (17), 2-methylthiazole-5- carboxylic acid, HOBt, and HBTU in THF is added DIEA slowly. The reaction is kept at the same temperature for 4 h and then diluted with EtOAc and brine. The layers are separated, and the aqueous layer is extracted with EtOAc. The organic layers are combined and dried over Na2S04- The Na2S04 is removed by filtration, and the volatiles are removed under reduced pressure. The resulting residue is purified by flash chromatography using a mixture of hexane and ethyl acetate to provide benzyl ester (18) as white solid.

References: [1]Patent: US2014/113855,2014,A1 .Location in patent: Paragraph 0279; 0290; 0291.
[2]Patent: WO2017/211818,2017,A1 .Location in patent: Page/Page column 29; 32.

23
[ 40004-69-1 ]
[ 4316-98-7 ]
5-(6-chloro-9H-purin-8-yl)-2-methylthiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trichlorophosphate; at 160℃; for 0.5h;Microwave irradiation;	6-chloropyrimidine-4,5-diamine (200mgs, 1.3mmol) and <strong>[40004-69-1]2-methylthiazole-5-carboxylic acid</strong> (218 mgs, 1 .5 mmol) were dissolved in phosphoryl chloride (4 mL) in a 10 mL microwave vial. The reaction mixture was stirred at 160°C for 30 min in a microwave reactor. After cooling down to room temperature reaction mixture was diluted with diethyl-ether and solids filtered out. Solids were re-dissolved in dichloromethane and extracted with aqueous saturated solution of sodium bicarbonate. Organic layer was dried over Mg2SO4 and evaporated under reduced pressure. Solids were suspended in ACN and stirred over 1 hr. Solids were filtered out to yield 5-(6-chloro-9H-purin-8-yl)-2- methylthiazole.

References: [1]Patent: WO2015/187684,2015,A1 .Location in patent: Page/Page column 261-262.

24
[ 40004-69-1 ]
5-(8-(2-methylthiazol-5-yl)-9H-purin-6-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile [ No CAS ]

References: [1]Patent: WO2015/187684,2015,A1 .

25
[ 40004-69-1 ]
methyl L-threoninate hydrochloride [ No CAS ]
(2S,3R)-3-hydroxy-2-(2-methylthiazole-5-carboxamido)butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: The title compound was prepared as described in Intermediate 3, by substituting 2- methylthiazole-5-carboxylic acid for 5-methylisoxazole-3-carboxylic acid.

References: [1]Patent: WO2015/195950,A1 .Location in patent: Page/Page column 51.
Patent: ,2015, .Location in patent: Page/Page column 51.

26
[ 40004-69-1 ]
(S)-2-amino-N-{(S)-1-[(S)-1-benzyl-2-((R)-2-methyloxiranyl)-2-oxo-ethylcarbamoyl]-2-difluoromethoxy-ethyl}-3-difluoromethoxy-propionamide trifluoroacetate [ No CAS ]
2-methyl-1,3-thiazole-5-carboxylic acid ((S)-1-{(S)-1-[(s)-1-benzyl-2-((R)-2-methyloxiranyl)-2-oxo-ethylcarbamoyl]-2-difluoromethoxy-ethylcarbamoyl}-2-difluoromethoxy-ethyl)amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.6%	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 0 - 20℃;	To a solution of the compound of Formula XV(a), (S)-2-amino-N?{(S)-1-[(S)-1-benzyl-2-((R)-2-methyl-oxiranyl)-2-oxo-ethylcarbamoyl]-2-difluoromethoxy-ethyl}-3-difluoromethoxy-propionamide TFA salt (2.2 g, 3.70 mmol), <strong>[40004-69-1]2-methyl-thiazole-5-carboxylic acid</strong> (0.635 g, 4.44 mmol), HOBt (0.649 g, 4.81 mmol) and HBTU (1.82 g, 4.81 mmol) in THF (70 mL) was added DIPEA (1.29 mL, 7.4 mmol) dropwise at 0° C. The reaction mixture was allowed to warm up to room temperature and was stirred overnight. The mixture was then quenched with ice water, washed with NaHCO3 and brine and extracted with 2×100 mL of ethyl acetate. The organic layer was dried over magnesium sulphate and concentrated. The crude product was purified by column chromatography, eluting with 70percent to 80percent ethyl acetate in hexanes, to give the compound of Formula I of Example 1. (2.11 g, 94.6percent) as a pale-yellowish solid. 1H NMR (300 MHz, CDCl3): delta (ppm) 8.10 (s, 1H), 7.28-7.25 (m, 3H), 7.20 (dd, 2H), 6.82 (d, 1H), 6.79 (d, 1H), 6.65 (d, 1H), 6.18 (wt, 1H), 6.14 (wt, 1H), 4.90-4.65 (m, 2H), 4.60 (td, 1H), 4.35 (dd, 1H), 4.25 (dd, 1H), 4.05 (td, 1H), 3.95 (dd, 1H), 3.30 (d, 1H), 3.28 (dd, 1H), 3.16 (d, 1H), 2.90 (dd, 1H), 2.85 (dd, 1H), 2.75 (s, 3H), 1.41 (s, 3H).

References: [1]Patent: US9441012,2016,B2 .Location in patent: Page/Page column 63-65.

27
[ 40004-69-1 ]
(2S)-2-amino-1-[4-[2-(4-amino-6-chloro-2-methylpyrimidin-5-yl)ethyl]-1-piperidyl]propan-1-one [ No CAS ]
N-[(1S)-2-[4-[2-(4-amino-6-chloro-2-methylpyrimidin-5-yl)ethyl]-1-piperidyl]-1-methyl-2-oxoethyl]-2-methylthiazole-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 20℃; for 12h;	Dissolve (2S)-2-ammo-l~[4~[2-(4-ammo-6-ehloro-2-methyl-pyrimidin-5- yl)ethyl]-l-piperidyl]propan-l-one (600 mg, 1.84 mmol) and 2-methylthiazole-5- carboxylic acid (290 mg, 2,03 mmol) in THF (12.3 mL). Add 1 -hydroxy-?- azabenzotriazole (281 mg, 2.03 mmol), l -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (430 mg, 2.21 mmol) and TEA (0.77 mL, 5,52 mmol). Stir the mixture at room temperature for 12 hours. Dilute the mixture with EtOAc, filter through a SPE cartridge (ISOLUTE® HM-N) washing with EtOAc and remove the solvent under reduced pressiffe. Purify the crude mixture by mass-guided SFC (Waters ZQ MS; 4- nitrobenzene-sulfon amide column, eluting with 0,14 mM ammonia in MeOH/C02) to obtain the title compound as a yellow tar (626 mg, 75percent). LC-ES/MS m/z. (35C1/37C1) 451/453 (M-f-H).

References: [1]Patent: WO2016/168225,2016,A1 .Location in patent: Page/Page column 49-50.

28
[ 40004-69-1 ]
(2S)-2-amino-1-[4-[2-(4-amino-6-chloro-2-methylpyrimidin-5-yl)ethyl]-1-piperidyl]propan-1-one dihydrochloride salt [ No CAS ]
N-[(1S)-2-[4-[2-(4-amino-6-chloro-2-methylpyrimidin-5-yl)ethyl]-1-piperidyl]-1-methyl-2-oxoethyl]-2-methylthiazole-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12.8 g	With propylphosphonic anhydride; N-ethyl-N,N-diisopropylamine; In dichloromethane; ethyl acetate; at 5 - 20℃;	Dissolve (25)-2-amino- 1 -[4-[2-(4-amino-6-chloro-2-methyl-pyrimidin-5- yl)ethyl]-l -piperidyl]propan-l-one dihydrochloride (21.0 g, 52.66 mmol), 2-methyl-5- thiazolecarboxylic acid (11.31 g, 78,99 mmol) and DIPEA (36.7 mL, 210.65 mmol) in DCM (210 mL). Stir until complete dissolution and then cool in an ice bath (internal temperature 5 °C). Add dropwise a solution of 1 -propanephosphonic anhydride (50percent solution in EtOAc, 50.27 g, 78.99 mmol) over 5 min to maintain the internal temperature between 5-10 °C. Stir in ice bath for 1 hour, allow to warm to room temperature and stir overnight. Dilute with DCM (200 mL) and wash with saturated aqueous sodium bicarbonate (300 mL). Extract the aqueous layer with DCM (3 * 100 mL) and wash the combined organic layers with saturated ammonium chloride (300 mL), water (300 mL) and brine (500 mL). Dry over MgS04, filter and remove solvent in vacuum. Purify the crude mixture by chromatography (330 g silica gel column) eluting with 15-60percent THF in EtOAc to give the title compound as a pale yellow solid (12.8 g, 54percent). LC-ES/MS m/z' (35C1/37C3) 451/453 (M+H).

References: [1]Patent: WO2016/168225,2016,A1 .Location in patent: Page/Page column 53-54.

29
[ 40004-69-1 ]
tert-butyl 2-(bromomethyl)thiazole-5-carboxylate [ No CAS ]